new research topics in pharmacology

New antibiotic class effective against multidrug-resistant bacteria

Scientists at Uppsala University have discovered a new class of antibiotics with potent activity against multi-drug resistant bacteria, and have shown that it cures bloodstream infections in mice. The new antibiotic class is described in an article in the scientific journal PNAS .

Antibiotics are the foundation of modern medicine and over the last century have dramatically improved the lives of people around the world. Nowadays we tend to take antibiotics for granted and rely heavily on them to treat or prevent bacterial infections, including for example, to reduce the risk of infections during cancer therapy, during invasive surgery and transplants, and in mothers and preterm babies. Increasingly though, the global rise in antibiotic resistance threatens their effectiveness. In order to ensure access to effective antibiotics in the future, development of novel therapeutics to which there is no existing resistance is essential.

Researchers at Uppsala University have recently published their work in the Proceedings of the National Academy of Sciences of the USA describing a new class of antibiotics developed as a part of multi-national consortia. The class of compounds they describe target a protein, LpxH, which is used in a pathway by Gram-negative bacteria to synthesize their outermost layer of protection from the environment, called lipopolysaccharide. Not all bacteria produce this layer, but those that do include the organisms that have been identified by the World Health Organization as being the most critical to develop novel treatments for, including Escherichia coli and Klebsiella pneumoniae that have already developed resistance to available antibiotics. The researchers were able to show that this new antibiotic class is highly active against multidrug-resistant bacteria and was able to treat bloodstream infections in a mouse model, demonstrating the promise of this class. Importantly, since this compound class is completely new and the protein LpxH has not yet been exploited as a target for antibiotics there is no pre-existing resistance to this class of compounds. This is in contrast to the many 'me-too' antibiotics of existing classes currently in clinical development. While the current results are very promising there will be considerable additional work required before compounds of this class will be ready for clinical trials.

The work to discover and develop this new class of antibiotics was supported by the EU project ENABLE which was funded through the Innovative Medicines Initiative's New Drugs 4 Bad Bugs program (ND4BB). The ENABLE project, led by researchers at Uppsala University and the pharmaceutical company GlaxoSmithKline, brought together stakeholders from across Europe representing academia and large and small pharmaceutical companies to pool resources and expertise to advance early-stage antibiotic development. This antibiotic class now continues to be developed in the follow-on project, ENABLE-2, an antibiotic drug discovery platform funded by Swedish Research Council, the National Research Programme on Antibiotic Resistance and Sweden's innovation agency Vinnova to continue the momentum generated by the original ENABLE project.

• Pharmaceuticals
• Infectious Diseases
• Pharmacology
• Wounds and Healing
• Microbes and More
• Biotechnology
• Antibiotic resistance
• Penicillin-like antibiotics
• Antiviral drug
• Drug discovery
• Rocky Mountain spotted fever
• Breastfeeding
• Pharmaceutical company

Story Source:

Materials provided by Uppsala University . Note: Content may be edited for style and length.

Journal Reference :

• Douglas L. Huseby, Sha Cao, Edouard Zamaratski, Sanjeewani Sooriyaarachchi, Shabbir Ahmad, Terese Bergfors, Laura Krasnova, Juris Pelss, Martins Ikaunieks, Einars Loza, Martins Katkevics, Olga Bobileva, Helena Cirule, Baiba Gukalova, Solveiga Grinberga, Maria Backlund, Ivailo Simoff, Anna T. Leber, Talía Berruga-Fernández, Dmitry Antonov, Vivekananda R. Konda, Stefan Lindström, Gustav Olanders, Peter Brandt, Pawel Baranczewski, Carina Vingsbo Lundberg, Edgars Liepinsh, Edgars Suna, T. Alwyn Jones, Sherry L. Mowbray, Diarmaid Hughes, Anders Karlén. Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria . Proceedings of the National Academy of Sciences , 2024; 121 (15) DOI: 10.1073/pnas.2317274121

Cite This Page :

Explore More

• Drug Development Made Easier
• RNA That Doesn't Age
• 'Rainbow' Detected On an Exoplanet
• Spears and Throwing Sticks 300,000 Years Old
• High Carbon Impact of Tourism at Yellowstone
• Extreme Starburst Galaxy
• Asthma: Disease May Be Stoppable
• Stellar Collisions and Zombie-Like Survivors
• Tiny Robot Swarms Inspired by Herd Mentality
• How the Brain Regulates Emotions

Trending Topics

Strange & offbeat.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Pharmacological Reviews

New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship contributions.

