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Medical Nutrition Therapy: A Case Based Approach

Kathryn M. Kolasa, PhD, RDN, LDN Kathryn M. Kolasa Affiliations Brody School of Medicine at East Carolina University, 3080 Dartmouth Dr, Greenville, NC 27858 Search for articles by this author

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Inclusion of any material in this section does not imply endorsement by the Society for Nutrition Education and Behavior. Evaluative comments contained in the reviews reflect the views of the authors. Review abstracts are either prepared by the reviewer or extracted from the product literature. Prices quoted are those provided by the publishers at the time materials were submitted. They may not be current when the review is published. Reviewers receive a complimentary copy of the resource as part of the review process.

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DOI: https://doi.org/10.1016/j.jneb.2022.02.003

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Exploring the effects of the dietary fiber compound mediated by a longevity dietary pattern on antioxidation, characteristic bacterial genera, and metabolites based on fecal metabolomics

Age-related dysbiosis of the microbiota has been linked to various negative health outcomes. This study aims to investigate the effects of a newly discovered dietary fiber compound (DFC) on aging, intestinal m...

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Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer

Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise ...

Association between dietary antioxidant capacity and type 2 diabetes mellitus in Chinese adults: a population-based cross-sectional study

Higher intakes of dietary antioxidants have been linked to a lower type 2 diabetes mellitus (T2DM) risk. However, few studies have comprehensively examined the overall dietary antioxidant capacity, assessed by...

Unraveling the therapeutic efficacy of resveratrol in Alzheimer’s disease: an umbrella review of systematic evidence

Resveratrol (RV), a natural compound found in grapes, berries, and peanuts, has been extensively studied for its potential in treating Alzheimer’s disease (AD). RV has shown promise in inhibiting the formation...

Higher ultra-processed food intake is associated with an increased incidence risk of cardiovascular disease: the Tehran lipid and glucose study

Cardiovascular disease (CVD) is a major cause of death worldwide, although limited data are currently available regarding the impact of consuming ultra-processed food (UPF) on its incidence. Given the increase...

The acute effect of a β-glucan-enriched oat bread on gastric emptying, GLP-1 response, and postprandial glycaemia and insulinemia: a randomised crossover trial in healthy adults

The cereal fibre β-glucan reduces postprandial glycaemia, however, the underlying mechanisms are not fully understood. Thus, the aim of this study was to investigate the acute effect of a β-glucan-enriched oat...

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress

Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely asso...

Enhancing cardiometabolic health: unveiling the synergistic effects of high-intensity interval training with spirulina supplementation on selected adipokines, insulin resistance, and anthropometric indices in obese males

This study investigated the combined effects of 12 weeks of high-intensity interval training (HIIT) and spirulina supplementation on adipokine levels, insulin resistance, anthropometric indices, and cardioresp...

The difference between 2-hour post-challenge and fasting plasma glucose associates with the risk of cardiovascular disease in a normoglycemic population: the Tehran lipid and glucose study

Elevated fasting plasma glucose (FPG) and 2-hour post-challenge glucose (2hPG) levels are known to be independent risk factors for cardiovascular disease (CVD). However, there is limited data on the associatio...

Effects of a dietary intervention with lacto-ovo-vegetarian and Mediterranean diets on apolipoproteins and inflammatory cytokines: results from the CARDIVEG study

Apolipoproteins have been recently proposed as novel markers of cardiovascular disease (CVD) risk. However, evidence regarding effects of diet on apolipoproteins is limited.

Association of gestational metabolic syndrome with the Chinese Healthy Eating Index in mid-pregnancy: a cross-sectional study

This study aims to investigate the relationship between gestational metabolic syndrome (GMS) and the Chinese Healthy Eating Index (CHEI) in mid-pregnancy, and to identify potentially beneficial or high-risk di...

Oxyresveratrol attenuates bone resorption by inhibiting the mitogen-activated protein kinase pathway in ovariectomized rats

Bone is continuously produced by osteoblasts and resorbed by osteoclasts to maintain homeostasis. Impaired bone resorption by osteoclasts causes bone diseases such as osteoporosis and arthritis. Most pharmacol...

Revisiting the interconnection between lipids and vitamin K metabolism: insights from recent research and potential therapeutic implications: a review

Vitamin K is a lipophilic vitamin, whose absorption, transportation, and distribution are influenced by lipids. The plasma vitamin K level after supplementation is predominantly a lipid-driven effect and indep...

D-mannose promotes the degradation of IDH2 through upregulation of RNF185 and suppresses breast cancer

D-mannose, an epimer of glucose, which is abundant in some fruits, such as cranberry, has been previously reported to inhibit urinary tract infection. In recent years, the potential function of D-mannose has b...

Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic r...

Effect of probiotic supplementation on lipoprotein-associated phospholipase A2 in type 2 diabetic patients: a randomized double blind clinical controlled trial

It has been recently reported that lipoprotein-associated phospholipase A2 (Lp-PLA2) may predict the risk of cardiovascular disease. The effect of multi-strain probiotics on Lp-PLA2 in patients with type 2 dia...

Deficiency of Trex1 leads to spontaneous development of type 1 diabetes

Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the importa...

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Amelioration of Atherosclerosis by lycopene is linked to the modulation of gut microbiota dysbiosis and related gut-heart axis activation in high-fat diet-fed ApoE −/− mice

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Correction: The association between dietary quality scores with C-reactive protein and novel biomarkers of inflammation platelet-activating factor and lipoprotein-associated phospholipase A2: a cross-sectional study

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Exploring the underlying mechanisms of fisetin in the treatment of hepatic insulin resistance via network pharmacology and in vitro validation

To characterize potential mechanisms of fisetin on hepatic insulin resistance (IR) using network pharmacology and in vitro validation.

Intrauterine growth restriction alters kidney metabolism at the end of nephrogenesis

This study investigated the effect of uteroplacental insufficiency (UPI) on renal development by detecting metabolic alterations in the kidneys of rats with intrauterine growth restriction (IUGR).

A comparative study on indicators of vitamin A status and risk factors for sensitivity and specificity of the methods to detect vitamin A deficiency

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Early adulthood weight change, midlife “Life’s essential 8” health status and risk of cardiometabolic diseases: a chinese nationwide cohort study

The association between weight change during early adulthood and cardiometabolic diseases remains uncertain in Chinese population. Whether the association varies with comprehensive cardiovascular health (CVH) ...

Healthy lifestyle scores associate with incidence of type 2 diabetes mediated by uric acid

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Effect of weight change on the association between overall and source of carbohydrate intake and risk of metabolic syndrome: Tehran lipid and glucose study

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The Correction to this article has been published in Nutrition & Metabolism 2023 20 :52

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Correction: The effects of a low carbohydrate diet combined with partial meal replacement on obese individuals

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Serum cholinesterase is associated with incident diabetic retinopathy: the Shanghai Nicheng cohort study

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Nutrition & Metabolism

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Nutrient Utilization in Humans: Metabolism Pathways

Where does the energy that makes life possible come from? Humans obtain energy from three classes of fuel molecules: carbohydrates, lipids, and proteins. The potential chemical energy of these molecules is transformed into other forms, such as thermal, kinetic, and other chemical forms.

Nutrients of Human Metabolism

Carbohydrates, lipids, and proteins are the major constituents of foods and serve as fuel molecules for the human body. The digestion (breaking down into smaller pieces) of these nutrients in the alimentary tract and the subsequent absorption (entry into the bloodstream) of the digestive end products make it possible for tissues and cells to transform the potential chemical energy of food into useful work.

The major absorbed end products of food digestion are monosaccharides, mainly glucose (from carbohydrates); monoacylglycerol and long-chain fatty acids (from lipids); and small peptides and amino acids (from protein ). Once in the bloodstream, different cells can metabolize these nutrients. We have long known that these three classes of molecules are fuel sources for human metabolism , yet it is a common misconception (especially among undergraduates) that human cells use only glucose as a source of energy. This misinformation may arise from the way most textbooks explain energy metabolism, emphasizing glycolysis (the metabolic pathway for glucose degradation) and omitting fatty acid or amino acid oxidation. Here we discuss how the three nutrients (carbohydrates, proteins, and lipids) are metabolized in human cells in a way that may help avoid this oversimplified view of the metabolism.

Historical Overview of Energy Metabolism

One of Lavoisier's main questions at this time was: How does oxygen's role in combustion relate to the process of respiration in living organisms? Using a calorimeter to make quantitative measurements with guinea pigs and later on with himself and his assistant, he demonstrated that respiration is a slow form of combustion (Figure 1). Based on the concept that oxygen burned the carbon in food, Lavoisier showed that the exhaled air contained carbon dioxide, which was formed from the reaction between oxygen (present in the air) and organic molecules inside the organism. Lavoisier also observed that heat is continually produced by the body during respiration. It was then, in the middle of the nineteenth century, that Justus Liebig conducted animal studies and recognized that proteins, carbohydrates, and fats were oxidized in the body. Finally, pioneering contributions to metabolism and nutrition came from the studies of a Liebig's protégé, Carl von Voit, and his talented student, Max Rubner. Voit demonstrated that oxygen consumption is the result of cellular metabolism, while Rubner measured the major energy value of certain foods in order to calculate the caloric values that are still used today. For example, carbohydrates and proteins produce approximately 4 kcal/g of energy, whereas lipids can generate up to 9 kcal/g. Rubner's observations proved that, for a resting animal, heat production was equivalent to heat elimination, confirming that the law of conservation of energy, implied in Lavoisier's early experiments, was applicable to living organisms as well. Therefore, what makes life possible is the transformation of the potential chemical energy of fuel molecules through a series of reactions within a cell, enabled by oxygen, into other forms of chemical energy, motion energy, kinetic energy, and thermal energy.