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

• Ackeifi C, Swartz E, Kumar K, Liu H, Chalada S, Karakose E, Scott DK, Garcia-Ocaña A, Sanchez R, DeVita RJ, et al. (2020) Pharmacologic and genetic approaches define human pancreatic β cell mitogenic targets of DYRK1A inhibitors . JCI Insight 5 :e132594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Adachi T, Yasuda K, Okamoto Y, Shihara N, Oku A, Ueta K, Kitamura K, Saito A, Iwakura I, Yamada Y, et al. (2000) T-1095, a renal Na+-glucose transporter inhibitor, improves hyperglycemia in streptozotocin-induced diabetic rats . Metabolism 49 :990–995. [ PubMed ] [ Google Scholar ]
• Alexiadou K, Tan TM (2020) Gastrointestinal peptides as therapeutic targets to mitigate obesity and metabolic syndrome . Curr Diab Rep 20 :26. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, Robertson D, Jain M, Petrone M, et al. (2018) MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study . Lancet 391 :2607–2618. [ PubMed ] [ Google Scholar ]
• Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell . Prog Biophys Mol Biol 54 :87–143. [ PubMed ] [ Google Scholar ]
• Ashcroft FM, Rorsman P (1990) ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion . Biochem Soc Trans 18 :109–111. [ PubMed ] [ Google Scholar ]
• Baeyens L, Hindi S, Sorenson RL, German MS (2016) β-Cell adaptation in pregnancy . Diabetes Obes Metab 18 ( Suppl 1 ):63–70. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bailey CJ (1992) Biguanides and NIDDM . Diabetes Care 15 :755–772. [ PubMed ] [ Google Scholar ]
• Ben Nasr M, Tezza S, D’Addio F, Mameli C, Usuelli V, Maestroni A, Corradi D, Belletti S, Albarello L, Becchi G, et al. (2017) PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes . Sci Transl Med 9 :eaam7543. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bergmann NC, Lund A, Gasbjerg LS, Meessen ECE, Andersen MM, Bergmann S, Hartmann B, Holst JJ, Jessen L, Christensen MB, et al. (2019) Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study . Diabetologia 62 :665–675. [ PubMed ] [ Google Scholar ]
• Bernal-Mizrachi E, Kulkarni RN, Scott DK, Mauvais-Jarvis F, Stewart AF, Garcia-Ocaña A (2014) Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map . Diabetes 63 :819–831. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, et al.; EXSCEL Study Group (2018) Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis . Lancet Diabetes Endocrinol 6 :105–113. [ PubMed ] [ Google Scholar ]
• Bliss M (1982) Banting’s, Best’s, and Collip’s accounts of the discovery of insulin . Bull Hist Med 56 :554–568. [ PubMed ] [ Google Scholar ]
• Bochenek MA, Veiseh O, Vegas AJ, McGarrigle JJ, Qi M, Marchese E, Omami M, Doloff JC, Mendoza-Elias J, Nourmohammadzadeh M, et al. (2018) Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques . Nat Biomed Eng 2 :810–821. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, et al. (2015) Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion . Nat Med 21 :512–517. [ PubMed ] [ Google Scholar ]
• Bonora E, Cigolini M, Bosello O, Zancanaro C, Capretti L, Zavaroni I, Coscelli C, Butturini U (1984) Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects . Curr Med Res Opin 9 :47–51. [ PubMed ] [ Google Scholar ]
• Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis . N Engl J Med 313 :353–360. [ PubMed ] [ Google Scholar ]
• Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF (2010) Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence . Popul Health Metr 8 :29. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, et al. (2007) Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment . Nat Med 13 :340–347. [ PubMed ] [ Google Scholar ]
• Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M (2016) The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies . Diabetes Care 39 :198–205. [ PubMed ] [ Google Scholar ]
• Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes . Diabetes Care 27 :2628–2635. [ PubMed ] [ Google Scholar ]
• Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, Jaffe JL, Coch RW, Haldeman JM, MacDonald PE, et al. (2019a) β Cell tone is defined by proglucagon peptides through cAMP signaling . JCI Insight 4 :e126742. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Capozzi ME, Wait JB, Koech J, Gordon AN, Coch RW, Svendsen B, Finan B, D’Alessio DA, Campbell JE (2019b) Glucagon lowers glycemia when β-cells are active . JCI Insight 5 :e129954. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Carboneau BA, Allan JA, Townsend SE, Kimple ME, Breyer RM, Gannon M (2017) Opposing effects of prostaglandin E 2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation . Mol Metab 6 :548–559. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chae H, Augustin R, Gatineau E, Mayoux E, Bensellam M, Antoine N, Khattab F, Lai BK, Brusa D, Stierstorfer B, et al. (2020) SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans . Mol Metab 42 :101071. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chamberlain CE, Scheel DW, McGlynn K, Kim H, Miyatsuka T, Wang J, Nguyen V, Zhao S, Mavropoulos A, Abraham AG, et al. (2014) Menin determines K-RAS proliferative outputs in endocrine cells . J Clin Invest 124 :4093–4101. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK (2011) PDGF signalling controls age-dependent proliferation in pancreatic β-cells . Nature 478 :349–355. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen H, Kleinberger JW, Takane KK, Salim F, Fiaschi-Taesch N, Pappas K, Parsons R, Jiang J, Zhang Y, Liu H, et al. (2015) Augmented Stat5 signaling bypasses multiple impediments to lactogen-mediated proliferation in human β-cells . Diabetes 64 :3784–3797. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Cha-Molstad H, Szabo A, Shalev A (2009) Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein . Am J Physiol Endocrinol Metab 296 :E1133–E1139. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Hui ST, Couto FM, Mungrue IN, Davis DB, Attie AD, Lusis AJ, Davis RA, Shalev A (2008a) Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes . FASEB J 22 :3581–3594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A (2008b) Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis . Diabetes 57 :938–944. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chou DH, Webber MJ, Tang BC, Lin AB, Thapa LS, Deng D, Truong JV, Cortinas AB, Langer R, Anderson DG (2015) Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates . Proc Natl Acad Sci USA 112 :2401–2406. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P (2017) Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells . Mol Metab 6 :1024–1039. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans . J Clin Endocrinol Metab 88 :4696–4701. [ PubMed ] [ Google Scholar ]
• Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, et al. (2020) GDF15 mediates the effects of metformin on body weight and energy balance . Nature 578 :444–448. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Colli ML, Hill JLE, Marroquí L, Chaffey J, Dos Santos RS, Leete P, Coomans de Brachène A, Paula FMM, Op de Beeck A, Castela A, et al. (2018) PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction . EBioMedicine 36 :367–375. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• RISE Consortium (2019) Lack of durable improvements in β-cell function following withdrawal of pharmacological interventions in adults with impaired glucose tolerance or recently diagnosed type 2 diabetes . Diabetes Care 42 :1742–1751. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, et al. (2017) Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling . J Clin Invest 127 :3835–3844. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets . J Clin Invest 126 :1857–1870. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dai C, Walker JT, Shostak A, Bouchi Y, Poffenberger G, Hart NJ, Jacobson DA, Calcutt MW, Bottino R, Greiner DL, et al. (2020) Dapagliflozin does not directly affect human α or β cells . Endocrinology 161 :bqaa080. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, Bloom SR (2001) Oxyntomodulin inhibits food intake in the rat . Endocrinology 142 :4244–4250. [ PubMed ] [ Google Scholar ]
• Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR (2002) Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats . Am J Physiol Endocrinol Metab 283 :E1173–E1177. [ PubMed ] [ Google Scholar ]
• Defronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Gastaldelli A, Henry RR, Kitabchi AE, et al.; ACT NOW Study (2013) Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates . Diabetes 62 :3920–3926. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Delaunay F, Khan A, Cintra A, Davani B, Ling ZC, Andersson A, Ostenson CG, Gustafsson J, Efendic S, Okret S (1997) Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids . J Clin Invest 100 :2094–2098. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Desai T, Shea LD (2017) Advances in islet encapsulation technologies . Nat Rev Drug Discov 16 :338–350. [ PubMed ] [ Google Scholar ]
• Devaraj S, Venkatachalam A, Chen X (2016) Metformin and the gut microbiome in diabetes . Clin Chem 62 :1554–1555. [ PubMed ] [ Google Scholar ]
• Doloff JC, Veiseh O, Vegas AJ, Tam HH, Farah S, Ma M, Li J, Bader A, Chiu A, Sadraei A, et al. (2017) Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates . Nat Mater 16 :671–680. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Donath MY, Dinarello CA, Mandrup-Poulsen T (2019) Targeting innate immune mediators in type 1 and type 2 diabetes . Nat Rev Immunol 19 :734–746. [ PubMed ] [ Google Scholar ]
• Drucker DJ (2018) Mechanisms of action and therapeutic application of glucagon-like peptide-1 . Cell Metab 27 :740–756. [ PubMed ] [ Google Scholar ]
• Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line . Proc Natl Acad Sci USA 84 :3434–3438. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, Lam TK (2015) Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats . Nat Med 21 :506–511. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Eguchi K, Nagai R (2017) Islet inflammation in type 2 diabetes and physiology . J Clin Invest 127 :14–23. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El Khatib MM, Sakuma T, Tonne JM, Mohamed MS, Holditch SJ, Lu B, Kudva YC, Ikeda Y (2015) β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection . Gene Ther 22 :430–438. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, Mondesir D, Esmaeili A, Hartigan C, Thompson MJ, et al. (2017) Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial . Lancet 389 :369–380. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S, Fontaine E, Almeida A, Leverve X (2008) Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons . J Mol Neurosci 34 :77–87. [ PubMed ] [ Google Scholar ]
• El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I . J Biol Chem 275 :223–228. [ PubMed ] [ Google Scholar ]
• Elrick H, Stimmler L, Hlad CJ Jr, Arai Y (1964) Plasma Insulin Response to Oral and Intravenous Glucose Administration . J Clin Endocrinol Metab 24 :1076–1082. [ PubMed ] [ Google Scholar ]
• Engin F, Yermalovich A, Nguyen T, Hummasti S, Fu W, Eizirik DL, Mathis D, Hotamisligil GS (2013) Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes [published correction appears in Sci Transl Med (2013) 5 :214er11] . Sci Transl Med 5 :211ra156. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients . BMJ 330 :1304–1305. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Evans-Molina C, Robbins RD, Kono T, Tersey SA, Vestermark GL, Nunemaker CS, Garmey JC, Deering TG, Keller SR, Maier B, et al. (2009) Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure . Mol Cell Biol 29 :2053–2067. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Fernández-Real JM, López-Bermejo A, Ropero AB, Piquer S, Nadal A, Bassols J, Casamitjana R, Gomis R, Arnaiz E, Pérez I, et al. (2008) Salicylates increase insulin secretion in healthy obese subjects . J Clin Endocrinol Metab 93 :2523–2530. [ PubMed ] [ Google Scholar ]
• Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B (2014) Metformin: from mechanisms of action to therapies . Cell Metab 20 :953–966. [ PubMed ] [ Google Scholar ]
• Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus . Nat Rev Endocrinol 15 :569–589. [ PubMed ] [ Google Scholar ]
• Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state . J Clin Invest 120 :2355–2369. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Frias JPBastyr EJ 3rd, Vignati L, Tschöp MH, Schmitt C, Owen K, Christensen RHDiMarchi RD (2017) The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes . Cell Metab 26 :343–352.e2. [ PubMed ] [ Google Scholar ]
• Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA (2020) Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens . Diabetes Obes Metab 22 :938–946. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, et al. (2018) Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial . Lancet 392 :2180–2193. [ PubMed ] [ Google Scholar ]
• Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O’Neill HM, Ford RJ, Palanivel R, O’Brien M, et al. (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin . Nat Med 19 :1649–1654. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, et al.; REWIND Investigators (2019) Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial . Lancet 394 :121–130. [ PubMed ] [ Google Scholar ]
• Giugliano D, Ceriello A, Saccomanno F, Quatraro A, Paolisso G, D’Onofrio F (1985) Effects of salicylate, tolbutamide, and prostaglandin E2 on insulin responses to glucose in noninsulin-dependent diabetes mellitus . J Clin Endocrinol Metab 61 :160–166. [ PubMed ] [ Google Scholar ]
• Goudy KS, Tisch R (2005) Immunotherapy for the prevention and treatment of type 1 diabetes . Int Rev Immunol 24 :307–326. [ PubMed ] [ Google Scholar ]
• Gregg BE, Moore PC, Demozay D, Hall BA, Li M, Husain A, Wright AJ, Atkinson MA, Rhodes CJ (2012) Formation of a human β-cell population within pancreatic islets is set early in life . J Clin Endocrinol Metab 97 :3197–3206. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P (2012) Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors . Diabetes Obes Metab 14 :83–90. [ PubMed ] [ Google Scholar ]
• Harlan DM (2016) Islet transplantation for hypoglycemia unawareness/severe hypoglycemia: caveat emptor . Diabetes Care 39 :1072–1074. [ PubMed ] [ Google Scholar ]
• Harrower AD (1991) Efficacy of gliclazide in comparison with other sulphonylureas in the treatment of NIDDM . Diabetes Res Clin Pract 14 ( Suppl 2 ):S65–S67. [ PubMed ] [ Google Scholar ]
• He L, Wondisford FE (2015) Metformin action: concentrations matter . Cell Metab 21 :159–162. [ PubMed ] [ Google Scholar ]
• Hedrington MS, Davis SN (2019) Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes . Expert Opin Pharmacother 20 :2229–2235. [ PubMed ] [ Google Scholar ]
• Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, et al.; Clinical Islet Transplantation Consortium (2016) Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia . Diabetes Care 39 :1230–1240. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, Matsumoto I, Ihm SH, Zhang HJ, Parkey J, et al. (2005) Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes . JAMA 293 :830–835. [ PubMed ] [ Google Scholar ]
• Hernandez AFGreen JBJanmohamed SD’Agostino RB Sr , Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MCet al.; Harmony Outcomes committees and investigators (2018) Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial . Lancet 392 :1519–1529. [ PubMed ] [ Google Scholar ]
• Hiatt WR, Kaul S, Smith RJ (2013) The cardiovascular safety of diabetes drugs--insights from the rosiglitazone experience . N Engl J Med 369 :1285–1287. [ PubMed ] [ Google Scholar ]
• Hirshberg B, Preston EH, Xu H, Tal MG, Neeman Z, Bunnell D, Soleimanpour S, Hale DA, Kirk AD, Harlan DM (2003) Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model . Transplantation 76 :55–60. [ PubMed ] [ Google Scholar ]
• Hu W, Jiang C, Guan D, Dierickx P, Zhang R, Moscati A, Nadkarni GN, Steger DJ, Loos RJF, Hu C, et al. (2019) Patient adipose stem cell-derived adipocytes reveal genetic variation that predicts antidiabetic drug response . Cell Stem Cell 24 :299–308.e6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, et al.; PIONEER 6 Investigators (2019) Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes . N Engl J Med 381 :841–851. [ PubMed ] [ Google Scholar ]
• Imamura M, Nakanishi K, Suzuki T, Ikegai K, Shiraki R, Ogiyama T, Murakami T, Kurosaki E, Noda A, Kobayashi Y, et al. (2012) Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus . Bioorg Med Chem 20 :3263–3279. [ PubMed ] [ Google Scholar ]
• Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, et al.; ADOPT Study Group (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy . N Engl J Med 355 :2427–2443. [ PubMed ] [ Google Scholar ]
• Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, Kravitz BG, Herman WH, Viberti G, Holman RR; ADOPT Study Group (2011) Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT . Diabetes 60 :1552–1560. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, et al. (2010) Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women . Diabetes 59 :1899–1905. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kemp CB, Knight MJ, Scharp DW, Lacy PE, Ballinger WF (1973) Transplantation of isolated pancreatic islets into the portal vein of diabetic rats . Nature 244 :447. [ PubMed ] [ Google Scholar ]
• Kim HI, Cha JY, Kim SY, Kim JW, Roh KJ, Seong JK, Lee NT, Choi KY, Kim KS, Ahn YH (2002) Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells . Diabetes 51 :676–685. [ PubMed ] [ Google Scholar ]
• Kim HI, Kim JW, Kim SH, Cha JY, Kim KS, Ahn YH (2000) Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter . Diabetes 49 :1517–1524. [ PubMed ] [ Google Scholar ]
• Kim SH, Liu A, Ariel D, Abbasi F, Lamendola C, Grove K, Tomasso V, Ochoa H, Reaven G (2014) Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study . Diabetes Care 37 :1944–1950. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Koffert JP, Mikkola K, Virtanen KA, Andersson AD, Faxius L, Hällsten K, Heglind M, Guiducci L, Pham T, Silvola JMU, et al. (2017) Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial . Diabetes Res Clin Pract 131 :208–216. [ PubMed ] [ Google Scholar ]
• Koh A, Mannerås-Holm L, Yunn NO, Nilsson PM, Ryu SH, Molinaro A, Perkins R, Smith JG, Bäckhed F (2020) Microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory AMPK phosphorylation . Cell Metab 32 :643–653.e4. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 7-36: a physiological incretin in man . Lancet 2 :1300–1304. [ PubMed ] [ Google Scholar ]
• Kuhre RE, Ghiasi SM, Adriaenssens AE, Wewer Albrechtsen NJ, Andersen DB, Aivazidis A, Chen L, Mandrup-Poulsen T, Ørskov C, Gribble FM, et al. (2019) No direct effect of SGLT2 activity on glucagon secretion . Diabetologia 62 :1011–1023. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF (2012) Human β-cell proliferation and intracellular signaling: driving in the dark without a road map . Diabetes 61 :2205–2213. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kurosaki E, Ogasawara H (2013) Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data . Pharmacol Ther 139 :51–59. [ PubMed ] [ Google Scholar ]
• Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use . Diabetes 49 :999–1005. [ PubMed ] [ Google Scholar ]
• Lambeir AM, Scharpé S, De Meester I (2008) DPP4 inhibitors for diabetes--what next? Biochem Pharmacol 76 :1637–1643. [ PubMed ] [ Google Scholar ]
• Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes . Diabetologia 50 :752–763. [ PubMed ] [ Google Scholar ]
• Lebovitz HE (2019) Thiazolidinediones: the forgotten diabetes medications . Curr Diab Rep 19 :151. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, Ehrlich SF, Mamtani R, Bilker W, Vaughn DJ, et al. (2015) Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes . JAMA 314 :265–277. [ PubMed ] [ Google Scholar ]
• Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, Zhang L, Shen J, Bala MM, Sohani ZN, et al. (2016) Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies . BMJ 352 :i610. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Link JT (2003) Pharmacological regulation of hepatic glucose production . Curr Opin Investig Drugs 4 :421–429. [ PubMed ] [ Google Scholar ]
• Luippold G, Klein T, Mark M, Grempler R (2012) Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes mellitus . Diabetes Obes Metab 14 :601–607. [ PubMed ] [ Google Scholar ]
• Maganti AV, Tersey SA, Syed F, Nelson JB, Colvin SC, Maier B, Mirmira RG (2016) Peroxisome proliferator-activated receptor-γ activation augments the β-cell unfolded protein response and rescues early glycemic deterioration and β cell death in non-obese diabetic mice . J Biol Chem 291 :22524–22533. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Makrilakis K (2019) The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expect . Int J Environ Res Public Health 16 :2720. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M (2007) The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients . Diabetologia 50 :2486–2494. [ PubMed ] [ Google Scholar ]
• Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, Morgan NG, Eizirik DL (2012) Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes . Diabetologia 55 :2417–2420. [ PubMed ] [ Google Scholar ]
• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al.; SUSTAIN-6 Investigators (2016a) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes . N Engl J Med 375 :1834–1844. [ PubMed ] [ Google Scholar ]
• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al.; LEADER Steering Committee; LEADER Trial Investigators (2016b) Liraglutide and cardiovascular outcomes in type 2 diabetes . N Engl J Med 375 :311–322. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Massollo M, Marini C, Brignone M, Emionite L, Salani B, Riondato M, Capitanio S, Fiz F, Democrito A, Amaro A, et al. (2013) Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice . J Nucl Med 54 :259–266. [ PubMed ] [ Google Scholar ]
• McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract . Diabetologia 59 :426–435. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• McIntyre N, Holdsworth CD, Turner DS (1964) New interpretation of oral glucose tolerance . Lancet 2 :20–21. [ PubMed ] [ Google Scholar ]
• McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al.; DAPA-HF Trial Committees and Investigators (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction . N Engl J Med 381 :1995–2008. [ PubMed ] [ Google Scholar ]
• Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans . Diabetes 57 :1584–1594. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, et al. (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes . J Med Chem 51 :1145–1149. [ PubMed ] [ Google Scholar ]
• Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Záková L, Kletvíková E, Jiráček J, et al. (2013) How insulin engages its primary binding site on the insulin receptor . Nature 493 :241–245. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP . Nature 494 :256–260. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Minkowski O (1892) Weitere Mitteilungen über den Diabetes mellitus nach Extirpation des Pankreas . Berliner Klinische Wochenschrift 29 :90–93. [ Google Scholar ]
• Misbin RI (2004) The phantom of lactic acidosis due to metformin in patients with diabetes . Diabetes Care 27 :1791–1793. [ PubMed ] [ Google Scholar ]
• Mudaliar S, Armstrong DA, Mavian AA, O’Connor-Semmes R, Mydlow PK, Ye J, Hussey EK, Nunez DJ, Henry RR, Dobbins RL (2012) Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2, improves serum glucose profiles in type 1 diabetes . Diabetes Care 35 :2198–2200. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL (2011) Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell . Endocrinology 152 :4610–4619. [ PubMed ] [ Google Scholar ]
• Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, et al. (2019) Glucagon-like peptide 1 (GLP-1) . Mol Metab 30 :72–130. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Munir KM, Lamos EM (2017) Diabetes type 2 management: what are the differences between DPP-4 inhibitors and how do you choose? Expert Opin Pharmacother 18 :839–841. [ PubMed ] [ Google Scholar ]
• Naftanel MA, Harlan DM (2004) Pancreatic islet transplantation . PLoS Med 1 :e58. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Nauck M, Stöckmann F, Ebert R, Creutzfeldt W (1986a) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes . Diabetologia 29 :46–52. [ PubMed ] [ Google Scholar ]
• Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W (1986b) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses . J Clin Endocrinol Metab 63 :492–498. [ PubMed ] [ Google Scholar ]
• Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, et al.; Wellcome Trust Case Control Consortium (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A . Nature 450 :887–892. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism . Nature 440 :470–476. [ PubMed ] [ Google Scholar ]
• Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, et al. (2010) Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus . J Med Chem 53 :6355–6360. [ PubMed ] [ Google Scholar ]
• Ohnishi ST, Endo M, editors. (1981) The Mechanism of Gated Calcium Transport Across Biological Membranes , Academic Press, New York. [ Google Scholar ]
• Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA (2020) Excitotoxicity and overnutrition additively impair metabolic function and identity of pancreatic β-cells . Diabetes 69 :1476–1491. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Osum KC, Burrack AL, Martinov T, Sahli NL, Mitchell JS, Tucker CG, Pauken KE, Papas K, Appakalai B, Spanier JA, et al. (2018) Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes . Sci Rep 8 :8295. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain . Biochem J 348 :607–614. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ozanne SE, Guest PC, Hutton JC, Hales CN (1995) Intracellular localization and molecular heterogeneity of the sulphonylurea receptor in insulin-secreting cells . Diabetologia 38 :277–282. [ PubMed ] [ Google Scholar ]
• Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes . Science 313 :1137–1140. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Paty BW, Harmon JS, Marsh CL, Robertson RP (2002) Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets . Transplantation 73 :353–357. [ PubMed ] [ Google Scholar ]
• Penesova A, Koska J, Ortega E, Bunt JC, Bogardus C, de Courten B (2015) Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes . Diabetes Obes Metab 17 :608–612. [ PubMed ] [ Google Scholar ]
• Perdigoto AL, Quandt Z, Anderson M, Herold KC (2019) Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome . Lancet Diabetes Endocrinol 7 :421–423. [ PubMed ] [ Google Scholar ]
• Perley MJ, Kipnis DM (1967) Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects . J Clin Invest 46 :1954–1962. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Pernicova I, Korbonits M (2014) Metformin--mode of action and clinical implications for diabetes and cancer . Nat Rev Endocrinol 10 :143–156. [ PubMed ] [ Google Scholar ]
• Preiss D, Dawed A, Welsh P, Heggie A, Jones AG, Dekker J, Koivula R, Hansen TH, Stewart C, Holman RR, et al.; DIRECT consortium group (2017) Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes . Diabetes Obes Metab 19 :356–363. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes . J Clin Invest 116 :1802–1812. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Pueyo ME, Darquy S, Capron F, Reach G (1993) In vitro activation of human macrophages by alginate-polylysine microcapsules . J Biomater Sci Polym Ed 5 :197–203. [ PubMed ] [ Google Scholar ]
• Pybus F (1924) Notes on suprarenal and pancreatic grafting . Lancet 204 :550–551. [ Google Scholar ]
• Quattrin T, Haller MJ, Steck AK, Felner EI, Li Y, Xia Y, Leu JH, Zoka R, Hedrick JA, Rigby MR, et al.; T1GER Study Investigators (2020) Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes . N Engl J Med 383 :2007–2017. [ PubMed ] [ Google Scholar ]
• Rachdi L, Kariyawasam D, Aïello V, Herault Y, Janel N, Delabar JM, Polak M, Scharfmann R (2014a) Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance . Cell Cycle 13 :2221–2229. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rachdi L, Kariyawasam D, Guez F, Aïello V, Arbonés ML, Janel N, Delabar JM, Polak M, Scharfmann R (2014b) Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass . Diabetologia 57 :960–969. [ PubMed ] [ Google Scholar ]
• Rege NK, Phillips NFB, Weiss MA (2017) Development of glucose-responsive ‘smart’ insulin systems . Curr Opin Endocrinol Diabetes Obes 24 :267–278. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin . Diabetologia 60 :1577–1585. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rewers M, Gottlieb P (2009) Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future . Diabetes Care 32 :1769–1782. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, Zeissler M, Leete P, Krogvold L, Dahl-Jørgensen K, et al. (2016) Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes . Diabetologia 59 :2448–2458. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rickels MR, Liu C, Shlansky-Goldberg RD, Soleimanpour SA, Vivek K, Kamoun M, Min Z, Markmann E, Palangian M, Dalton-Bakes C, et al. (2013) Improvement in β-cell secretory capacity after human islet transplantation according to the c7 protocol . Diabetes 62 :2890–2897. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rickels MR, Robertson RP (2019) Pancreatic islet transplantation in humans: recent progress and future directions . Endocr Rev 40 :631–668. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rodriguez-Calvo T, Suwandi JS, Amirian N, Zapardiel-Gonzalo J, Anquetil F, Sabouri S, von Herrath MG (2015) Heterogeneity and lobularity of pancreatic pathology in type 1 diabetes during the prediabetic phase . J Histochem Cytochem 63 :626–636. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rojas LB, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes . Diabetol Metab Syndr 5 :6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rosen ED, Kulkarni RN, Sarraf P, Ozcan U, Okada T, Hsu CH, Eisenman D, Magnuson MA, Gonzalez FJ, Kahn CR, et al. (2003) Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis . Mol Cell Biol 23 :7222–7229. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, Hale PM; Repaglinide Versus Nateglinide Comparison Study Group (2004) Repaglinide versus nateglinide monotherapy: a randomized, multicenter study . Diabetes Care 27 :1265–1270. [ PubMed ] [ Google Scholar ]
• Sampaio MS, Kuo HT, Bunnapradist S (2011) Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients . Clin J Am Soc Nephrol 6 :1198–1206. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Saponaro C, Gmyr V, Thévenet J, Moerman E, Delalleau N, Pasquetti G, Coddeville A, Quenon A, Daoudi M, Hubert T, et al. (2019) The GLP1R agonist liraglutide reduces hyperglucagonemia induced by the SGLT2 inhibitor dapagliflozin via somatostatin release . Cell Rep 28 :1447–1454.e4. [ PubMed ] [ Google Scholar ]
• Saponaro C, Mühlemann M, Acosta-Montalvo A, Piron A, Gmyr V, Delalleau N, Moerman E, Thévenet J, Pasquetti G, Coddeville A, et al. (2020) Interindividual heterogeneity of SGLT2 expression and function in human pancreatic islets . Diabetes 69 :902–914. [ PubMed ] [ Google Scholar ]
• Satin LS, Tavalin SJ, Kinard TA, Teague J (1995) Contribution of L- and non-L-type calcium channels to voltage-gated calcium current and glucose-dependent insulin secretion in HIT-T15 cells . Endocrinology 136 :4589–4601. [ PubMed ] [ Google Scholar ]
• Schwartz AV, Chen H, Ambrosius WT, Sood A, Josse RG, Bonds DE, Schnall AM, Vittinghoff E, Bauer DC, Banerji MA, et al. (2015) Effects of TZD use and discontinuation on fracture rates in ACCORD Bone Study . J Clin Endocrinol Metab 100 :4059–4066. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Shalev A, Pise-Masison CA, Radonovich M, Hoffmann SC, Hirshberg B, Brady JN, Harlan DM (2002) Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway . Endocrinology 143 :3695–3698. [ PubMed ] [ Google Scholar ]
• Shankar SS, Shankar RR, Mixson LA, Miller DL, Pramanik B, O’Dowd AK, Williams DM, Frederick CB, Beals CR, Stoch SA, et al. (2018) Native oxyntomodulin has significant glucoregulatory effects independent of weight loss in obese humans with and without type 2 diabetes . Diabetes 67 :1105–1112. [ PubMed ] [ Google Scholar ]
• Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen . N Engl J Med 343 :230–238. [ PubMed ] [ Google Scholar ]
• Sharma RB, O’Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, Arvan P, Alonso LC (2015) Insulin demand regulates β cell number via the unfolded protein response . J Clin Invest 125 :3831–3846. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sims EK, Mirmira RG, Evans-Molina C (2020) The role of beta-cell dysfunction in early type 1 diabetes . Curr Opin Endocrinol Diabetes Obes 27 :215–224. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, Emmett MJ, Briggs ER, Fang B, Everett LJ, et al. (2015) Genetic variation determines PPARγ function and anti-diabetic drug response in vivo . Cell 162 :33–44. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Crutchlow MF, Ferrari AM, Raum JC, Groff DN, Rankin MM, Liu C, De León DD, Naji A, Kushner JA, et al. (2010) Calcineurin signaling regulates human islet beta-cell survival . J Biol Chem 285 :40050–40059. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Hirshberg B, Bunnell DJ, Sumner AE, Ader M, Remaley AT, Rother KI, Rickels MR, Harlan DM (2012) Metabolic function of a suboptimal transplanted islet mass in nonhuman primates on rapamycin monotherapy . Cell Transplant 21 :1297–1304. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Soleimanpour SA, Stoffers DA (2013) The pancreatic β cell and type 1 diabetes: innocent bystander or active participant? Trends Endocrinol Metab 24 :324–331. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, et al. (2018) Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors . Diabetes 67 :1471–1480. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stancill JS, Cartailler JP, Clayton HW, O’Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA (2017) Chronic β-cell depolarization impairs β-cell identity by disrupting a network of Ca 2+ -regulated genes . Diabetes 66 :2175–2187. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stewart AF, Hussain MA, García-Ocaña A, Vasavada RC, Bhushan A, Bernal-Mizrachi E, Kulkarni RN (2015) Human β-cell proliferation and intracellular signaling: part 3 . Diabetes 64 :1872–1885. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Stojanovic I, Dimitrijevic M, Vives-Pi M, Mansilla MJ, Pujol-Autonell I, Rodríguez-Fernandez S, Palova-Jelínkova L, Funda DP, Gruden-Movsesijan A, Sofronic-Milosavljevic L, et al. (2017) Cell-based tolerogenic therapy, experience from animal models of multiple sclerosis, type 1 diabetes and rheumatoid arthritis . Curr Pharm Des 23 :2623–2643. [ PubMed ] [ Google Scholar ]
• Sturek JM, Castle JD, Trace AP, Page LC, Castle AM, Evans-Molina C, Parks JS, Mirmira RG, Hedrick CC (2010) An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells . J Clin Invest 120 :2575–2589. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Suga T, Kikuchi O, Kobayashi M, Matsui S, Yokota-Hashimoto H, Wada E, Kohno D, Sasaki T, Takeuchi K, Kakizaki S, et al. (2019) SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels . Mol Metab 19 :1–12. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, et al. (2018) Gut microbiota and intestinal FXR mediate the clinical benefits of metformin . Nat Med 24 :1919–1929. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sutherland DE, Matas AJ, Najarian JS (1978) Pancreatic islet cell transplantation . Surg Clin North Am 58 :365–382. [ PubMed ] [ Google Scholar ]
• Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, Evans-Molina C, Rickus JL, Maier B, Mirmira RG (2012) Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model . Diabetes 61 :818–827. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Thielen LA, Chen J, Jing G, Moukha-Chafiq O, Xu G, Jo S, Grayson TB, Lu B, Li P, Augelli-Szafran CE, et al. (2020) Identification of an anti-diabetic, orally available small molecule that regulates TXNIP expression and glucagon action . Cell Metab 32 :353–365.e8. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, Bossart M, et al. (2019) A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials . Diabetes Obes Metab 21 :120–128. [ PubMed ] [ Google Scholar ]
• Vallon V (2015) The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus . Annu Rev Med 66 :255–270. [ PubMed ] [ Google Scholar ]
• Vasseur M, Debuyser A, Joffre M (1987) Sensitivity of pancreatic beta cell to calcium channel blockers. An electrophysiologic study of verapamil and nifedipine . Fundam Clin Pharmacol 1 :95–113. [ PubMed ] [ Google Scholar ]
• Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, et al. (2016) Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates . Nat Biotechnol 34 :345–352. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, Asterholm IW, Benrick A, Briant LJB, Chibalina MV, et al. (2019) Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion . Nat Commun 10 :139. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wallner K, Shapiro AM, Senior PA, McCabe C (2016) Cost effectiveness and value of information analyses of islet cell transplantation in the management of ‘unstable’ type 1 diabetes mellitus . BMC Endocr Disord 16 :17. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wang H, Bender A, Wang P, Karakose E, Inabnet WB, Libutti SK, Arnold A, Lambertini L, Stang M, Chen H, et al. (2017) Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas . Nat Commun 8 :767. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wang Y, An H, Liu T, Qin C, Sesaki H, Guo S, Radovick S, Hussain M, Maheshwari A, Wondisford FE, O’Rourke B, He L (2019) Metformin improves mitochondrial respiratory activity through activation of AMPK . Cell Rep 29 :1511–1523.e5. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Westerman J, Wirtz KW, Berkhout T, van Deenen LL, Radhakrishnan R, Khorana HG (1983) Identification of the lipid-binding site of phosphatidylcholine-transfer protein with phosphatidylcholine analogs containing photoactivable carbene precursors . Eur J Biochem 132 :441–449. [ PubMed ] [ Google Scholar ]
• World Health Organization (2020) World Health Organization Diabetes Fact Sheet . [ Google Scholar ]
• Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME, van der Velden WJ, Stutsman C, Cardona GR, et al. (2020) Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist . JCI Insight 5 :e140532. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Williams P (1894) Notes on diabetes treated with extract and by grafts of sheep’s pancreas . BMJ 2 :1303–1304. [ Google Scholar ]
• Williamson RT (1901) On the treatment of glycosuria and diabetes mellitus with sodium salicylate . BMJ 1 :760–762. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Witters LA (2001) The blooming of the French lilac . J Clin Invest 108 :1105–1107. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al.; DECLARE–TIMI 58 Investigators (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes . N Engl J Med 380 :347–357. [ PubMed ] [ Google Scholar ]
• Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, et al. (2017) Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug . Nat Med 23 :850–858. [ PubMed ] [ Google Scholar ]
• Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, et al. (2005) Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial . Diabetes 54 :2390–2395. [ PubMed ] [ Google Scholar ]
• Xu G, Chen J, Jing G, Shalev A (2012) Preventing β-cell loss and diabetes with calcium channel blockers . Diabetes 61 :848–856. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Yang JF, Gong X, Bakh NA, Carr K, Phillips NFB, Ismail-Beigi F, Weiss MA, Strano MS (2020) Connecting rodent and human pharmacokinetic models for the design and translation of glucose-responsive insulin . Diabetes 69 :1815–1826. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Yu O, Azoulay L, Yin H, Filion KB, Suissa S (2018) Sulfonylureas as initial treatment for type 2 diabetes and the risk of severe hypoglycemia . Am J Med 131 :317.e11–317.e22. [ PubMed ] [ Google Scholar ]
• Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action . J Clin Invest 108 :1167–1174. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al.; EMPA-REG OUTCOME Investigators (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes . N Engl J Med 373 :2117–2128. [ PubMed ] [ Google Scholar ]