Energy Conservation: Mechanisms of ATP Synthesis

Energy metabolism is the general process by which living cells acquire and use the energy needed to stay alive, to grow, and to reproduce. How is the energy released while breaking the chemical bonds of nutrient molecules captured for other uses by the cells? The answer lies in the coupling between the oxidation of nutrients and the synthesis of high-energy compounds, particularly ATP , which works as the main chemical energy carrier in all cells.

There are two mechanisms of ATP synthesis: 1. oxidative phosphorylation , the process by which ATP is synthesized from ADP and inorganic phosphate (Pi) that takes place in mitochondrion; and 2. substrate-level phosphorylation, in which ATP is synthesized through the transfer of high-energy phosphoryl groups from high-energy compounds to ADP. The latter occurs in both the mitochondrion, during the tricarboxylic acid (TCA) cycle, and in the cytoplasm , during glycolysis. In the next section, we focus on oxidative phosphorylation, the main mechanism of ATP synthesis in most of human cells. Later we comment on the metabolic pathways in which the three classes of nutrient molecules are degraded

Oxidative Phosphorylation: The Main Mechanism of ATP Synthesis in Most Human Cells

The electrons are transferred from NADH to O 2 through three protein complexes: NADH dehydrogenase, cytochrome reductase, and cytochrome oxidase. Electron transport between the complexes occurs through other mobile electron carriers, ubiquinone and cytochrome c. FAD is linked to the enzyme succinate dehydrogenase of the TCA cycle and another enzyme, acyl-CoA dehydrogenase of the fatty acid oxidation pathway. During the reactions catalyzed by these enzymes, FAD is reduced to FADH 2 , whose electrons are then transferred to O 2 through cytochrome reductase and cytochrome oxidase, as described for NADH dehydrogenase electrons (Figure 2).

The electron transfer through the components of ETS is associated with proton (H + ) pumping from the mitochondrial matrix to intermembrane space of the mitochondria. These observations led Peter Mitchell, in 1961, to propose his revolutionary chemiosmotic hypothesis. In this hypothesis, Mitchell proposed that H + pumping generates what he called the proton motive force, a combination of the pH gradient across the inner mitochondrial membrane and the transmembrane electrical potential, which drives the ATP synthesis from ADP and Pi. ATP is synthesized by the ATP synthase complex, through which H+ protons return to the mitchondrial matrix (Figure 2, far right). Paul Boyer first described the ATP synthase catalytic mechanism and showed both that the energy input from the H + gradient was used for ATP release from the catalytic site, and that the three active sites of the enzyme worked cooperatively in such a way that ATP from one site could not be released unless ADP and Pi were available to bind to another site.

Oxidation of Carbohydrates, Proteins, and Fats Converge on the Tricarboxylic Acid Cycle

The TCA cycle is also known as the Krebs cycle, named after its discoverer, Sir Hans Kreb. Krebs based his conception of this cycle on four main observations made in the 1930s. The first was the discovery in 1935 of the sequence of reactions from succinate to fumarate to malate to oxaloacetate by Albert Szent-Gyorgyi, who showed that these dicarboxylic acids present in animal tissues stimulate O 2 consumption. The second was the finding of the sequence from citrate to α-ketoglutarate to succinate, in 1937, by Carl Martius and Franz Knoop. Next was the observation by Krebs himself, working on muscle slice cultures, that the addition of tricarboxylic acids even in very low concentrations promoted the oxidation of a much higher amount of pyruvate, suggesting a catalytic effect of these compounds. And the fourth was Krebs's observation that malonate, an inhibitor of succinate dehydrogenase, completely stopped the oxidation of pyruvate by the addition of tricarboxylic acids and that the addition of oxaloacetate in the medium in this condition generated citrate, which accumulated, thus elegantly showing the cyclic nature of the pathway.

Pathways for Nutrient Degradation that Converge onto the TCA Cycle

In the second part of glycolysis, the majority of the free energy obtained from the oxidation of the aldehyde group of glyceraldehyde 3-phosphate (G3P) is conserved in the acyl-phosphate group of 1,3- bisphosphoglycerate (1,3-BPG), which contains high free energy. Then, part of the potential energy of 1,3BPG, released during its conversion to 3-phosphoglycerate, is coupled to the phosphorylation of ADP to ATP. The second reaction where ATP synthesis occurs is the conversion of phosphoenolpyruvate (PEP) to pyruvate. PEP is a high-energy compound due to its phosphate-ester bond, and therefore the conversion reaction of PEP to pyruvate is coupled with ADP phosphorylation. This mechanism of ATP synthesis is called substrate-level phosphorylation.

For complete oxidation, pyruvate molecules generated in glycolysis are transported to the mitochondrial matrix to be converted into acetyl-CoA in a reaction catalyzed by the multienzyme complex pyruvate dehydrogenase (Figure 5). When Krebs proposed the TCA cycle in 1937, he thought that citrate was synthesized from oxaloacetate and pyruvate (or a derivative of it). Only after Lipmann's discovery of coenzyme A in 1945 and the subsequent work of R. Stern, S. Ochoa, and F. Lynen did it become clear that the molecule acetyl-CoA donated its acetyl group to oxaloacetate. Until this time, the TCA cycle was seen as a pathway to carbohydrate oxidation only. Most high school textbooks reflect this period of biochemistry knowledge and do not emphasize how the lipid and amino acid degradation pathways converge on the TCA cycle.

The Fatty Acid Oxidation Pathway Intersects the TCA Cycle

Amino acid transamination/deamination contributes to the tca cycle, references and recommended reading.

Holmes, F. L. Lavoisier and the Chemistry of Life . Madison: University of Wisconsin Press, 1985.

Krebs, H. Nobel Prize Lecture (1953) . Nobelprize.org, 2010.

Kresge, N., Simoni, R. D., & Hill, R. L. ATP synthesis and the binding change mechanism: The work of Paul D. Boyer. Journal of Biological Chemistry 281 , e18 (2006).

Lusk, G. The Elements of the Science of Nutrition , 4th ed. Philadelphia: W. B. Saunders, 1931.

Luz, M. R. M. P. Glucose as the sole metabolic fuel: A study on the possible influence of teachers' knowledge on the establishment of a misconception among Brazilian high school stucents. Advances in Physiological Education 32 , 225–230 (2008) doi:10.1152/advan.00050.2007.

Luz, M. R. M. P. et al . Glucose as the sole metabolic fuel: The possible influence of formal teaching on the establishment of a misconception about the energy-yielding metabolism among Brazilian students . Biochemistry and Molecular Biology Education 36 , 407–416 (2008) doi:10.1002/bmb.20235.

Oliveira, G. A. et al . Students' misconception about energy yielding metabolism: Glucose as the sole metabolic fuel. Advances in Physiological Education 27 , 97–101 (2003 doi:10.1152/advan.00009.2003.

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Journal of Health, Metabolism and Nutrition Studies is a peer-reviewed journal that publishes original research articles, reviews, and case studies covering the broad and multidisciplinary field of health sciences, metabolism and human nutrition. This interdisciplinary journal serves as a platform for researchers, healthcare professionals, nutritionists, and practitioners to contribute to the understanding of the complex relationships between health, metabolism, and nutritional factors. Encompassing a broad spectrum of topics, including food science and technology, metabolic disorders, nutritional interventions, dietary patterns, and their impact on health outcomes, the journal aims to address challenges and opportunities in the dynamic fields of health, metabolism, and nutrition. As an open-access publication, it promotes the accessibility of high-quality research, fostering collaboration and knowledge exchange on a global scale. The journal strives to contribute to evidence-based practices, inform public health initiatives, and advance our understanding of the crucial connections between lifestyle, nutrition, and overall well-being.