• About The Guide to PHARMACOLOGY
• About NC-IUPHAR
• Database Content
• Contributors
• Linking to us

Privacy and Cookie Policy

• Other channels
• Nuclear receptors
• Catalytic receptors
• Transporters
• Other protein targets
• Target search tools
• Ligand list
• Ligand families
• Ligand search
• Terms and symbols
• Nomenclature guidelines
• Publications
• Download data and reports
• Web services
• Slides and posters
• Immunopharmacology Meeting 2018
• Latest news
• Latest pairings
• Concise Guide to PHARMACOLOGY
• Useful links
• Pharmacology search
• Immuno Portal
• Malaria Portal
• Guide to IMMUNOPHARMACOLOGY Portal

Hot Topics in Pharmacology

Coronavirus information.

We collate information related to SARS-CoV-2 and COVID-19 on a dedicated coronavirus information page . This contains details of ligands and targets relevant to COVID-19 and links to useful resources and publications.

Recent publications of interest recommended by NC-IUPHAR

2024: mar | jan 2023: nov | oct | sep | aug | jul | may | apr.

• MFSD7c functions as a transporter of choline at the blood-brain barrier. Nguyen XTA, Le TNU, Nguyen TQ, Thi Thuy Ha H, Artati A, Leong NCP, Nguyen DT, Lim PY, Susanto AV, Huang Q et al. . MFSD7c functions as a transporter of choline at the blood-brain barrier. (2024)   Cell Res , 34 (3): 245-257. [PMID: 38302740 ]
• Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport. Boytsov D, Madej GM, Horn G, Blaha N, Köcher T, Sitte HH, Siekhaus D, Ziegler C, Sandtner W, Roblek M. Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport. (2024)   Proc Natl Acad Sci U S A , 121 (13): e2319686121. [PMID: 38507452 ]
• Activation of GPR81 by lactate drives tumour-induced cachexia. Liu X, Li S, Cui Q, Guo B, Ding W, Liu J, Quan L, Li X, Xie P, Jin L et al. . Activation of GPR81 by lactate drives tumour-induced cachexia. (2024)   Nat Metab , [Epub ahead of print]. [PMID: 38499763 ]
• The kainate receptor GluK2 mediates cold sensing in mice. Cai W, Zhang W, Zheng Q, Hor CC, Pan T, Fatima M, Dong X, Duan B, Xu XZS. The kainate receptor GluK2 mediates cold sensing in mice. (2024)   Nat Neurosci , [Epub ahead of print]. [PMID: 38467901 ]
• An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure. Xu J, Choi R, Gupta K, Warren HR, Santhanam L, Pluznick JL. An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure. (2024)   Sci Adv , 10 (12): eadk1487. [PMID: 38507492 ]
• Understanding the provenance and quality of methods is essential for responsible reuse of FAIR data. Weissgerber TL, Gazda MA, Nilsonne G, Ter Riet G, Cobey KD, Prieß-Buchheit J, Noro J, Schulz R, Tijdink JK, Bobrov E et al. . Understanding the provenance and quality of methods is essential for responsible reuse of FAIR data. (2024)   Nat Med , [Epub ahead of print]. [PMID: 38514869 ]
• Promoting gender equity in the scientific and health workforce is essential to improve women's health. Vieira Machado C, Araripe Ferreira C, de Souza Mendes Gomes MA. Promoting gender equity in the scientific and health workforce is essential to improve women's health. (2024)   Nat Med , [Epub ahead of print]. [PMID: 38519768 ]

January 2024

• Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Cervia-Hasler C, Brüningk SC, Hoch T, Fan B, Muzio G, Thompson RC, Ceglarek L, Meledin R, Westermann P, Emmenegger M et al. . Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. (2024)   Science , 383 (6680): eadg7942. [PMID: 38236961 ]
• EPAC1 enhances brown fat growth and beige adipogenesis. Reverte-Salisa L, Siddig S, Hildebrand S, Yao X, Zurkovic J, Jaeckstein MY, Heeren J, Lezoualc'h F, Krahmer N, Pfeifer A. EPAC1 enhances brown fat growth and beige adipogenesis. (2024)   Nat Cell Biol , 26 (1): 113-123. [PMID: 38195707 ]
• Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity. Chiu TY, Lazar DC, Wang WW, Wozniak JM, Jadhav AM, Li W, Gazaniga N, Theofilopoulos AN, Teijaro JR, Parker CG. Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity. (2024)   Nat Chem Biol , [Epub ahead of print]. [PMID: 38191941 ]
• Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme. Sosinsky A, Ambrose J, Cross W, Turnbull C, Henderson S, Jones L, Hamblin A, Arumugam P, Chan G, Chubb D et al. . Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme. (2024)   Nat Med , 30 (1): 279-289. [PMID: 38200255 ]
• Structural basis of prostaglandin efflux by MRP4. Pourmal S, Green E, Bajaj R, Chemmama IE, Knudsen GM, Gupta M, Sali A, Cheng Y, Craik CS, Kroetz DL et al. . Structural basis of prostaglandin efflux by MRP4. (2024)   Nat Struct Mol Biol , [Epub ahead of print]. [PMID: 38216659 ]
• Biased agonists of GPR84 and insights into biological control. Luscombe VB, Wang P, Russell AJ, Greaves DR. Biased agonists of GPR84 and insights into biological control. (2023)   Br J Pharmacol , [Epub ahead of print]. [PMID: 38148720 ]

November 2023

• Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Boby ML, Fearon D, Ferla M, Filep M, Koekemoer L, Robinson MC, COVID Moonshot Consortium‡, Chodera JD, Lee AA, London N et al. . Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. (2023)   Science , 382 (6671): eabo7201. [PMID: 37943932 ]

October 2023

• The IUPHAR/BPS Guide to PHARMACOLOGY in 2024. Harding SD, Armstrong JF, Faccenda E, Southan C, Alexander SPH, Davenport AP, Spedding M, Davies JA. The IUPHAR/BPS Guide to PHARMACOLOGY in 2024. (2024)   Nucleic Acids Res , 52 (D1): D1438-D1449. [PMID: 37897341 ]
• ADCdb: the database of antibody-drug conjugates. Shen L, Sun X, Chen Z, Guo Y, Shen Z, Song Y, Xin W, Ding H, Ma X, Xu W et al. . ADCdb: the database of antibody-drug conjugates. (2024)   Nucleic Acids Res , 52 (D1): D1097-D1109. [PMID: 37831118 ]
• TTD: Therapeutic Target Database describing target druggability information. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F. TTD: Therapeutic Target Database describing target druggability information. (2024)   Nucleic Acids Res , 52 (D1): D1465-D1477. [PMID: 37713619 ]
• Functional screening and rational design of compounds targeting GPR132 to treat diabetes. Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW et al. . Functional screening and rational design of compounds targeting GPR132 to treat diabetes. (2023)   Nat Metab , 5 (10): 1726-1746. [PMID: 37770763 ]
• Genome-wide association analysis reveals insights into the molecular etiology underlying dilated cardiomyopathy. Zheng SL, Henry A, Cannie D, Lee M, Miller D, McGurk KA, Bond I, Xu X, Issa H, Francis C et al. . Genome-wide association analysis reveals insights into the molecular etiology underlying dilated cardiomyopathy. (2023)   medRxiv , Preprint. DOI: https://www.medrxiv.org/content/10.1101/2023.09.28.23295408v1
• An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism. Lees JA, Dias JM, Rajamohan F, Fortin JP, O'Connor R, Kong JX, Hughes EAG, Fisher EL, Tuttle JB, Lovett G et al. . An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism. (2023)   Nat Commun , 14 (1): 5938. [PMID: 37741852 ]
• Cryo-EM structures of human GPR34 enable the identification of selective antagonists. Xia A, Yong X, Zhang C, Lin G, Jia G, Zhao C, Wang X, Hao Y, Wang Y, Zhou P et al. . Cryo-EM structures of human GPR34 enable the identification of selective antagonists. (2023)   Proc Natl Acad Sci U S A , 120 (39): e2308435120. [PMID: 37733739 ]

September 2023

• The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase. Medoh UN, Hims A, Chen JY, Ghoochani A, Nyame K, Dong W, Abu-Remaileh M. The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase. (2023)   Science , 381 (6663): 1182-1189. [PMID: 37708259 ]
• Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine. Li Y, Liu S, Zhou K, Wang Y, Chen Y, Hu W, Li S, Li H, Wang Y, Wang Q et al. . Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine. (2023)   Science , 381 (6663): 1189-1196. [PMID: 37708282 ]
• Exploring DrugCentral: from molecular structures to clinical effects. Halip L, Avram S, Curpan R, Borota A, Bora A, Bologa C, Oprea TI. Exploring DrugCentral: from molecular structures to clinical effects. (2023)   J Comput Aided Mol Des , 37 (12): 681-694. [PMID: 37707619 ]
• Role of sphingolipids in the host-pathogen interaction. Matos GS, Fernandes CM, Del Poeta M. Role of sphingolipids in the host-pathogen interaction. (2023)   Biochim Biophys Acta Mol Cell Biol Lipids , 1868 (11): 159384. [PMID: 37673393 ]
• Dynamic lipidome alterations associated with human health, disease and ageing. Hornburg D, Wu S, Moqri M, Zhou X, Contrepois K, Bararpour N, Traber GM, Su B, Metwally AA, Avina M et al. . Dynamic lipidome alterations associated with human health, disease and ageing. (2023)   Nat Metab , 5 (9): 1578-1594. [PMID: 37697054 ]
• Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity. Paukštytė J, López Cabezas RM, Feng Y, Tong K, Schnyder D, Elomaa E, Gregorova P, Doudin M, Särkkä M, Sarameri J et al. . Global analysis of aging-related protein structural changes uncovers enzyme-polymerization-based control of longevity. (2023)   Mol Cell , 83 (18): 3360-3376.e11. [PMID: 37699397 ]
• Mitochondrial degradation: Mitophagy and beyond. Uoselis L, Nguyen TN, Lazarou M. Mitochondrial degradation: Mitophagy and beyond. (2023)   Mol Cell , 83 (19): 3404-3420. [PMID: 37708893 ]
• How many kinases are druggable? A review of our current understanding. Anderson B, Rosston P, Ong HW, Hossain MA, Davis-Gilbert ZW, Drewry DH. How many kinases are druggable? A review of our current understanding. (2023)   Biochem J , 480 (16): 1331-1363. [PMID: 37642371 ]
• AI-powered therapeutic target discovery. Pun FW, Ozerov IV, Zhavoronkov A. AI-powered therapeutic target discovery. (2023)   Trends Pharmacol Sci , 44 (9): 561-572. [PMID: 37479540 ]

August 2023

• What is a cell type?. Fleck JS, Camp JG, Treutlein B. What is a cell type?. (2023)   Science , 381 (6659): 733-734. [PMID: 37590360 ]
• Create a culture of experiments in environmental programs. Ferraro PJ, Cherry TL, Shogren JF, Vossler CA, Cason TN, Flint HB, Hochard JP, Johansson-Stenman O, Martinsson P, Murphy JJ et al. . Create a culture of experiments in environmental programs. (2023)   Science , 381 (6659): 735-737. [PMID: 37590363 ]
• International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023. Burris TP, de Vera IMS, Cote I, Flaveny CA, Wanninayake US, Chatterjee A, Walker JK, Steinauer N, Zhang J, Coons LA et al. . International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023. (2023)   Pharmacol Rev , 75 (6): 1233-1318. [PMID: 37586884 ]
• A method for structure determination of GPCRs in various states. Guo Q, He B, Zhong Y, Jiao H, Ren Y, Wang Q, Ge Q, Gao Y, Liu X, Du Y et al. . A method for structure determination of GPCRs in various states. (2024)   Nat Chem Biol , 20 (1): 74-82. [PMID: 37580554 ]
• A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs. Sutherland JJ, Yonchev D, Fekete A, Urban L. A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs. (2023)   Nat Commun , 14 (1): 4323. [PMID: 37468498 ]
• Metal-ion transporter SLC39A8 is required for brain manganese uptake and accumulation. Liu Q, Jenkitkasemwong S, Prami TA, McCabe SM, Zhao N, Hojyo S, Fukada T, Knutson MD. Metal-ion transporter SLC39A8 is required for brain manganese uptake and accumulation. (2023)   J Biol Chem , 299 (8): 105078. [PMID: 37482277 ]
• Cross-talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39. Hershfinkel M. Cross-talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39. (2023)   J Physiol , [Epub ahead of print]. [PMID: 37462604 ]
• Identification of ligand-receptor pairs that drive human astrocyte development. Voss AJ, Lanjewar SN, Sampson MM, King A, Hill EJ, Sing A, Sojka C, Bhatia TN, Spangle JM, Sloan SA. Identification of ligand-receptor pairs that drive human astrocyte development. (2023)   Nat Neurosci , 26 (8): 1339-1351. [PMID: 37460808 ]
• Jeffrey Clifton Watkins FRS - The father of the glutamate receptor. Collingridge GL, Evans RH, Jane DE, Lodge D. Jeffrey Clifton Watkins FRS - The father of the glutamate receptor. (2023)   Neuropharmacology ,: 109650 [Epub ahead of print]. [PMID: 37474350 ]
• The manifold costs of being a non-native English speaker in science. Amano T, Ramírez-Castañeda V, Berdejo-Espinola V, Borokini I, Chowdhury S, Golivets M, González-Trujillo JD, Montaño-Centellas F, Paudel K, White RL et al. . The manifold costs of being a non-native English speaker in science. (2023)   PLoS Biol , 21 (7): e3002184. [PMID: 37463136 ]
• Spartin is a receptor for the autophagy of lipid droplets. Spartin is a receptor for the autophagy of lipid droplets. (2023)   Nat Cell Biol , 25 (8): 1085-1086. [PMID: 37474818 ]
• Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform. Zeghal M, Laroche G, Freitas JD, Wang R, Giguère PM. Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform. (2023)   Nat Commun , 14 (1): 3684. [PMID: 37407564 ]
• Mammalian type opsin 5 preferentially activates G14 in Gq-type G proteins triggering intracellular calcium response. Sato K, Yamashita T, Ohuchi H. Mammalian type opsin 5 preferentially activates G14 in Gq-type G proteins triggering intracellular calcium response. (2023)   J Biol Chem , 299 (8): 105020. [PMID: 37423300 ]
• Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. Nayak SR, Joseph D, Höfner G, Dakua A, Athreya A, Wanner KT, Kanner BI, Penmatsa A. Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. (2023)   Nat Struct Mol Biol , 30 (7): 1023-1032. [PMID: 37400654 ]
• Molecular basis for substrate recognition and transport of human GABA transporter GAT1. Zhu A, Huang J, Kong F, Tan J, Lei J, Yuan Y, Yan C. Molecular basis for substrate recognition and transport of human GABA transporter GAT1. (2023)   Nat Struct Mol Biol , 30 (7): 1012-1022. [PMID: 37400655 ]
• Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38. Armstrong JF, Campo B, Alexander SPH, Arendse LB, Cheng X, Davenport AP, Faccenda E, Fidock DA, Godinez-Macias KP, Harding SD et al. . Advances in malaria pharmacology and the online guide to MALARIA PHARMACOLOGY: IUPHAR review 38. (2023)   Br J Pharmacol , 180 (15): 1899-1929. [PMID: 37197802 ]
• The VGNC: expanding standardized vertebrate gene nomenclature. Jones TEM, Yates B, Braschi B, Gray K, Tweedie S, Seal RL, Bruford EA. The VGNC: expanding standardized vertebrate gene nomenclature. (2023)   Genome Biol , 24 (1): 115. [PMID: 37173739 ]
• A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Gong GQ, Bilanges B, Allsop B, Masson GR, Roberton V, Askwith T, Oxenford S, Madsen RR, Conduit SE, Bellini D et al. . A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. (2023)   Nature , 618 (7963): 159-168. [PMID: 37225977 ]
• Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage. Liu HW, Gong LN, Lai K, Yu XF, Liu ZQ, Li MX, Yin XL, Liang M, Shi HS, Jiang LH et al. . Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage. (2023)   Neuron , 111 (10): 1609-1625.e6. [PMID: 36921602 ]
• FDA approves first-in-class NK3 receptor antagonist for hot flushes. Mullard A. FDA approves first-in-class NK3 receptor antagonist for hot flushes. (2023)   Nat Rev Drug Discov , 22 (7): 526. [PMID: 37208488 ]
• Identification and classification of papain-like cysteine proteinases. Ozhelvaci F, Steczkiewicz K. Identification and classification of papain-like cysteine proteinases. (2023)   J Biol Chem , 299 (6): 104801. [PMID: 37164157 ]
• Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na V 1.7. Wisedchaisri G, Gamal El-Din TM, Zheng N, Catterall WA. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na V 1.7. (2023)   Proc Natl Acad Sci U S A , 120 (14): e2219624120. [PMID: 36996107 ]

Sponsors list

• Pharmacy and Clinical Pharmacology

Explore JAMA Network Open’s collection on clinical pharmacy and pharmacology, including topics in drug safety and development, pharmacogenetics, and more.

Publication

Article type.

This cross-sectional study examines the proportion of supply chain issue reports associated with drug shortages overall and during the COVID-19 pandemic.

• Drug Shortages—A Study in Complexity JAMA Network Open Opinion April 5, 2024 Health Policy Coronavirus (COVID-19) Regulatory Agencies Pharmacoeconomics Clinical Pharmacy and Pharmacology Full Text | pdf link PDF open access

This systematic review and meta-analysis assesses associations of sodium glucose cotransporter-2 inhibitors (SGL2i) with functional capacity and quality of life outcomes among patients with heart failure (HF).

This cross-sectional study uses payment data publicly disclosed by pharmaceutical companies affiliated with the Japan Pharmaceutical Manufacturers Association to describe their financial relationships with the subspecialty societies of the Japanese Society of Internal Medicine.

This systematic review and network meta-analysis investigates the risk of adverse clinical events associated with different durations of dual antiplatelet therapy for older adults after percutaneous coronary intervention.

• Optimizing Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Older Adults JAMA Network Open Opinion March 28, 2024 Cardiology Clinical Pharmacy and Pharmacology Acute Coronary Syndromes Adverse Drug Events Bleeding and Transfusion Full Text | pdf link PDF open access

This secondary analysis of the ECOG-ACRIN E1A11 trial analyzes the association of patient-reported adverse effects with early treatment discontinuation in patients with multiple myeloma.

This economic evaluation examines the health expenditures related to medicines used for treatment of diabetes worldwide.

This diagnostic study evaluates the current diagnostic practices for managing suspected heparin-induced thrombocytopenia.

This cohort study investigates the association of an emergency department peer recovery support service with postdischarge addiction treatment initiation among patients admitted for nonfatal opioid overdose in New Jersey.

This case-control study assesses whether the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and oral anticoagulants was associated with increased risk of major bleeding vs oral anticoagulant use alone among UK adults.

This cohort study investigates the association of specific attention-deficit/hyperactivity disorder (ADHD) medications with hospitalization outcomes and work disability among Swedish adolescents and adults with ADHD.

This cohort study examines the natural history and response to treatment of sodium glucose cotransporter 2 (SGLT2) inhibitor–associated ketoacidosis compared with that of type 1 diabetes–associated ketoacidosis.

This randomized clinical trial compares COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir.

• Network Meta-Analyses—Better Than Nothing? JAMA Network Open Opinion March 7, 2024 Oncology Surgical Oncology Cancer Biomarkers Lung Cancer Targeted and Immune Therapy Full Text | pdf link PDF open access

This systematic review with network meta-analysis compares the efficacy associated with 10 drugs for the treatment of antipsychotic-induced akathisia.

This meta-analysis compares the efficacy and safety of neoadjuvant-adjuvant anti–programmed cell death 1 (PD-1) and anti–programmed death ligand 1 (PD-L1) therapy with neoadjuvant-only anti–PD-1 and anti–PD-L1 therapy for patients with resectable non–small cell lung cancer (NSCLC).

This randomized clinical trial investigates whether P2Y12 inhibitor monotherapy after 3 months of dual antiplatelet therapy (DAPT) was noninferior to 12 months of DAPT following percutaneous coronary intervention with a drug-eluting stent.

This cohort study examines the risks of cardiovascular disease after 6 months of methylphenidate treatment in individuals with attention-deficit/hyperactivity disorder.

This qualitative study describes the experiences of older adults and primary care practitioners with opioids for treatment of chronic pain and patient-practitioner conversations about opioid deprescribing.

Select Your Interests

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• American Indian or Alaska Natives
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Artificial Intelligence
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Climate Change
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life, Hospice, Palliative Care
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Policy
• Health Systems Science
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Palliative Care
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Primary Care
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Reproductive Health
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing
• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

Articles on Pharmacology

Displaying 1 - 20 of 61 articles.

What is minoxidil, the anti-balding hair growth treatment? Here’s what the science says

Jacinta L. Johnson , University of South Australia and Kirsten Staff , University of South Australia

Mauritius sea sponge produces chemicals that can kill liver cancer cells – findings are a positive first step

Rima Beesoo , Leibniz Centre for Tropical Marine Research (ZMT)

Can at-home DNA tests predict how you’ll respond to your medications? Pharmacists explain the risks and benefits of pharmacogenetic testing

Kayla B. Rowe , University of Pittsburgh ; Lucas A. Berenbrok , University of Pittsburgh , and Philip Empey , University of Pittsburgh

Bipolar disorder isn’t the same for everyone. So people should have more say in how they’re treated

Gordon Parker , UNSW Sydney and Michael Spoelma , UNSW Sydney

Illegal, occasionally deadly, and not much fun. What is the frog toxin Kambô and why do people use it?

Martin Williams , Swinburne University of Technology

Prescription drugs’ fine print is important – a toxicologist explains how to decode package inserts to take medications safely and increase their effectiveness

Brad Reisfeld , Colorado State University

Picking mushrooms can go horribly wrong. Here’s what can happen, according to a toxicologist

Darren Roberts , UNSW Sydney

Why cough medicines containing pholcodine can be deadly even if you took them months before surgery

Nial Wheate , University of Sydney and Tina Hinton , University of Sydney

Is my medicine making me feel hotter this summer? 5 reasons why

Nial Wheate , University of Sydney and Jessica Pace , University of Sydney

500-year -old horn container discovered in South Africa sheds light on pre-colonial Khoisan medicines

Justin Bradfield , University of Johannesburg

Drinking alcohol this Christmas and New Year? These medicines really don’t mix

Timing matters for medications – your circadian rhythm influences how well treatments work and how much they might harm you

Tobias Eckle , University of Colorado Anschutz Medical Campus

New warning about the risks of combining ibuprofen and codeine: a necessary step

Francisco López-Muñoz , Universidad Camilo José Cela and Jose Antonio Guerra Guirao , Universidad Complutense de Madrid

Drugs – 4 essential reads on how they’re made, how they work and how context can make poison a medicine

Vivian Lam , The Conversation

An entirely new illicit drug has been discovered by Australian chemists. Here’s how they did it

David Caldicott , Australian National University and Malcolm McLeod , Australian National University

When monkeys use the forest as a pharmacy

Olivier Kaisin , Université de Liège

Lying down, sitting, leaning over? What science says about the best way to take your medicine

Elise Schubert , University of Sydney ; Nial Wheate , University of Sydney , and Tina Hinton , University of Sydney

5 drugs that changed the world (and what went wrong)

Philippa Martyr , The University of Western Australia

Why are drug names so long and complicated? A pharmacist explains the logic behind the nomenclature

Jasmine Cutler , University of South Florida

Africa is a treasure trove of medicinal plants: here are seven that are popular

Adeyemi Oladapo Aremu , North-West University and Nox Makunga , Stellenbosch University

Related Topics

• Antibiotics
• Drug development
• Medications
• Pharmaceuticals

Top contributors

Associate Professor of the School of Pharmacy, University of Sydney

University of Sydney

Professor of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus

Lecturer, Pharmacology, Women's Health, School of Biomedical Sciences, The University of Western Australia

Professor of Medicine and Chair of Clinical Pharmacology, University of Newcastle

Associate Lecturer, Sydney Pharmacy School, University of Sydney

Associate Professor of Pharmacology, University of Sydney

HERA Program Director - Health Workforce Optimisation Centre for the Business & Economics of Health, The University of Queensland

Distinguished Professor of Pharmacy Practice, University of Connecticut

Emeritus Professor, University of South Australia

Assistant Professor of History, University at Buffalo

Conjoint Associate Professor in clinical pharmacology and toxicology, St Vincent’s Healthcare Clinical Campus, UNSW Sydney

Senior lecturer, Australian National University

Molecular Imaging Post-Doctoral Research Assistant, University of Hull

Postdoctoral Research - Institute of Sport, Exercise and Active Living (ISEAL), Victoria University

• X (Twitter)
• Unfollow topic Follow topic

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals

Pharmaceutics articles from across Nature Portfolio

Pharmaceutics is the scientific discipline concerned with the process of creating the dosage form (such as a pill for oral administration or a powder for intravenous injection) of a therapeutic that is to be used by patients. It encompasses drug formulation and manufacturing.