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http://orcid.org/0000-0002-1457-5070 Jenny Blythe 1 ,
Timothy Eden 1 , 2 , 3 ,
http://orcid.org/0000-0002-2163-2619 Elaine Macaninch 3 , 4 , 5 ,
http://orcid.org/0000-0003-2920-9847 Kathy Martyn 3 , 4 , 5 ,
Sumantra Ray 3 ,
Nimesh Patel 1 and
Karin Fernandes 1
1 Barts and The London School of Medicine and Dentistry , Queen Mary Universoty of London , London , UK
2 Imperial College Healthcare NHS Trust , London , UK
3 St John's Innovation Centre , NNEdPro Global Centre for Nutrition & Health , Cambridge , UK
4 Nutrition and Dietetics , Brighton and Sussex University Hospitals NHS Trust , Brighton , UK
5 SHS , University of Brighton , Brighton , UK
Correspondence to Dr Jenny Blythe, Barts and The London School of Medicine and Dentistry, London, UK; j.blythe{at}qmul.ac.uk

https://doi.org/10.1136/bmjnph-2022-000513

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nutrition assessment
nutritional treatment
nutrient deficiencies
preventive counselling

It has already been recognised both nationally and internationally that medical undergraduate teaching in nutrition is limited. 1–3 Despite the development of a more detailed nutrition curriculum in 2013 by the UK Intercollegiate Group on Nutrition (ICGN), 4 there has been little guidance on its implementation or information on its uptake and impact on nutrition in medical education. In 2016, all UK medical school faculty were invited to participate in a survey of current nutrition training, and one-third (11 of 32) of medical schools responded. 5 Three felt that nutrition training was already adequate, which they reported was due to increased teaching time and better organisation. The presence of a ‘nutrition lead’ was associated with greater mean dedicated nutrition teaching hours (25.4 vs 16.2) and greater likelihood of teaching the four core nutrition topics from the ICGN nutrition curriculum (5/5 vs 2/5, p=0.08). The majority of responders felt their training was inadequate. Cited barriers included ‘a lack of prioritisation’, an ‘inability to devote time to nutrition’ and a ‘difficulty organising topics and teaching sessions’.

GMC Outcomes for graduates diet and nutrition-related outcomes

GMC outcomes for graduates

To recognise where addiction, poor nutrition, self-neglect, environmental exposure or financial or social deprivation are contributing to ill health. And take action by seeking advice from colleagues and making appropriate referrals.

Newly qualified doctors must be able to apply biomedical scientific principles, methods and knowledge to medical practice and integrate these into patient care. This must include nutrition (among other considerations).

To discuss the role and impact of nutrition to the health of individual patients and societies.

They must be able to: explain the concept of wellness or well-being as well as illness, and be able to help and empower people to achieve the best health possible, including promoting lifestyle changes such as smoking cessation, avoiding substance misuse and maintaining a healthy weight through physical activity and diet.

Communicate clearly, sensitively and effectively when discussing issues that may be sensitive for the patient, such as alcohol consumption, smoking, diet and weight management or sexual behaviour.

GMC, General Medical Council.

Most recently in 2021, the Association for Nutrition, published its UK Undergraduate Curriculum in Nutrition for Medical Doctors , outlining explicit knowledge, assessment and skills in nutrition as well as expected ‘graduate fundamentals’. 7 The report acknowledged that as well as the five GMC outcomes where nutrition was specifically mentioned, that ‘nutrition and its role in health and disease can also be applicable to many more outcomes and applies across multiple clinical areas’. However, despite the report including ‘Teaching Points’ under their relevant curriculum statements, there is currently no further guidance given in regard to either implementation or evaluation of nutrition curriculum.

This paper aims to address this gap by providing case study examples of nutrition teaching and evaluation and sharing points for practice from the teaching teams. We use a realist review strategy for synthesising the evidence, as this has been recognised as an effective strategy to focus on providing explanations for why interventions may or may not work, in what contexts, how and in what circumstances. 8

Case study 1: working with third sector organisations – Barts and the London and Bags of Taste

There was the opportunity to expand the nutrition curriculum within the Barts and The London timetable, specifically within the general practice (GP) teaching time allocation. The academic GP department was put in touch with local organisation Bags of Taste through a practice-based social prescriber.

Bags of Taste is a cooking and dietary behaviour change programme, and works specifically with people in poverty to improve their diets and finances. 9 Their four-stage programme, based on behaviour change methodologies, is outlined in box 2 below.

Outline of bags of taste 4-stage programme (9)

Outreach to people who would not normally attend a cooking class.

Community based, free, cooking classes teach people how to make £1 meals.

£3 bags of ingredients, sourced locally, sufficient for four meals, commit participants to continuous learning at home.

Keep participants engaged long-term by joining the volunteer workforce (bagging up ingredients and teaching on future courses)

To date, the programme has taught over 2500 members of the public, and provided ingredients bags for over 30 000 meals. Post course survey data has shown that participant’s takeaway consumption has reduced 50%–100% with up to 30% increase in vegetable consumption and typical household savings of approximately £1400 per annum. 9

Year 3 medical students were all allocated to spend a half-day with the organisation’s representatives in small groups (maximum 12 students) based in a community setting. Apart from lectures related to nutrition metabolism, the students had had no previous teaching on nutrition. An initial meeting with medical school representatives from the GP academic department and Bags of Taste had established joint educational aims.

After a brief introduction to the organisation, students observed a recipe from the course being cooked, and undertook a short practical cooking session, where there was the opportunity to discuss food poverty.

At the end of the session, students were given a bag of ingredients to take home. They were invited to cook the recipe they had observed at home, just like participants on the course would be expected to do. The students were also asked to write a reflection about what the activity had taught them overall about barriers to healthy eating. A thematic analysis of the reflections submitted by the students was then undertaken.

A total of 228 number of students undertook the half day of teaching, and over 85% either agreed or strongly agreed with the statement ‘I enjoyed the session with Bags of Taste’. A summary of the main themes and sub-themes derived from thematic analysis of the reflections is summarised below ( table 1 ).

View inline

Summary of themes and subthemes from medical student feedback

A joint project between educationalists and charity sector organisations is an example of interprofessional education (IPE), defined as ‘occasions when two or more professions learn with, from and about each other to improve collaboration and the quality of care’. 10 In such IPE projects, it is important to establish shared language and goals, on occasion defining explicitly, to improve engagement between parties. The joint educational goals established, the written reflection activity and the placement of an IPE activity mid-way in the curriculum have all been acknowledged as effective IPE techniques. 11

It was initially considered running the half-day teaching in a medical school building, but not only was it felt the activity would have higher fidelity run in a community setting, it also proved impossible to find an approved educational setting to undertake a cooking demonstration. There is a certain paradox that as medical student educators we are encouraged to be innovative and provide inspiring educational experiences for our students, but then do not have the appropriate resources or mechanisms ‘in-house’ to undertake them. Finally, the cost of running the course was ultimately prohibitive in continuing the activity in its initial format, although Bags of Taste have remained participants in teaching via contribution to a problem-based learning scenario involving food poverty.

Take-home messages

When working across organisations, it is important initially to establish joint goals and anticipate any barriers in terms of indemnity, delivery and remittance.

It is important to provide scaffolding to students when we expect them to work with professionals outside their own specialty and spheres of knowledge to support IPE learning.

Where nutrition teaching is placed in the curriculum, and by which academic discipline it is championed (eg, basic sciences, public health, primary care), will impact on both how it is delivered, and how it is perceived by both the student body and the educational institution.

Case study 2: specialist nutrition medical educator – creation of a new role at Brighton and Sussex Medical School

Following the development of the ICGN nutrition curriculum 4 and as part of a strategy to implement the recommendations, a 2015 Brighton and Sussex Medical School (BSMS) curriculum review was undertaken. It revealed that nutrition was only explicitly included in a single first-year module, although it was implicit within other aspects of the curriculum (including symposia). The review concluded that although nutrition education was present, explicit signposting depended very much on the interests of individual lecturers and was not linked to prior or future learning or included as key objectives. Therefore, nutrition teaching was not always obvious to the learners, there was no explicit nutrition education strand, and limited evidence of assessment or progression of learning.

Key recommendations of the review included the creation of a nutrition lead post and improved integration of nutrition throughout the curriculum, so the relevance of nutrition to clinical conditions would be discussed in context. A further recommendation was to have explicit nutrition content within taught modules, including assessment within examinations and to increase clinical opportunities to allow students to participate in nutrition related clinics and research projects.

In response, BSMS developed the role of a research and education dietitian to work with a Principal Lecturer in Nutrition alongside the Faculty, and to act as the ‘Nutrition Lead’ to integrate nutrition into the existing spiral curriculum. This role involved working on the findings of the curriculum review; to clearly identify where nutrition teaching was already taught and where gaps were present. By working with curriculum module leads, opportunities for increasing nutrition content were identified with clear learning objectives and assessment strategies to create a more cohesive and visible nutrition strand.

In 2019, a 2-year review revealed that explicit nutrition content had increased from inclusion in one module in 2015 to nine modules in 2019.

Nutrition is now integrated into undergraduate modules through either direct lectures or symposia, with clinical exposure across the first 4 years of the curriculum, and opportunities in the final year within student rotations to engage with nutrition and dietetic staff. Nutrition education includes mandatory lectures, tutorials and learning resources as well as training in clinical nutrition assessment and communication skills. In addition, students can choose self-selected components and nutrition-related research projects.

The development of a clear nutrition strand has supported an increasing number of medical students approaching faculty for nutrition related research projects, resulting in the publication of peer-reviewed papers and UK and international conference presentations. 12–14 In addition, medical students have developed a student-led volunteering opportunity, An Apple a Day 15 to deliver teaching sessions in local secondary schools focusing on delivering core health and healthy eating messages. Further changes noted include an increasing number of students choosing to intercalate on nutrition related and public health topics, and faculty now contacting nutrition educators (rather than vice versa) to request inclusion of nutrition related content into their modules.