Latest Research and Reviews

Valency based novel quantitative structure property relationship (QSPR) approach for predicting physical properties of polycyclic chemical compounds

• Mishal Ismaeel
• Fikadu Tesgera Tolasa

N-benzyl-N-methyldecan-1-amine, derived from garlic, and its derivative alleviate 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice

• Phatcharaporn Budluang
• Young-Hwa Chung

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2

• Laura Schmitt
• Ilka Lechtenberg
• Sebastian Wesselborg

Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease

Treatments for tuberculosis have markedly improved in recent years, but lung disease caused by nontuberculous mycobacteria (NTM) is on the rise and lacks effective cures. This Review discusses promising small-molecule drug candidates and innovative clinical trial designs and highlights how lessons from tuberculosis therapeutic development can be applied to NTM disease.

• Véronique Dartois
• Thomas Dick

Apomorphine is a potent inhibitor of ferroptosis independent of dopaminergic receptors

• Akihiko Miyauchi
• Chika Watanabe
• Hitoshi Osaka

A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders

Gandhi, Zivkovic, Østergaard and colleagues describe a bispecific antibody, HMB-001, which could be used for the prophylactic treatment of patients with genetic bleeding disorders, currently treated acutely with recombinant coagulation factor VIIa. HMB-001 can bind and accumulate endogenous FVIIa and localize it to sites of vascular injury by targeting it to the TREM-like transcript-1 receptor selectively expressed on activated platelets.

• Prafull S. Gandhi
• Minka Zivkovic
• Johan H. Faber

News and Comment

Stopping the bleed when platelets don’t stick.

Defects in platelet adhesion at sites of injury can lead to excessive bleeding. A study by Gandhi et al. investigates a new bispecific antibody as a possible therapy to prevent bleeding in patients with inherited defects in platelet adhesion.

• Ammon M. Fager
• Dougald M. Monroe

Fast, instrument-free and low-cost selection of high-affinity aptamers

We designed a method for fast aptamer selection by integrating biomaterials science, engineering principles and biology. Aptamer candidates dynamically interacting with immobilized targets in a three-dimensional, non-fouling and macroporous polyethylene glycol hydrogel were rapidly enriched and selected with high affinity against five protein targets.

Clinical translation of radiotheranostics for precision oncology

Radiotheranostics combines disease-specific molecular imaging and radionuclide therapy. We present new and promising targets, tracers and isotopes for radiotheranostics and outline the road to clinical translation of the 177 Lu–LNC1004 radiopharmaceutical, which has recently been approved by the US Food and Drug Administration (FDA) for a phase I clinical trial.

• Jingjing Zhang
• Tianzhi Zhao
• Xiaoyuan Chen

Distinguishing and predicting drug patents

Drug patents are different. To improve their quality ex ante, regulators can use predictive models.

• Colleen V. Chien
• Nicholas Halkowski
• Jeffrey Kuhn

Biosimilar anti-VEGF—Yardsticks to ensure biosimilarity

• Ashish Sharma
• Nikulaa Parachuri
• Baruch D. Kuppermann

Faricimab phase 3 DME trial significance of personalized treatment intervals (PTI) regime for future DME trials

• Nilesh Kumar
• Carl D. Regillo

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Pharmacology Research Paper Topics

In this page on pharmacology research paper topics , we explore the diverse and dynamic field of pharmacology and provide valuable resources for students who are tasked with writing research papers in this discipline. Pharmacology, as a branch of science, encompasses the study of how drugs interact with biological systems, aiming to understand their mechanisms of action, therapeutic uses, and potential side effects. With the growing importance of pharmacology in healthcare and drug development, it is crucial for students to delve into relevant pharmacology research paper topics that contribute to advancing knowledge and addressing current challenges in the field. Additionally, we highlight iResearchNet’s writing services, offering students the opportunity to order custom pharmacology research papers tailored to their specific needs. Our team of expert writers, equipped with in-depth knowledge of pharmacology and related fields, ensures high-quality, well-researched papers that adhere to the highest academic standards.

In the field of pharmacology, research plays a critical role in advancing our understanding of drugs, their mechanisms of action, and their impact on human health. As students of pharmacology, you may be tasked with writing research papers that explore various aspects of this dynamic discipline. To assist you in your research journey, we have curated a comprehensive list of pharmacology research paper topics that cover a wide range of subfields and emerging areas of interest. Whether you are interested in drug discovery, clinical pharmacology, pharmacogenomics, or drug safety, this list provides a wealth of ideas to inspire and guide your research endeavors.

Academic Writing, Editing, Proofreading, And Problem Solving Services

Get 10% off with 24start discount code.

Drug Discovery and Development

• Role of Artificial Intelligence in Drug Discovery
• Personalized Medicine: Tailoring Drug Therapy to Individual Patients
• Drug Repurposing: Exploring New Indications for Existing Drugs
• Pharmacogenomics and Drug Response Prediction
• Nanomedicine: Applications in Drug Delivery and Targeting
• Innovative Approaches for Drug Formulation and Delivery
• Drug Combinations: Synergistic Effects and Therapeutic Opportunities
• Natural Products as Sources of Novel Therapeutic Agents
• Virtual Screening and Molecular Docking in Drug Design
• Pharmacokinetics and Pharmacodynamics of New Drug Entities

Clinical Pharmacology

• Precision Dosing: Optimizing Drug Therapy for Individual Patients
• Pharmacokinetic Variability in Special Populations (Pediatrics, Geriatrics, Pregnant Women)
• Drug-Drug Interactions: Mechanisms and Clinical Implications
• Adverse Drug Reactions: Identification, Prevention, and Management
• Pharmacovigilance and Drug Safety Monitoring
• Therapeutic Drug Monitoring: Rationale and Practical Considerations
• Clinical Trials in Pharmacology: Design, Implementation, and Analysis
• Drug Development and Regulatory Approval Processes
• Pharmacoeconomics: Evaluating the Cost-Effectiveness of Drug Therapy
• Ethical Considerations in Clinical Pharmacology Research

Neuropharmacology and Psychopharmacology

• Mechanisms of Action and Therapeutic Applications of Antidepressant Drugs
• Neurotransmitter Systems and Their Role in Mental Health Disorders
• Psychotropic Drugs and Their Impact on Cognitive Functioning
• Novel Approaches for Targeting Neurodegenerative Disorders
• Pharmacological Management of Substance Use Disorders
• Pharmacogenetics in Psychiatry: Implications for Individualized Treatment
• Role of Neuroinflammation in Neurological and Psychiatric Disorders
• Neuropharmacology of Sleep and Wakefulness
• Pharmacotherapy for Schizophrenia: Current Trends and Future Directions
• Novel Treatments for Anxiety and Mood Disorders

Pharmacokinetics and Drug Metabolism

• Drug Transporters and Their Role in Drug Disposition
• Pharmacogenetics and Personalized Drug Therapy
• Pharmacokinetic Variability and Its Impact on Drug Response
• Drug Metabolism Pathways and Enzyme Polymorphisms
• Drug-Drug Interactions: Mechanisms and Clinical Significance
• Predictive Modeling in Pharmacokinetics and Dose Optimization
• Pharmacokinetics in Special Populations: Pediatrics and Geriatrics
• Impact of Genetic Variation on Drug Clearance and Toxicity
• Role of Pharmacokinetics in Individualizing Drug Dosage
• Strategies for Improving Oral Bioavailability of Drugs

Pharmacology of Infectious Diseases

• Antimicrobial Resistance: Mechanisms, Epidemiology, and Strategies
• Development of Novel Antiviral Agents: Challenges and Opportunities
• Pharmacotherapy for Bacterial Infections: Current Approaches and Future Directions
• Antifungal Drugs: Mechanisms of Action and Resistance
• Host-Pathogen Interactions and Their Implications for Drug Development
• Pharmacokinetic Considerations in the Treatment of Viral Infections
• Targeting Virulence Factors in Bacterial Pathogens
• Drug Combination Therapy for Multidrug-Resistant Infections
• Pharmacogenomics of Antimicrobial Agents
• New Approaches for Antiparasitic Drug Development

Cardiovascular Pharmacology

• Novel Antiplatelet Agents: Mechanisms and Clinical Applications
• Antihypertensive Therapy: Current Strategies and Future Perspectives
• Pharmacotherapy for Heart Failure: Advancements and Challenges
• Role of Pharmacogenomics in Cardiovascular Drug Therapy
• Therapeutic Potential of Antiarrhythmic Agents
• Pharmacological Management of Dyslipidemia and Atherosclerosis
• Emerging Therapies for Pulmonary Hypertension
• Pharmacological Approaches to Preventing Thromboembolic Disorders
• Cardiotoxicity of Chemotherapeutic Agents: Mechanisms and Cardioprotective Strategies
• Targeting Inflammatory Pathways in Cardiovascular Disease

Pharmacology and Aging

• Geriatric Pharmacotherapy: Challenges and Approaches
• Age-Related Changes in Pharmacokinetics and Pharmacodynamics
• Polypharmacy and Its Impact on Older Adults
• Adverse Drug Reactions in the Elderly: Recognition and Prevention
• Pharmacological Management of Age-Related Neurodegenerative Disorders
• Geriatric Pharmacogenomics: Implications for Personalized Medicine
• Drug-Related Falls and Fractures in the Elderly: Prevention and Intervention
• Medication Adherence in Older Adults: Barriers and Strategies
• Geriatric Pain Management: Balancing Efficacy and Safety
• Optimizing Drug Therapy in Older Adults with Multiple Comorbidities

Pharmacology of Cancer

• Targeted Therapies for Solid Tumors: Recent Advances and Future Directions
• Immunotherapy in Cancer Treatment: Current Approaches and Challenges
• Pharmacogenomics of Chemotherapy: Implications for Personalized Treatment
• Drug Resistance in Cancer: Mechanisms and Strategies for Overcoming Resistance
• Pharmacokinetics and Pharmacodynamics of Anticancer Agents
• Combination Therapies in Oncology: Rationale and Clinical Outcomes
• Oncolytic Viruses: Exploiting Viral Infections for Cancer Treatment
• Cancer Stem Cells: Targeting Tumor Initiation and Progression
• Development of Novel Imaging Agents for Cancer Diagnosis and Monitoring
• Pharmacological Interventions for Cancer-Associated Pain Management

Pharmacology and Immunology

• Immune Checkpoint Inhibitors in Cancer Immunotherapy
• Autoimmune Diseases: Novel Pharmacological Approaches and Therapies
• Immunomodulatory Effects of Drugs: Implications for Therapeutic Interventions
• Role of Pharmacogenomics in Immunomodulatory Drug Therapy
• Immunopharmacology of Allergic Reactions: Mechanisms and Treatment Strategies
• Immunosuppressive Drugs in Transplantation: Balancing Efficacy and Safety
• Targeting Inflammatory Pathways in Autoimmune Disorders
• Immunopharmacological Interventions for Infectious Diseases
• Pharmacological Modulation of Cytokines in Inflammatory Disorders
• Vaccines: Advancements in Development and Delivery

Pharmacovigilance and Drug Safety

• Post-Marketing Surveillance: Detecting and Evaluating Adverse Drug Reactions
• Signal Detection in Pharmacovigilance: Methods and Applications
• Risk Management Strategies in Drug Development and Marketing
• Pharmacogenomic Biomarkers for Predicting Drug Safety
• Pharmacovigilance in Special Populations: Pregnant Women and Pediatrics
• Drug Safety Communication: Enhancing Patient Awareness and Education
• Role of Pharmacovigilance in Drug Regulatory Affairs
• Pharmacovigilance Data Mining: Leveraging Big Data for Drug Safety
• Pharmacovigilance Systems and Reporting Structures
• Pharmacogenetic Testing in Drug Safety Assessment

This comprehensive list of pharmacology research paper topics provides a broad range of ideas and areas to explore within the field of pharmacology. From drug discovery and development to clinical pharmacology, neuropharmacology, and pharmacokinetics, each category offers multiple topics for students to delve into and contribute to the advancement of pharmacological knowledge. Whether you are interested in the impact of pharmacogenomics on drug therapy, exploring novel treatment strategies, or investigating drug safety and pharmacovigilance, there is a wealth of research possibilities awaiting exploration. By selecting a topic of interest and following the expert advice on topic selection and research paper writing, students can embark on an enriching journey of discovery and make meaningful contributions to the field of pharmacology.

Pharmacology: Exploring the Range of Research Paper Topics

Pharmacology is a captivating and dynamic scientific discipline that focuses on the study of drugs and their effects on living organisms. It plays a crucial role in improving human health by advancing our understanding of how medications interact with biological systems. Within the field of pharmacology, there is a vast array of pharmacology research paper topics that offer students an opportunity to delve into various aspects of drug discovery, development, clinical application, and safety. In this article, we will explore the breadth and depth of pharmacology as a scientific field, highlighting the range of research paper topics it encompasses.

Drug Discovery and Development:  One exciting area of pharmacology research is drug discovery and development. This field involves the identification and development of new therapeutic agents to treat a wide range of diseases. Students interested in this area can explore topics such as the exploration of novel drug targets and therapeutic approaches, investigating natural products for drug development, advancements in targeted drug delivery systems, pharmacokinetics and pharmacodynamics of new drug entities, and understanding and overcoming drug resistance mechanisms.

Clinical Pharmacology:  Clinical pharmacology focuses on the application of pharmacological principles in the clinical setting. It plays a vital role in optimizing drug therapy and ensuring patient safety. Pharmacology research paper topics in this area may include pharmacogenomics, which explores the relationship between an individual’s genetic makeup and their response to medication. Other topics of interest include the identification, prevention, and management of adverse drug reactions, the design and ethical considerations in clinical trials, pharmacovigilance, and optimizing drug regimens for special populations such as pediatrics, geriatrics, and pregnant women.

Neuropharmacology and Psychopharmacology:  The field of neuropharmacology examines how drugs interact with the central nervous system and influence brain function. Pharmacology research paper topics in this area may involve investigating the mechanisms of action and therapeutic applications of psychotropic drugs, exploring neurotransmitter systems and their role in neurological disorders, pharmacological interventions for Alzheimer’s disease and other neurodegenerative disorders, the psychopharmacology of substance use disorders, and the pharmacological management of mental health disorders.

Pharmacokinetics and Drug Metabolism:  Pharmacokinetics and drug metabolism focus on understanding how drugs are absorbed, distributed, metabolized, and eliminated by the body. Pharmacology research paper topics in this area may include studying drug interactions, such as the mechanisms, predictions, and clinical implications of drug-drug interactions. Other topics of interest include pharmacogenetics and individual variations in drug response, the role of drug transporters in drug disposition, drug metabolism and its impact on drug-drug interactions, and the use of predictive modeling in pharmacokinetics and dosing optimization.

Pharmacology of Infectious Diseases:  The pharmacology of infectious diseases involves studying how drugs can effectively treat and prevent infections. Research topics in this area may include exploring antimicrobial resistance, including its mechanisms, epidemiology, and strategies to combat it. Additionally, students may investigate the development of new antiviral agents, the pharmacological management of bacterial infections, host-pathogen interactions, and the pharmacokinetic considerations in the treatment of infectious diseases.

Cardiovascular Pharmacology:  Cardiovascular pharmacology focuses on understanding the effects of drugs on the cardiovascular system. Research topics in this area may include exploring drug therapy for hypertension and current guidelines for treatment, novel anticoagulants in the prevention and treatment of thromboembolic disorders, pharmacological approaches to managing heart failure, drug-induced cardiotoxicity and strategies for prevention, and emerging pharmacotherapies for atherosclerosis and coronary artery disease.

Pharmacology and Aging:  Pharmacology and aging is a specialized field that investigates how drug therapy can be optimized in older adults. Research topics in this area may include exploring geriatric pharmacotherapy, age-related changes in pharmacokinetics and pharmacodynamics, the impact of polypharmacy on older adults, the recognition and prevention of adverse drug reactions, pharmacological management of age-related neurodegenerative disorders, and strategies for improving medication adherence in the elderly.

The field of pharmacology offers a wide range of exciting research paper topics that span from drug discovery and development to clinical pharmacology, neuropharmacology, pharmacokinetics, and beyond. By exploring these topics, students can contribute to the advancement of pharmacological knowledge and make meaningful contributions to the field. Remember to choose a research topic that aligns with your interests and career aspirations, and be sure to consult with your instructors or mentors for guidance throughout your research journey. With dedication, curiosity, and a passion for improving patient care, you have the opportunity to shape the future of pharmacology research.

How to Choose a Pharmacology Research Topic

Choosing the right research paper topic is crucial for a successful academic journey in pharmacology. It allows you to explore your interests, contribute to the field, and showcase your knowledge and skills. However, with the vast scope of pharmacology, selecting a research topic can be a daunting task. In this section, we will provide you with expert advice on how to choose pharmacology research paper topics that are engaging, relevant, and have the potential for significant contribution.

• Identify Your Interests : Start by identifying your areas of interest within pharmacology. Reflect on the topics that have captivated your attention during your coursework or sparked your curiosity. Consider whether you are more inclined towards drug discovery, clinical applications, pharmacokinetics, neuropharmacology, or any other subfield of pharmacology. This self-reflection will help you narrow down your options and select a topic that resonates with your passion.
• Stay Updated with Current Research : To choose a compelling research topic, it is essential to stay updated with the latest advancements and trends in pharmacology. Follow reputable scientific journals, attend conferences, and engage with the pharmacological community to gain insights into the ongoing research and emerging areas of interest. This will help you identify gaps in the current knowledge and select a topic that offers the potential for novel discoveries or addressing existing challenges.
• Consult with Faculty and Experts : Seek guidance from your faculty members, mentors, or experts in the field of pharmacology. They can provide valuable insights and suggest potential research areas based on their expertise and experience. Discuss your interests, goals, and research aspirations with them, and they can help you refine your research topic, provide relevant literature references, and offer valuable advice on the feasibility and scope of your chosen topic.
• Consider Practicality and Resources : When selecting a research topic, consider the practicality and availability of resources. Assess whether the necessary laboratory facilities, equipment, or access to clinical data are readily accessible to conduct your research. Additionally, consider the time and resources required to complete the research within the given timeframe. Choosing a topic that aligns with the available resources will enhance the feasibility and success of your research endeavor.
• Address Current Challenges or Gaps : Pharmacology is a field that constantly evolves, presenting new challenges and unanswered questions. Consider selecting a research topic that addresses current challenges or explores gaps in the existing knowledge. This could involve investigating the mechanisms of drug resistance, exploring novel drug targets, or optimizing drug regimens for specific patient populations. By tackling these challenges, you can contribute to the advancement of pharmacological science and make a meaningful impact.
• Collaborate with Peers : Consider collaborating with fellow students or researchers who share similar research interests. Collaborative research projects can provide a broader perspective, foster knowledge sharing, and enhance the overall quality of your research. Collaborating with peers also allows you to divide the workload, share resources, and receive feedback and support throughout the research process.
• Seek Ethical Considerations : When selecting a pharmacology research topic, it is essential to consider ethical considerations and adhere to the principles of research ethics. Ensure that your chosen topic respects patient confidentiality, follows the guidelines for the ethical use of animal subjects (if applicable), and aligns with the ethical principles outlined by regulatory bodies. Consulting with your institution’s ethics committee or research advisor can help ensure that your research project meets the required ethical standards.
• Evaluate Feasibility and Novelty : Evaluate the feasibility and novelty of your chosen research topic. Consider whether the research question is answerable within the available resources and time constraints. Additionally, assess whether your topic brings something new to the field, whether it fills a knowledge gap, or offers a fresh perspective on an existing topic. A balance between feasibility and novelty is essential for a successful research paper.
• Consult Literature Reviews : Conduct thorough literature reviews on your chosen topic to gain a comprehensive understanding of the existing research. Literature reviews help you identify gaps in the current knowledge and provide a foundation for your research question. They also enable you to build on previous findings, develop a robust research methodology, and position your research within the context of the broader field of pharmacology.
• Remain Flexible : Lastly, remain flexible throughout the process of choosing a research topic. As you delve deeper into the literature and research process, you may discover new avenues of interest or encounter unexpected challenges. It is essential to remain open to refining or adjusting your research topic based on new insights, emerging data, or feedback from your research advisors. Flexibility allows you to adapt and ensure that your research remains relevant and impactful.

Choosing a pharmacology research paper topic is an exciting and important step in your academic journey. By following expert advice, identifying your interests, staying updated with current research, seeking guidance, considering practicality and resources, addressing current challenges or gaps, collaborating with peers, adhering to ethical considerations, evaluating feasibility and novelty, consulting literature reviews, and remaining flexible, you can select a research topic that is engaging, relevant, and has the potential to contribute to the field of pharmacology. Remember, this is your opportunity to explore, innovate, and make a lasting impact in the dynamic field of pharmacology research.

How to Write a Pharmacology Research Paper

Writing a pharmacology research paper requires careful planning, organization, and attention to detail. It is an opportunity for you to showcase your understanding of the subject matter, critical thinking skills, and ability to communicate scientific information effectively. In this section, we will provide you with expert guidance on how to write a pharmacology research paper that is well-structured, informative, and compelling.

• Choose a Well-Defined Research Question : Start by formulating a clear and well-defined research question. Your research question should be focused, specific, and address a gap in the existing knowledge. Consider the significance of your research question in the context of pharmacology and how it contributes to the overall understanding of the field. A well-defined research question sets the foundation for your entire research paper.
• Conduct a Thorough Literature Review : Before diving into your research, conduct a thorough literature review on the chosen topic. Familiarize yourself with the existing research, theories, and findings related to your research question. This will provide you with a solid understanding of the current state of knowledge and help you identify gaps or areas for further investigation. Additionally, the literature review will inform your research methodology and discussion of results.
• Develop a Clear Structure : A well-structured research paper is essential for effectively conveying your ideas and findings. Begin with an engaging introduction that provides background information, context, and clearly states your research question. Follow with a comprehensive literature review that supports your research question and highlights the gaps in knowledge. Next, present your research methodology, including details on sample selection, data collection, and analysis methods. In the results section, present your findings in a clear and organized manner using tables, graphs, or figures as necessary. Finally, discuss your results, interpret their significance, and relate them back to your research question in the discussion section. Conclude with a concise summary of your findings and their implications.
• Use Reliable and Credible Sources : Ensure that the sources you use for your research paper are reliable, credible, and peer-reviewed. Consult reputable scientific journals, textbooks, and conference proceedings. Avoid relying solely on internet sources or non-scholarly publications. Citations are critical to acknowledge the work of other researchers and to support your claims and arguments. Use a consistent citation style, such as APA, MLA, or Chicago, and follow the guidelines carefully.
• Analyze and Interpret Your Data : If your research involves collecting and analyzing data, ensure that your data analysis is thorough and accurate. Use appropriate statistical methods to analyze your data and present the results in a clear and meaningful way. Interpret the findings in the context of your research question and discuss any limitations or potential sources of bias. Remember to relate your findings back to the existing literature and explain how they contribute to the broader understanding of pharmacology.
• Write Clearly and Concisely : Effective scientific writing is clear, concise, and free of unnecessary jargon. Use language that is precise and straightforward, avoiding ambiguous or vague statements. Clearly articulate your ideas and ensure that your arguments are logical and well-supported by evidence. Use appropriate scientific terminology, but also consider your target audience and strive to communicate your findings in a way that is accessible to readers who may not have expertise in pharmacology.
• Pay Attention to Formatting and Style : Follow the formatting and style guidelines specified by your instructor or the target journal. Pay attention to details such as font size, line spacing, margins, and headings. Use subheadings to organize your content and make it easier for readers to navigate. Adhere to the specific citation style required for your paper and ensure that your references are complete and accurate.
• Revise and Edit : Revision and editing are essential steps in the writing process. Take the time to review your research paper for clarity, coherence, and accuracy. Check for grammatical errors, spelling mistakes, and punctuation errors. Ensure that your ideas flow logically and that your paper is well-structured. Consider seeking feedback from peers, instructors, or mentors to gain different perspectives and improve the overall quality of your paper.
• Proofread : Before submitting your research paper, thoroughly proofread it to ensure that it is error-free. Check for any typos, inconsistencies, or formatting issues. Read your paper aloud to catch any awkward phrasing or unclear sentences. It can also be helpful to have someone else read your paper to identify any errors or areas that need improvement.
• Ethical Considerations : Ensure that your research paper adheres to ethical considerations. If your research involved human subjects, ensure that you have obtained the necessary approvals and informed consent. Respect patient confidentiality and anonymity when presenting your research findings. Adhere to the ethical guidelines set by your institution or the relevant regulatory bodies.