Research into the efficacy of teaching and student feedback is currently underway. Changes in nutrition knowledge, attitudes and practices as well as qualitative data on student experience is also currently being investigated.

The sustainability of ensuring that a medical school has nutrition content embedded in their curriculum and a dedicated nutrition lead with the knowledge and expertise to develop and support the delivering of nutrition education is challenging. To ensure continuity it is important that faculty value the importance of nutrition, alongside other medical specialties, as identified by the GMC 6 and the NHS Long Term Plan 16 and recognised in the forthcoming Medical Licensing Examination. 17

The medical school also was a key actor in the development of ERImNN (education and research in medical nutrition network), linking educators already delivering or interested in nutrition education, students, patient educators, public health and the third sector, in order to share resources and to increase the capacity of nutrition education within BSMS. 18

Increasing visibility of nutrition and involving a wide range of different professionals, including doctors, helps to change the culture and normalise nutrition within the curriculum.

Creating roles with specific responsibility for teaching helps to better match nutrition and incorporate, where relevant. Due to challenges with curriculum space, nutrition can be added in small (sometimes as little as a 15 min) chunks.

Medical students and practicing doctors are key in driving change and are best placed to advise on opportunities to include nutrition in their learning.

Practicing doctors are key, to act as role models supporting the delivery of nutrition education and demonstrating how nutrition is situated within their practice

Sustainability of nutrition teaching depends on a team approach (ERimNN) that includes medical students and faculty (rather than only relying on one individual nutrition champion).

Case study 3: development of a nutrition online learning module at Barts and The London Medical School

A nutrition online learning pilot was designed by a dual-trained dietitian and junior doctor (who had previously delivered Foundation Doctor training in nutrition) and a GP academic at the medical school. The medical school curriculum nutrition learning outcomes were used to form the basis of the content.

A PowerPoint presentation was initially made of the content and then this was developed into an interactive e-learning package and launched on the QMUL virtual learning environment (VLE) with support from the e-learning technician based at the medical school.

The content of the learning was a mix of didactic information and spot diagnoses via vignette or photographs, multiple choice questions, free text responses to questions and interactive activities (such as identifying specific foods containing gluten from a longer list of options).

Students were allocated to complete the online learning during one of their three academic terms in year 3. The online learning was allocated a 3-hour timeslot in the timetable for students to complete it. However, as the online learning was available for a 4-week period each term, it could be accessed as many times as the student wished to during that time. It was also reopened for all students in the run-up to the end of years exams.

Evaluation of the intervention was twofold. First, before and after the online learning, students were asked to rate their confidence in regard to 10 parameters about knowledge of nutrition. At the end of the package, students were also asked to rate the package in terms of content and volume, and also given the opportunity to provide free text feedback.

Second, in terms of evaluating the impact on learning, a related end-of-year practical ‘OSCE’ station was included.

A total of 240 third year students completed the online learning. There was a significant increase in confidence in all ten measured confidence parameters when tested with a Wilcoxon two-way t-test.

On a Likert scale, the majority of students either agreed or strongly agreed that the online content was appropriate, particularly highlighting the interactivity of the module as a useful tool in the free text. Free text allowed students to suggest improvements which included increased use of video and audio formats, reducing overall volume and creating the ability to stop and save the package and rejoin at a later time.

In the nutrition-related OSCE station, students achieved a mean station score of 7.4/10, with this and other examination metrics (such as fail rate and SD) comparable to other stations in the examination.

E-learning has gained popularity due to the potential benefits of allowing learners to tailor the pace and content of courses to their individual needs, increasing the accessibility of information to remote learners, decreasing costs and facilitating frequent content updates. 19 The technology required to develop this package was minimal, as an annotated PowerPoint presentation was quickly adapted to an interactive e-learning package on a VLE. A variety of formats to the learning was mindful of individual learning styles 20 and data on immediate impact on knowledge as well as content feedback could be collected, which may have been more challenging if content had been delivered in a lecture format.

In terms of future development, the plan is to modify the technology to allow breaking of up the learning, introduce either short videos and/or audio files within the package, and alter the balance between text and activities. External national accreditation of the module is also being explored.

Aligning learning outcomes to recognised internal and external learning outcomes (eg, medical school curriculum and GMC Outcomes for graduates) strengthened the case for adoption of the online module as core curriculum content. Likewise, linking learning to assessment and linking to external accreditation increases legitimacy of the activity with the student body.

Technology to develop the module was simple, but specific and protected time from the E-Learning Fellow (or equivalent) was required.

Feedback from students after the pilot allowed development of the platform in terms of creating a more effective balance of didactic and interactive material, as well as incorporating evidence from the literature of effective e-learning models.

The three case studies approached integrating nutrition education into the undergraduate medical curriculum in various different formats, but common themes across these innovations can be drawn out:

Curriculum issues: The undergraduate curriculum is already ‘packed’, 21 and the opportunity to include new content can be seized as an opportunity when an opening arises (such as in case studies 1 and 3), or as part of a recommendation post curriculum review (case study 2). The choice between making any new content core or optional, and its place and delivery format within the overall curriculum, will depend on many factors, and involve multiple academic stakeholders with various levels of power-as Prideuax reminds us, curriculum is ‘the result of human agency…often contested and problematic’. 22 Presenting new curriculum to decision-makers as a ‘solution’ to a current curriculum problem for them is one pragmatic suggestion from the authors to increase its chances of adoption, as well as explicit signposting and mapping content to internal curriculum and external (eg, GMC) outcomes. Mechanisms to support visibility and sustainability, including the embedding of nutrition into core learning outcomes and examinations as well as building a pool of qualified educators and resources for delivery, is key.

In this paper, we demonstrate how a range of different teaching methods can be used to reflect varied needs of medical schools to be easily integrated to compliment and enhance current teaching and is realistic within other priority subjects. The role of leadership and advocacy to champion nutrition education is also highlighted.

Legitimacy issues: as nutrition education content has historically been hidden and not explicit, finding its ‘place’ alongside the traditional basic and clinical science can be problematic for some stakeholders, including students and some academics. The authors’ experiences were often that nutrition was not viewed as ‘core’ by all stakeholders; it can be argued the decision to revise specific nutrition outcomes in the most recent edition of GMC Outcomes for graduates was a backwards step for explicit nutrition presence in the undergraduate curriculum. Explicitly mapping to internal and external outcomes, assessing nutrition-related outcomes in high stakes exams, and the physical presence of Nutrition Leads and Champions all assisted Nutrition to find legitimacy within the curriculum. Case 2 highlights the importance of the Nutrition Lead in terms of curriculum implementation, but also the importance of the multi-disciplinary team to support sustainability and to champion qualified doctor professional role models.

Interprofessional issues: Nutrition as a discipline has traditionally been delivered by a multiprofessional team, reflecting its clinical, behavioural and social constructs, and as such, the most effective education will need multi-professional teams across a range of disciplines and professions involved in its design and delivery. Case 1 took a public health and social science approach, while case 3 content was designed by clinicians from across medical and allied medical professional disciplines. IPE theory can support initial curriculum design and ongoing evaluation. As discussed, the focus of nutrition needs to reflect the module in which this is placed, where the practical application can clearly be related back to the role of a doctor within the wider multi-professional team. For example, the role of nutrition assessment and monitoring of disease related malnutrition in a clinical setting is very different to a public health role in disease prevention. It is important therefore that nutrition teaching is included across different modules to support clinical reasoning skills and appropriate application to different clinical settings. This includes when to refer on to nutrition professionals or how to link to community or third sector organisations. The authors recommend further research into nutrition education IPE with the potential to link multiple healthcare students and professionals. This may help to demonstrate distinct and shared roles and responsibilities for nutrition care across public health and clinical settings.

Further considerations

The need to consider the role of nutrition education in the undergraduate curriculum has never been greater, with increased focus on the role nutrition plays in prevention, treatment and recovery from COVID-19, 23–25 adding to what we already know about the leading role nutrition plays in the risk of metabolic disease. Furthermore, nutrition inequality has also been exposed as both a risk factor for COVID-19 26 and as a consequence of COVID-19 containment measures. 27 There are further concerns on how COVID-19 is likely to widen financial and racial disparities in health. 28 The relationship between poor diets and poverty could be explored in the medical school curriculum via public health and social science teaching. Medical students of today are the advocates of the patients of tomorrow and need to be equipped with broader societal concepts underpinning health risks and health inequalities to support the implementation of clinical sciences across diverse populations. The student voice is powerful and their engagement in innovative curriculum is imperative for its long-term embedding.

All of our cases use an IPE model for delivery to help solve the catch-22 situation that current doctors are not trained in nutrition. This model requires the use of other health professionals such as dietitians that, while providing the appropriate knowledge, may not reflect the best way to implement nutrition into medical practice.

Without suitably trained doctors as role models, students may not appreciate their role in nutrition care, thinking that this is solely the job of nutrition professionals. However, if doctors lack a basic understanding of nutrition and the skills to screen for and diagnose nutrition problems, patients will likely be missed.

The authors hope by sharing these case studies and demonstrating how nutrition can be included within traditional medical curricula using a variety of educational strategies, that it can provide a recipe, excusing the pun, for other institutions.

Data availability statement

No data are available.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

Given that this was curriculum development, formal ethical approval was not required.

Dimaria-Ghalili RA ,
Edwards M ,
Friedman G , et al
Fitzpatrick L ,
General Medical Council
Association for Nutrtion
Greenhalgh T ,
Westhorp G , et al
↵ Bags of Taste . Available: https://bagsoftaste.org/ [Accessed 30 Jun 22 ].
↵ The Centre for the Advancement of Interprofessional Education . Available: https://www.caipe.org [Accessed 30 Jun 22 ].
Winchester RL ,
Macaninch E , et al
Chakera AJ ,
Macaninch E
↵ An Apple A Day Work Book . Available: http://blogs.brighton.ac.uk/anappleaday/ [Accessed 30 Jun 22 ].
↵ NHS Long Term Plan . Available: https://www.longtermplan.nhs.uk/ [Accessed 30 Jun 2022 ].
Kwag KH , et al
Crowley J ,
Cawood AL ,
Walters ER ,
Smith TR , et al
Office for National Statistics
Weiser SD ,
Palar K , et al
Health Foundation/ Institute of health Equity

Twitter @DrTimothyEdenRD, @macaninch

Contributors JB, EM and KM created the first draft. JB led on redrafts TE, SR, NP and KM were sent all drafts for comment before submission.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests JB: since the educational activity, has been appointed as a Non Executive Director at Bags of Taste (unpaid role). EM: fractional contract and partial funding of PhD by Nnedpro, teaching contract with Brighton and Sussex Medical School. SR: cochair of Management Board, BMJ Nutrition, Prevention and Health.

Provenance and peer review Not commissioned; externally peer reviewed.

Read the full text or download the PDF:

Module 8: Metabolism and Nutrition

Introduction to metabolism and nutrition, learning objectives.

By the end of this section, you will be able to:

Describe the processes involved in anabolic and catabolic reactions
List and describe the steps necessary for carbohydrate, lipid, and protein metabolism
Explain the processes that regulate glucose levels during the absorptive and postabsorptive states
Explain how metabolism is essential to maintaining body temperature (thermoregulation)
Summarize the importance of vitamins and minerals in the diet

This photo shows a woman working out at a gym.

Figure 1. Metabolism is the sum of all energy-requiring and energy-consuming processes of the body. Many factors contribute to overall metabolism, including lean muscle mass, the amount and quality of food consumed, and the physical demands placed on the human body. (credit: “tableatny”/flickr.com)

Eating is essential to life. Many of us look to eating as not only a necessity, but also a pleasure. You may have been told since childhood to start the day with a good breakfast to give you the energy to get through most of the day. You most likely have heard about the importance of a balanced diet, with plenty of fruits and vegetables. But what does this all mean to your body and the physiological processes it carries out each day? You need to absorb a range of nutrients so that your cells have the building blocks for metabolic processes that release the energy for the cells to carry out their daily jobs, to manufacture new proteins, cells, and body parts, and to recycle materials in the cell.

This chapter will take you through some of the chemical reactions essential to life, the sum of which is referred to as metabolism. The focus of these discussions will be anabolic reactions and catabolic reactions. You will examine the various chemical reactions that are important to sustain life, including why you must have oxygen, how mitochondria transfer energy, and the importance of certain “metabolic” hormones and vitamins.

Metabolism varies, depending on age, gender, activity level, fuel consumption, and lean body mass. Your own metabolic rate fluctuates throughout life. By modifying your diet and exercise regimen, you can increase both lean body mass and metabolic rate. Factors affecting metabolism also play important roles in controlling muscle mass. Aging is known to decrease the metabolic rate by as much as 5 percent per year. Additionally, because men tend have more lean muscle mass then women, their basal metabolic rate (metabolic rate at rest) is higher; therefore, men tend to burn more calories than women do. Lastly, an individual’s inherent metabolic rate is a function of the proteins and enzymes derived from their genetic background. Thus, your genes play a big role in your metabolism. Nonetheless, each person’s body engages in the same overall metabolic processes.

Anatomy & Physiology. Provided by : OpenStax CNX. Located at : http://cnx.org/contents/[email protected] . License : CC BY: Attribution . License Terms : Download for free at http://cnx.org/contents/[email protected]

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2023-24 General Bulletin

Nutritional Biochemistry and Metabolism, BS

Degree: Bachelor of Science (BS) Major: Nutritional Biochemistry and Metabolism

Program Overview

Nutritional Biochemistry and Metabolism is the study of nutrients and their metabolic functions. This degree program also prepares the students for graduate studies in nutrition or metabolic research or for further training for careers in medicine, dentistry, and other allied health professions.

The BS in Nutritional Biochemistry and Metabolism is easily combined with majors such as Psychology, Sociology, Chemistry, Biology or Communication Sciences. It will also easily accommodate the requirements of a pre-health curriculum .

Didactic Program in Dietetics

Students interested in applying to dietetic internships must meet specific course requirements (Didactic Program in Dietetics) as required by the Accreditation Council for Education in Nutrition and Dietetics of the Academy of Nutrition and Dietetics. These requirements are met in the courses that comprise the Didactic Program in Dietetics (DPD). A department advisor should be consulted in the first year to plan the dietetics coursework.

The DPD at Case Western Reserve University is currently granted Accreditation by the Accreditation Council for Education in Nutrition and Dietetics of the Academy of Nutrition and Dietetics, 120 South Riverside Plaza, Suite 2000, Chicago, IL 60606-6995, 800.877.1600.

Undergraduate Policies

For undergraduate policies and procedures, please review the Undergraduate Academics section of the General Bulletin.

Accelerated Master's Programs

Undergraduate students may participate in accelerated programs toward graduate or professional degrees. For more information and details of the policies and procedures related to accelerated studies, please visit the Undergraduate Academics section of the General Bulletin.

Program Requirements

Students seeking to complete this major and degree program must meet the general requirements for bachelor's degrees and the Unified General Education Requirements . Students completing this program as a secondary major while completing another undergraduate degree program do not need to satisfy the school-specific requirements associated with this major.

Didactic Program in Dietetics (DPD) b

Excluding NTRN 370 .

Please contact DPD Director in Department of Nutrition to confirm DPD courses and other requirements.

Excluding NTRN 341 and NTRN 370 .

Sample Plan of Study

Unified General Education Requirement .

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Nutrition in Patients with Type 2 Diabetes: Present Knowledge and Remaining Challenges

Maria letizia petroni.

1 IRCCS-Azienda Ospedaliera di Bologna Sant’Orsola-Malpighi, I-40138 Bologna, Italy; [email protected] (M.L.P.); [email protected] (L.B.); [email protected] (F.M.); [email protected] (A.S.S.); [email protected] (P.C.); [email protected] (F.R.)

2 Department of Medical and Surgical Sciences, Alma Mater University of Bologna, I-40138 Bologna, Italy

Lucia Brodosi

Francesca marchignoli, anna simona sasdelli, paolo caraceni, giulio marchesini, federico ravaioli, associated data.

Not applicable.

Unhealthy behaviours, including diet and physical activity, coupled with genetic predisposition, drive type 2 diabetes (T2D) occurrence and severity; the present review aims to summarise the most recent nutritional approaches in T2D, outlining unmet needs. Guidelines consistently suggest reducing energy intake to counteract the obesity epidemic, frequently resulting in sarcopenic obesity, a condition associated with poorer metabolic control and cardiovascular disease. Various dietary approaches have been proposed with largely similar results, with a preference for the Mediterranean diet and the best practice being the diet that patients feel confident of maintaining in the long term based on individual preferences. Patient adherence is indeed the pivotal factor for weight loss and long-term maintenance, requiring intensive lifestyle intervention. The consumption of nutritional supplements continues to increase even if international societies do not support their systematic use. Inositols and vitamin D supplementation, as well as micronutrients (zinc, chromium, magnesium) and pre/probiotics, result in modest improvement in insulin sensitivity, but their use is not systematically suggested. To reach the desired goals, patients should be actively involved in the collaborative development of a personalised meal plan associated with habitual physical activity, aiming at normal body weight and metabolic control.

1. Introduction

Diabetes mellitus, namely type 2 diabetes (T2D), constitutes a significant challenge for health systems worldwide. According to the 2019 Diabetes Atlas of the International Diabetes Federation [ 1 ], 463 million adults are currently living with diabetes (1 on 11 individuals worldwide, but 1 in 5 are aged over 65). The total number is expected to increase further by 700 million in 2045. The economic impact is huge—driven by the direct costs of treatment and complications, the indirect costs of disability and premature death, and the intangible costs of poor quality of life.

Despite its characterizations as a disease of affluence, nutritional problems are frequent in T2D. Unhealthy lifestyles expressed by overnutrition and/or scarce physical activity, leading to overweight and obesity, add to genetic defects in the pathogenesis of the disease. Dietary restrictions are prescribed to reduce the incidence of T2D as well as to improve metabolic control [ 2 ], but weight loss is burdened by the loss of muscle mass [ 3 ] and sarcopenia adds to age-dependent muscle wasting [ 4 ], increasing frailty [ 5 ]. These two opposite needs make a correct nutritional approach mandatory to reduce disease burden, improve metabolic control, limit pharmacologic treatment and reduce the risk of impending cardiovascular disease.