Writing a pharmacology research paper requires careful planning, thorough research, effective communication, and attention to detail. By following the expert advice provided in this section, you can develop a well-structured and informative research paper that contributes to the field of pharmacology. Remember to choose a well-defined research question, conduct a thorough literature review, use reliable sources, analyze and interpret your data, write clearly and concisely, pay attention to formatting and style, revise and edit your paper, proofread for errors, and ensure ethical considerations are met. With diligence and commitment, your pharmacology research paper has the potential to make a meaningful impact in the field of pharmacology.

iResearchNet’s Writing Services

At iResearchNet, we understand the challenges that students face when it comes to writing high-quality pharmacology research papers. We recognize the importance of delivering well-researched, well-written, and timely papers that meet the rigorous standards of academic institutions. That’s why we offer a comprehensive range of writing services tailored specifically for students studying pharmacology. With our expertise and commitment to excellence, we are here to provide you with customized solutions to all your research paper needs.

• Expert Degree-Holding Writers : At iResearchNet, we have a team of expert writers who hold advanced degrees in pharmacology and related fields. They have in-depth knowledge of the subject matter and are well-versed in the latest research trends and methodologies. Our writers are experienced in crafting research papers that adhere to the highest academic standards and follow the guidelines provided by your institution.
• Custom Written Works : We understand that each research paper is unique, and that’s why we offer custom-written works tailored to your specific requirements. Our writers will collaborate with you to understand your research question, objectives, and any specific instructions provided by your instructor. This ensures that the final paper is original, well-researched, and meets your expectations.
• In-Depth Research : Our writers are skilled in conducting thorough and comprehensive research on pharmacology topics. They have access to reputable scientific databases, journals, and other reliable sources of information. By utilizing the latest research findings, our writers ensure that your research paper is based on current and relevant literature, enhancing the credibility and academic rigor of your work.
• Custom Formatting : We understand the importance of adhering to specific formatting styles in academic writing. Whether it’s APA, MLA, Chicago/Turabian, or Harvard, our writers are well-versed in these formatting styles and will ensure that your research paper is formatted correctly. This includes citing sources, creating reference lists, and formatting headings, margins, and page numbers according to the required style.
• Top Quality : At iResearchNet, we are committed to delivering top-quality research papers. Our writers pay meticulous attention to detail, ensuring that the content is accurate, coherent, and well-structured. They employ critical thinking skills to analyze and interpret data, present logical arguments, and provide insightful discussions. Our rigorous quality assurance process includes multiple levels of review and editing to ensure that the final paper meets the highest standards of academic excellence.
• Customized Solutions : We understand that every student’s research paper requirements are unique. That’s why we offer customized solutions to meet your specific needs. Whether you require assistance with topic selection, literature review, methodology, data analysis, or any other aspect of your research paper, our writers are here to provide personalized support and guidance.
• Flexible Pricing : We believe that quality academic assistance should be accessible to all students. That’s why we offer flexible pricing options to accommodate different budgetary constraints. Our pricing is competitive and transparent, without compromising on the quality of our services. We offer affordable rates tailored to the specific requirements of your research paper.
• Short Deadlines : We understand that students often face tight deadlines for submitting their research papers. At iResearchNet, we offer short deadlines as quick as 3 hours, ensuring that you receive your paper on time. Our writers are experienced in working under pressure without compromising the quality of the work. We prioritize timely delivery to help you meet your academic deadlines.
• Timely Delivery : We value your time and understand the importance of meeting deadlines. Our writers are committed to delivering your research paper on time, allowing you ample time for review and any necessary revisions. We have a proven track record of timely delivery, ensuring that you can submit your research paper without any concerns.
• 24/7 Support : We provide 24/7 customer support to address any questions or concerns you may have throughout the process. Our friendly and knowledgeable support team is available round the clock to assist you with any queries, provide updates on your paper, or address any issues that may arise. We are dedicated to ensuring a smooth and positive experience for our clients.
• Absolute Privacy : We understand the importance of confidentiality when it comes to academic assistance. At iResearchNet, we prioritize your privacy and guarantee absolute confidentiality. We have strict security measures in place to protect your personal information and ensure that your identity remains anonymous. Your research paper and personal details will be handled with the utmost confidentiality and professionalism.
• Easy Order Tracking : We have developed a user-friendly platform that allows you to easily track the progress of your research paper. You can communicate directly with your assigned writer, provide additional instructions or clarifications, and monitor the status of your paper throughout the writing process. Our streamlined order tracking system ensures transparency and enables effective collaboration.
• Money Back Guarantee : We are confident in the quality of our services and the expertise of our writers. In the unlikely event that you are not satisfied with the final research paper, we offer a money-back guarantee. We are committed to ensuring your complete satisfaction and will work with you to resolve any issues or concerns. Your academic success is our top priority.

At iResearchNet, we are dedicated to providing top-quality writing services tailored to meet the unique needs of students studying pharmacology. Our team of expert writers, in-depth research capabilities, custom formatting, top-quality papers, flexible pricing, timely delivery, 24/7 support, absolute privacy, easy order tracking, and money-back guarantee ensure that your research paper is in capable hands. We are here to support you throughout your academic journey and help you excel in your pharmacology studies. Place your order with iResearchNet and experience the difference of working with a trusted and reliable academic writing service.

Unlock Your Potential with iResearchNet

Are you struggling to write a compelling and well-researched pharmacology research paper? Do you find yourself overwhelmed with the demands of your academic workload? Don’t worry, iResearchNet is here to help you excel in your pharmacology studies and achieve the academic success you deserve.

At iResearchNet, we understand the challenges that students face when it comes to writing high-quality research papers in pharmacology. Our team of expert writers, in-depth research capabilities, and commitment to excellence make us the perfect partner to assist you in your academic journey. Whether you need assistance with topic selection, literature review, methodology, data analysis, or the entire writing process, we are here to provide you with a custom pharmacology research paper that meets your unique requirements.

Don’t let the challenges of writing a pharmacology research paper hinder your academic progress. Unlock your potential and achieve your goals with the support of iResearchNet’s pharmacology writing services. Place your order today and experience unparalleled excellence in academic writing. Our team of expert writers is ready to assist you in crafting a high-quality research paper that will impress your instructors and elevate your academic performance. Trust iResearchNet to be your reliable partner in pharmacology writing.

ORDER HIGH QUALITY CUSTOM PAPER

Main Content

Pharmacology - research topics.

The following Research Topics are led by experts in their field and contribute to the scientific understanding of pharmacology. These Research topics are published in the peer-reviewed journal Frontiers in Pharmacology , as open access articles .

Antiarrhythmic Role of Herbal Medicine and Plant Extracts

The effective treatment of arrhythmias using drug therapy has long posed a significant challenge. Many antiarrhythmic drugs suffer from uncertain efficacy and limited applications due to undesirable side effects. In recent times, herbal medicine and ...

Drug Metabolism and Transport: The Frontier of Personalized Medicine Volume II

This Research Topic is part of a series with: https://www.frontiersin.org/research-topics/44712/drug-metabolism-and-transport-the-frontier-of-personalized-medicine. There are many unique challenges in personalizing drug therapy. Research on ...

Pharmacological Actions of Drugs in the Brain: Exploring the Intricacies and Potential Therapeutic Applications

The Mediterranean Neuroscience Society Conference 2023. The study of pharmacological actions of drugs in the brain is a field that constantly uncovers new insights into the mechanisms of acti...

New Players on the Monoaminergic Field: Relevance to the Mental Disorder

Monoamines, namely, indole- (serotonin/5-HT and melatonin), imidazole- (histamine), and catecholamines (norepinephrine and dopamine), are an important family of neurotransmitters of the vertebrate central nervous system (CNS). <br/><br/>One of the ma...

Biologic Drugs in Immune-Mediated Inflammatory Diseases: Validation, Drug-Utilization, Effectiveness, Regulation, Costs, and Safety in the Real World

Immune-mediated inflammatory diseases (IMID) include many chronic inflammatory conditions having a common pathogenic feature: immune dysregulation. This leads to organ impairs in different clinical settings, such as rheumatologic (ankylosing spondyli...

Ovarian Cancer Targeted Medication: PARP Inhibitors, Anti-Angiogenic Drugs, Immunotherapy, and More – Volume II

This Research Topic is part of a series with:<br/><b><a href="https://www.frontiersin.org/research-topics/45228/ovarian-cancer-targeted-medication-parp-inhibitors-anti-angiogenic-drugs-immunotherapy-and-more">Ovarian Cancer Targeted Medication: PARP ...

Innovative Approaches to Overcome Resistance and Toxicities of Anti-Cancer Drugs

Although diagnosis and treatment of various cancer types have made significant strides recently, drug resistance is a major challenge faced in the cancer clinic. Cancer cells evolve continuously through a combination of genetic mutations, epigenetic ...

Metabolic reprogramming in cancer

Technological advancements over the past few decades have unraveled the diversity and adaptability of tumors, shedding light on key genetic aberrations and metabolic pathways that support tumor growth. Specifically, cancer cells alter their metabolic...

Modulation of the Crosstalk Between Tumor Cells and Microenvironmental Cells by Herbal Medicine

Cancer remains one of the most life-threatening diseases worldwide. Cancer therapies encompass surgical removal of malignant tumors, as well as the utilization of chemotherapeutic or targeted therapeutic drugs to directly eliminate cancer cells, amon...

Network Polypharmacology of ATP-binding Cassette (ABC) and Solute Carrier (SLC) Transporters

Polypharmacology is a research ‘hotspot’ at the intersection of medicinal chemistry, structural biology, clinical pharmacology, and molecular medicine. Having evolved from the specificity paradigm, it is generally accepted that drugs mostly exert the...

Internet Pharmacies and the Online Pharmacy Market: Trends, Perspectives and Challenges

The online pharmacy market is a rapidly developing channel of the pharmaceutical supply since the beginning of the century. Its actual size is yet relatively unknown, thousands of internet pharmacies are accessible on the web. Although online medicin...

Revealing the Unconventional Mechanisms of Mitochondria-Targeting Drugs in Heart-Related Diseases

The heart, as the largest energy consumer within the human body, relies primarily on mitochondria for its energy supply. Mitochondrial functionality is significant in heart disease progression, making it crucial to study and develop targeted medicati...

The Continuing Challenge of Medication Adherence

It is twenty years since the World Health Organization published their influential report on adherence to long-term therapies. Even though this report has been very highly cited and followed by a huge amount of research, treatment adherence continues...

Drug Discovery Derived from Herbal Medicine/Polypeptide for Neurological Diseases

The pursuit of drug candidates for neurological diseases including Parkinson' Disease (PD), Alzheimer's disease (AD), Spinal Cord Injury (SCI), and Neural Tube Defects (NTD), etc, is deemed as challenging due to the undesirable side effects of many d...

Emerging Trends in the Quality Check of Herbal Medicines, Supplements and 'Botanicals'

This Research Topic is dedicated to covering high-level aspects of “Emerging Trends in the Quality Check of Herbal Medicines, Supplements and ‘Botanicals'”. Due to the perceived health benefits that customers feel they obtain, as well as a quickly-ex...

Preventive Potential of Antioxidants in Age-Related Diseases

The worldwide increase in the aged population is emerging as an issue of great concern. The global life expectancy has increased from 66.8 years in 2000 to 73.4 years in 2019. Despite the increasing life expectancy reflecting positive human developme...

Restoring Barrier Function and Immunity: What Roles Can Traditional Medicines Play?

The health of human beings depends on the integrity of the mechanical barrier function of several organs like skin, lungs, and intestine which interact with either exotoxin or endotoxin to prevent them from evading. Besides the mechanical barrier fun...

Application of PKPD Modeling in Drug Discovery and Development

Applying PKPD modeling in drug discovery and development has emerged as a powerful and indispensable approach to understanding the intricate relationship between drug kinetics and pharmacological effects. The integration of PKPD modeling allows resea...

Cellular and Molecular Mechanisms in Metabolic Disorders: Role of Inflammation and Oxidative Stress

The complex relationships between metabolism, inflammation, and oxidative stress are key factors in the development and progression of metabolic disorders, including obesity, type 2 diabetes , cardiovascular disease, and kidney diseases. Altered met...

The Relationship Between Gut Microbiota and Metabolic Diseases

The human gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health. It is involved in various physiological functions, including digestion, vitamin synthesis, and immune system development. Recent research has demon...

Chemistry, Toxicity, Synthesis, Biological and Pharmacological Activities of Coumarins and their Derivatives: Recent Advances and Future Perspectives

Coumarins are compounds found in plants, in bond form as esters or glycosides and also in free form. They are also found in fungi and exert many therapeutic effects. The name ‘coumarin’ is obtained from Dipteryx odorata (Coumarouna odorata Aube), a p...