National and international guidelines for nutritional and lifestyle recommendations are available [ 5 , 6 , 7 , 8 , 9 ], together with protocols to guide weight loss to produce long-term T2D remission [ 10 ]. The proposed strategies (dietary prescription, lifestyle counselling, cognitive behaviour therapy), although all-inclusive of nutritional components, are markedly different in their approach and goals and should be known by clinicians approaching patients with T2D ( Table 1 ) [ 11 ]. The present review is intended to summarize the most recent nutritional approaches in T2D, also outlining unmet needs.

Comparison of strategies and goals of different dietary interventions.

Note that enrolment into counselling and behaviour therapy may be facilitated by motivational interviewing. Treatment may be provided either in individual or in group settings; group strategies are likely to enhance the coping skills of the participants, via relational and interpersonal communication with people experiencing similar difficulties.

2. Methods and Areas of Research

2.1. literature search.

The literature on T2D is immense. A PubMed search of June 2021, limited to the period 2016–2021 using the string “Type 2 diabetes” [MeSH Terms] AND “nutrition” [All Fields] AND “human” [MeSH Terms], retrieved 4865 references, including 887 review articles (234 systematic reviews), 255 meta-analyses and 760 clinical trials. The authors used the search to enucleate the most relevant data and unmet treatment needs. The reference lists of selected articles were used to retrieve older documents in order to provide a complete overview of present problems.

2.2. Diabetes, Obesity and Sarcopenia

The association between T2D and obesity is so strict that the term “diabesity” was originally used to indicate the dreadful association of the two conditions in a JAMA editorial in 1980 [ 12 ]. The term was finally proposed by Astrup and Finer [ 13 ], as well as by Zimmet et al. [ 14 ] and it is largely accepted inside the metabolic community. The accumulation of body fat characterizes obesity, but it is measured by a formula (the body mass index, i.e., weight (kg)/height 2 (m)), not at all considering body fat. Muscle mass is frequently increased in obesity but might be relatively scarce in quantity and quality compared to body fat.

Sarcopenia is particularly common in older patients, synergistically driven by age and obesity; body fat increases until the seventh decade of life (the median age of patients with diabetes attending diabetes centres) and decreases thereafter [ 15 ]. At the same time, sedentariness progressively reduces muscle mass, finally resulting in sarcopenic obesity [ 16 ], frequently associated with cardiometabolic disorders [ 17 ].

By definition, sarcopenia implies a quantitatively reduced muscle mass, as measured by dual-energy X-ray absorptiometry (DXA), the commonly accepted gold standard. Several studies have validated the use of bioelectrical impedance analysis (BIA), an easy, time-saving, and cost-effective bedside technique for assessing regional muscle mass and body composition [ 18 , 19 ]. BIA-assessed sarcopenia is defined by the skeletal muscle mass index (SMI), calculated as total appendicular skeletal mass (ASM, kg) divided by body weight (kg) × 100. These measurements do not consider qualitative muscle mass, and most recent guidelines suggest that functional measurements (e.g., low muscle strength by handgrip) should be primarily used to characterize sarcopenia, with quantitative data as supportive measures [ 20 ].

The prevalence of sarcopenia in diabetes has been extensively investigated. In a recent narrative review, the prevalence of sarcopenia varied between 7% and 29% [ 21 ], according to age and metabolic control, but higher figures are frequently reported. A systematic review with meta-analysis including 15 studies confirmed a prevalence varying up to 50% [ 22 ], again driven by age and metabolic control. A study with BIA concluded that patients with T2D have an enlarged ectopic fat at the expense of skeletal muscle, i.e., relative sarcopenia [ 23 ], and lower muscle mass is coupled with decreased muscle strength [ 24 ], also predicting diabetes in the general population [ 25 ]. The contribution of diabetes duration remains controversial [ 21 , 22 ], but older patients with T2D, with an expected longer duration of disease, show a larger decline in appendicular lean mass, muscle strength, and functional capacity compared with normoglycemic controls [ 26 ]. Notably, when compared with matched control populations, the risk of sarcopenia increased systematically in the presence of T2D (odds ratio (OR) 1.55; 95% confidence interval (CI) 1.25–1.91; p < 0.001 [ 22 ] and OR 1.63; 95% CI 1.20–2.22; p = 0.002 [ 27 ]). This indicates a need for preventive measures to limit quantitative and qualitative muscle defects by effective nutritional treatments.

2.3. Metabolic Control

The primary defect in T2D is insulin resistance, a condition where normal insulin levels are associated with lower metabolic effects or where higher than normal insulin levels are needed to elicit a normal metabolic response. Insulin resistance accounts for diffuse impairment in whole body, as well as in selective defects in different organs and tissues (liver, muscle, adipose tissue).

Whole-body insulin resistance mainly reflects muscle insulin resistance [ 28 ], reducing glucose and amino acid uptake in the postprandial phase, as well accelerating glycogen and amino acid release in the post-absorptive state, also accelerated by glucagon release [ 29 ]. Glucagon constitutes the link between muscle and liver in substrate disposal; by stimulating hepatic glucose production and ketogenesis, glucagon favours the utilization of substrates released in the periphery, whereas high insulin concentrations favour hepatic fat deposition. In both obese and nonobese subjects, higher plasma insulin levels have been associated with a linear increase in the rates of hepatic de novo lipogenesis [ 30 ], as supported by the hypoglycaemic effects of glucagon suppression of glucagon-receptor antagonists [ 31 , 32 ]. In the hepatocytes, fatty acids may be derived from de novo lipogenesis, uptake of non-esterified fatty acids and low-density lipoproteins, or lipolysis of intracellular triacylglycerol. Their accumulation due to higher synthesis and decreased export in the presence of high insulin concentrations in the portal vein is the likely cause of fatty liver disease, occurring in up to 73% of patients with T2D [ 33 ].

The link between muscle tissue and the liver is exerted by amino acids ( Figure 1 ) [ 34 ]. Branched-chain amino acids, bypassing the liver in the post-prandial state, serve as nitrogen carriers to the periphery, whereas alanine and glutamine are used to carry nitrogen from the periphery to the liver, intestine and kidney. In insulin-resistant states, including obesity [ 35 ], the post-load uptake of branched-chain amino acids is impaired, possibly leading to defective amino acid supply to the muscle tissue and sarcopenia. In summary, the complex trafficking of glucose, lipid and amino acid in response to insulin resistance should be considered in the treatment of diabetes.

An external file that holds a picture, illustration, etc.
Object name is nutrients-13-02748-g001.jpg

Interorgan amino acid exchange in the postabsorptive state and after meals in diabetes. Note the importance of BCAAs (valine, isoleucine and leucine) as nitrogen carriers to the muscle tissue (lean mass) in the post-prandial period (blue arrows) and the reverse importance of alanine and glutamine as nitrogen carriers to central organs in the post-absorptive state (liver, kidney, intestine) (green arrows). In this context, the regulatory role of the pancreas (altered secretion of insulin and glucagon) and the adipose tissue (lipolysis, release of free fatty acids and inflammatory adipokines in the general circulation, particularly in the post-absorptive state) is pivotal for the regulation of hepatic and whole-body homeostasis (red arrows).

3. Medical Nutrition Therapy for Type 2 Diabetes

The foundation of medical nutrition therapy (MNT) of T2D is to achieve glucose, lipids, and blood pressure within the target range to prevent, delay or manage microvascular and macrovascular complications [ 36 , 37 ].

MNT plays a pivotal role in the overall management of diabetes, and patients with T2D should be actively involved with their healthcare team for the collaborative development of a personalized meal plan. If these patients are referred to a registered dietitian or a nutritionist proficient in providing diabetes-specific treatment, an absolute reduction of glycated A1C haemoglobin of up to 1.9% may be observed [ 8 ]. Continuous dietary counselling integrated with mobile apps and wearable devices has also been advocated to facilitate the real-time assessment of dietary intake, to strengthen adherence, and support motivation and self-efficacy [ 38 ].

3.1. Comparison between Different Guidelines

Table 2 summarizes the main nutritional recommendations for patients with T2D, derived from guidelines, and the dietary patterns with a high degree of evidence [ 5 , 6 , 7 , 8 , 9 ]. All proposed interventions are designed to reduce energy intake and promote 5–10% loss of initial body weight, leading to improved insulin sensitivity, blood glucose and blood pressure control, and reduced lipid levels [ 39 ]. Regular mealtimes and a healthy diet should be combined with increased physical activity [ 4 ].

Summary of nutritional recommendations for type 2 diabetes, as derived from international guidelines.

The optimal distribution of macronutrients as a percentage of total energy is highly variable, from 45% to 60% for carbohydrates, from 15% to 20% for proteins and 20% to 35% for fats, suggesting no ideal percentage of calories from macronutrients [ 7 ]. As to carbohydrates, high-fibre sources (30–50 g/day of dietary fibre, ≥30% as soluble fibres) and minimally processed, low-glycaemic index carbohydrates should be preferred to improve glycaemic control, LDL-cholesterol and cardiovascular (CV) risk. Overall, reducing carbohydrate intake for individuals with T2D has been shown to improve blood glucose [ 6 ]; a systematic review and meta-analysis (9 studies with 734 patients) confirmed a beneficial effect of low-carb diets vs. normal-or high-carb diets on HbA1c and on short-term weight loss, not on long-term weight loss [ 40 ]. Food plans should emphasize the consumption of non-starchy vegetables, with minimal added sugars, fruits, whole grains, and dairy products [ 41 ]. Using non-nutritive sweeteners as substitutes for added sugar (sucrose, high fructose corn syrup, fructose, glucose) can reduce daily calories and total carbohydrates. For those who regularly consume sugary drinks, consuming a low calorie or unsweetened drink can be an alternative, but both should be consumed with caution.

Additionally, recommendations on protein intake do not differ from the general population (1.0–1.2 g/kg body weight or corrected body weight for patients with overweight/obese); protein intake should be reduced to 0.8 g/kg body weight in subjects with chronic diabetic nephropathy [ 36 ]. At present, there is some inconsistency across guidelines from different countries as to protein sources (some do not limit animal proteins) and as to allowed maximal amount of protein intake (1.2–1.5 g/kg/day) [ 42 ]. A recent meta-analysis of 54 RCTs (4344 participants) showed a significant effect of moderate high-protein diets (20–45% of total energy) vs. low-protein diets (10–23%) on weight loss and weight loss maintenance, total fat mass reduction and cardiometabolic risk [ 43 ]. The authors suggest that the effects might also be due to the blood-pressure-lowering effect of bioactive peptides that inhibit the angiotensin-converting enzyme activity observed in protein isolates [ 44 ].

Among dietary fats, it is recommended to avoid trans-fatty acids as much as possible and to consume less than 7–9% of the total daily energy from saturated fatty acids (SFAs). SFAs should be replaced with polyunsaturated fatty acids (PUFAs), mainly mixed sources of omega-3/omega-6, and with monounsaturated fatty acids (MUFAs) of vegetable origin whole grains, nuts and seed (rich in alpha-linolenic fatty acid) [ 36 , 45 ].

The recommendations have largely focused on the quality of the diet and the importance of a healthy eating pattern that contains nutrient-rich foods, with less attention to the percentage of specific nutrients, with a reduction in daily caloric intake (250–500 kcal) for subjects with overweight and obesity [ 6 ]. Several dietary patterns have been studied and proposed, but no single dietary pattern should be preferred [ 8 ]. Individual preferences and treatment goals will determine the long-term use of these models; systematic reviews and meta-analyses have shown that a Mediterranean-style dietary pattern significantly improves hard outcomes such as glycaemic control, systolic blood pressure, total cholesterol, HDL-cholesterol and triglycerides [ 46 ]. The Mediterranean diet is characterised by a moderate-to-low carbohydrate intake, entirely covering the micronutrient needs [ 47 ]. Additionally, a low fat diet, i.e., the DASH-diet, promoted in the prevention of cardiovascular disease and the treatment of high blood pressure [ 48 ], has also reached consensus [ 49 ]. In a review comparing low-carbohydrate and ketogenic diets, the vegan diet, and the Mediterranean diet, all diets improved glycaemic control and weight loss, but patient adherence and long-term manageability were pivotal factors for the efficacy of each diet [ 50 ].

3.2. Intensive Lifestyle Intervention

Intensive lifestyle intervention (ILI) that supports behaviour changes, as initially experienced in the Finnish Diabetes Prevention Study and the U.S. Diabetes Prevention Program [ 51 , 52 ], represents the recommended approach to prevent and/or delay the onset of T2D in prediabetic patients [ 5 ]. The ILI behaviour approach combines diet and physical activity interventions with the goal to achieve and maintain a 7% loss of initial body weight and to increase moderate-intensity physical activity to at least 150 min/week. The effect of ILI has also been investigated in the treatment of T2D. The Look AHEAD study randomized 5145 individuals with T2D and associated overweight or obesity to either ILI or diabetes support and education (as control group), having cardiovascular outcomes as primary goal. Weight loss was achieved by reducing caloric intake to 1200–1800 kcal/day depending on baseline weight using portion-controlled meal plans, calorie-counting techniques, and meal replacements combined to moderate physical activity to ≥175 min/week. ILI was delivered as individual and group sessions over the first year, with a median follow-up of 9.6 years. [ 53 ]. After one year, the average weight loss in the ILI group was 8.6%, compared with 0.7% in the control group, with 55% of ILI participants having lost ≥7% of their initial b.w. vs. 7% of controls. This led to remission of T2D in 11.2% of ILI participants vs. 2.0% in controls. However, by the fifth year of follow-up, ILI participants had regained half of their initial weight loss, and the study was closed at the end of the follow-up (10-years) after an interim analysis had shown that the intervention had failed its primary outcome [ 54 ]. Thus, the critical point becomes how to achieve long-term weight loss maintenance, a difficult task in the general population [ 55 ], and a core problem in T2D treatment with approaches based on lifestyle changes. Although more effective than behaviour change in inducing and sustaining remission of T2D, bariatric surgery also suffers from reduced durability over time [ 56 ].

A novel approach was tested in the DIRECT trial, a primary care-led management intervention in patients with T2D diagnosed by less than 6 years and not receiving insulin. The ILI strategy was preceded by a commercial very-low-calorie diet followed by stepwise food reintroduction. Primary outcomes were weight loss ≥15 kg and T2D remission. At 12 months, almost half of participants achieved T2D remission off all glucose-lowering medications [ 57 ]; this percentage dropped to 36% at 24 months [ 58 ]. Notably, the maintenance of diabetes remission paralleled weight loss maintenance and particularly fat removal from the liver and pancreas, suggesting recovered insulin secretion [ 59 ]. With the limits of durability, all these data support the use of ILI, including dietary interventions, as an effective adjuvant treatment to improve glycaemic control [ 60 ].

Another approach is the so-called intermittent fasting, which has gained increased popularity for treating T2D based on very limited literature [ 61 ]. This term encompasses various eating behaviours that avoid (or limit) nutrient and energy intake for a significant amount of time (a full day or a time-restricted feeding between 6 to 8 h) on a regular intermittent schedule. Intermittent fasting is claimed to improve glucose control, insulin resistance and to induce weight loss by generating a ‘metabolic switch’, i.e., a sort of rejuvenation of the metabolic homeostasis, leading to increased health span and longevity [ 62 ], but no advantage over conventional caloric restriction has been proven. Moreover, this regimen could carry the risk of hypoglycaemia even when following a medication dose-change protocol and should only be used under strict medical control and/or continuous glucose monitoring [ 63 ].

Finally, the use of mobile apps and wearable devices has recently gained consensus to facilitate weight loss. The use of these devices allows a direct analysis of daily calorie intake and physical activity (daily steps), translated into calorie consumption [ 64 ]. This provides immediate feedback and is likely to support long-term adherence to well-defined goals [ 38 ]. Several commercial apps are available, and have been tested in the prevention and treatment of diabetes in trials mimicking the U.S. Diabetes Prevention trial [ 52 ]. Toro-Ramos et al. confirmed a modest efficacy of weight loss for app users after 6 and 12 months of systematic use in subjects with prediabetes compared with usual care [ 65 ], and similar studies are available with the most recent apps that also support by tailored messages interactivity [ 66 ]. Although all these supports are expected to improve long-term weight loss, and a few patients may really reach impressive results [ 67 ], their use is biased by higher attrition rates [ 68 ]. Nonetheless, the possibility to reach a larger audience makes this approach a useful opportunity.

4. Nutritional Supplements for Metabolic Control

International diabetes societies do not support the use of nutritional supplements in diabetes, but their use continues to increase in several countries, despite lack of evidence and uncertainty on safety [ 36 ]. A complete analysis of available products (combinations may account for several hundreds) is outside the scope of this review, but a few of them are of interest. Their putative mechanism(s) of action are summarized in Table 3 [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. They are not expected to replace diet and glucose-lowering drugs but might be confidently used, provided their safety is proven.

Putative mechanism(s) responsible for the beneficial effects of nutrition supplements and micronutrients on diabetes risk and glycaemic control.

Abbreviations: HOMA-IR, homeostasis model assessment of insulin resistance; IL, interleukin; TNF, tumor-necrosis factor.

4.1. Inositols

Several reviews and meta-analyses have been published on the treatment of gestational diabetes with myo-inositol (MI) or D-chiro-inositol (DCI) [ 70 , 90 , 91 , 92 , 93 ]. A Cochrane review was inconclusive [ 94 ]; MI supplementation did not reduce the need for insulin or produce any significant effect on blood glucose. Conflicting data have also been reported using DCI or the combination of MI and DCI, and the optimum dosage to achieve a significant effect on glucose metabolism remains unsettled [ 91 ]. A position statement of the two largest Italian diabetes societies concluded that MI (at the dose of 4 g/day) might be safely used for the prevention and treatment of gestational diabetes [ 95 ], but the level of evidence and the strength of recommendations are low. No data are available on the use of MI or DCI to treat insulin resistance outside gestational diabetes. Studies are in progress on the combined use of MI and myo-inositol hexa-phosphate (IP6), or phytic acid, showing more effective anti-oxidant and glucose-lowering activity in experimental animals [ 96 ], but no clinical data are available.

The use of inositol(s) in polycystic ovary syndrome is not considered in the present review; in that setting, specific hormonal activity is likely to produce clinical effects [ 97 ].

4.2. Vitamin D

Vitamin D levels are frequently suboptimal in T2D, probably driven by overweight/obesity, and specifically by visceral adiposity [ 98 ], and have been associated with chronic inflammation and insulin resistance, as well as impaired insulin release [ 99 ]. Epidemiological studies support the existence of a relationship between low vitamin D levels and the presence of T2D, metabolic syndrome [ 100 , 101 ], nonalcoholic fatty liver disease (NAFLD) [ 102 ], cardiovascular risk factors [ 103 ] and insulin resistance, also tested by glucose clamp [ 75 ]. However, a clear association between vitamin D levels, insulin and glucose metabolism has not been systematically confirmed by intervention studies, and a causal association has never been established [ 104 ]. In a subset of the RECORD trial, a placebo-controlled trial of oral vitamin D 3 and/or calcium supplementation for the secondary prevention of osteoporotic fractures in older people, vitamin D 3 at the daily dose of 800 IU with or without 1000 mg of calcium did not prevent the development of T2D and did not reduce the need for glucose-lowering drugs in T2D patients [ 105 ]. Although the effects on insulin sensitivity have long been conflicting [ 73 ], a recent systematic review with metanalysis confirmed that vitamin D supplementation resulted in a significant improvement in HOMA-IR (standardized mean difference = −0.57; 95% CI: −1.09 to −0.04), particularly when vitamin D was administered in large doses and for a short period of time to nonobese, vitamin D deficient patients, or to individuals with optimal glucose control at baseline [ 106 ]. Data have been confirmed in another recent study in vitamin D-deficient adults randomized to high dose vitamin D supplementation. The HOMA value of insulin resistance was significantly reduced, and a lower rate of progression toward diabetes was observed vs. the control group (3% vs. 22%; p = 0.002) [ 107 ].

Of note, vitamin D has been extensively used also to treat sarcopenia, considering the role of insulin resistance extending from glucose metabolism to protein and amino acid metabolism, as discussed below.

4.3. Niacin

Niacin is a water-soluble derivative of pyridine, present in several forms (namely as nicotinic acid or nicotinamide), also named as vitamin B3. It is a derivative of vitamin B, frequently associated with inositols as inositol hexanicotinate. The effects on insulin release from islet β-cells have been extensively investigated in T2D with secondary failure of sulfonylureas, where niacin at the daily dose of 1.5 g significantly restored C-peptide release [ 108 ]. However, a meta-analysis of eight trials where niacin was used to treat hyperlipidemia in 2110 T2D patients showed no significant effects on plasma glucose (weighted mean difference (WMD), 0.18 mmol/L; 95% CI, −0.14 to 0.50) and HbA1c levels (WMD, 0.39%; 95% CI, −0.15 to 0.94) [ 109 ]. Niacin appeared to cause a deterioration of glucose control, in keeping with data observed in a meta-analysis of 11 trials in patients without diabetes at entry, where niacin was used to treat dyslipidaemia and prevent cardiovascular events [ 110 ] (relative risk of de novo T2D: 1.34 (95% CI 1.21–1.49)). Similar results were provided by the large trial of combination treatment with niacin plus laropiprant [ 111 ], where niacin treatment (2 g/day for a median of 3.9 years) was associated with an increased incidence of de novo T2D (rate ratio, 1.32; 95% CI 1.16–1.51) and deterioration in metabolic control in subjects with diabetes (1.55; 1.34–1.78) [ 112 ]. This deleterious effect is similar to the well-known, mild negative effect of statins on glucose metabolism. It adds to the well-known poor tolerability of niacin because of flushing, occurring at pharmacologic doses.

4.4. Nutraceuticals

Natural compounds derived from plant extracts, spices, herbs, and essential oils have been tested for alleged benefits in managing patients with metabolic syndrome [ 77 , 113 ]. They include Mediterranean diet components, olive oil and its anti-oxidant components, natural legumes and cereals, as well as specific compounds, alone or in combination. Curcumin [ 114 ], cinnamon [ 115 , 116 ], berberine [ 117 , 118 ], citrus flavonoids [ 119 , 120 ], quercetin [ 121 , 122 ], the bioactive compounds of garlic [ 123 , 124 ], red yeast rice [ 125 ] and neem extracts [ 126 ] have all demonstrated some activity on insulin sensitivity, but studies are usually of poor quality and very few received extensive validation, although supported by systematic reviews [ 119 ]. They may be included in dietary recommendations but should never replace pharmacologic treatment.

Resveratrol, a polyphenol present in plants such as grapes and nuts and mainly in derivatives (wine), merits a specific citation [ 127 , 128 , 129 ]. A recent Cochrane review identified three RCTs with a total of 50 participants who received graded doses of daily oral resveratrol for 4–5 weeks vs. placebo. Studies had a low risk of bias, but the analysis did not demonstrate any significant effect on glucose and HbA1c levels, with the limit of a short observation period. The authors found eight more ongoing RCTs with approximately 800 participants, likely to contribute more solid results [ 128 ]. Clinical studies in patients with insulin resistance and NAFLD have shown promising results [ 130 ], but even moderate alcohol intake is questioned in these patients due to the negative effects of alcohol on hepatic and extrahepatic cancers, which outweigh the possible beneficial effects on the cardiovascular system, largely derived from retrospective studies [ 131 ]. Finally, alcohol provides extra calories that should be considered in patients on dietary restriction, the pivotal intervention to reduce body weight and NAFLD burden.

Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by modification of gut microbiota. Clinical data are specifically referred to gestational diabetes [ 132 , 133 ]; in these women four high-quality RCTs (288 participants) showed that treatment was associated with a significant reduction in insulin resistance (HOMA-IR: −0.69%; 95% CI −1.24, −0.14, p = 0.01), not in fasting glucose (−0.13 mmol/L; 95% CI −0.32, 0.06, p = 0.18) or LDL-cholesterol (−0.16 mmol/L; 95% CI −0.45, 0.13, p = 0.67) [ 133 ]. In the general diabetes population, the most recent review identified 38 studies totalling 2086 participants fitting pre-defined criteria to be included in a meta-analysis [ 134 ]. Overall, the use of prebiotics, probiotics or synbiotics reduced fasting glucose (−0.58 mmol/L; 95% CI −0.86, −0.30; p < 0.01), total cholesterol (−0.14 mmol/L; 95% CI −0.26, −0.02, p = 0.02) and triglyceride levels (−0.11 mmol/L; 95% CI −0.20, −0.02, p = 0.01) and increased HDL-cholesterol (0.04 mmol/L; 95% CI 0.01, 0.07, p < 0.01), but failed to reach the significance threshold in HbA1c (−2.17 mmol/mol; 95% CI, −4.37 to 0.03; p = 0.05) and had no effect on LDL-cholesterol [ 134 ].

Fructans are compounds acting as prebiotics, i.e., non-digestible food ingredients neither metabolized nor absorbed while passing through the upper gastrointestinal tract and fermented by bacteria in the colon. They include fructo-oligosaccharides, galacto-oligosaccharides, lactulose and large polysaccharides (inulin, resistant starches, cellulose, hemicellulose, pectin and gum) [ 135 , 136 ]. Diets rich in fructans might improve glucose metabolism in T2D also via decreased intake and intestinal absorption of food, adding to modifications of gut microbiota [ 137 , 138 ]. A systematic review with meta-analysis of 25 studies did not provide evidence for a beneficial effect on BMI, but inulin-type carbohydrate supplementation reduced fasting glucose (−16.4 mg/dL; 95% CI, −17.6 to −15.2), HbA1c (−0.58%; 95% CI, −0.78 to −0.39), and HOMA-IR (−0.99%; 95% CI, −1.76 to −0.2). However, a large heterogeneity was demonstrated, raising doubts on data validity [ 139 ].

4.5. Other Micronutrients

4.5.1. zinc.

Zinc deficiency is common in T2D [ 140 ], likely as an effect of both hyperzincuria [ 141 ] and reduced intestinal absorption [ 142 ], resulting in insulin resistance [ 143 ]. Its antioxidant role further strengthens the importance of zinc levels for diabetes control and the prevention of microvascular complications [ 144 ].

In the clinical setting, a systematic review with meta-analysis of 12 studies in T2D patients showed that zinc supplementation resulted in a significant reduction of fasting blood glucose (pooled mean difference, −18.1 mg/dL; 95% CI −33.8 to −2.41) and HbA1c (−0.54 %; 95%CI, –0.86 to –0.21), accompanied by a systematic reduction of total and LDL-cholesterol levels [ 145 ]. Among diabetes-related complications, zinc supplementation was shown to reduce lipoperoxidation [ 146 ] and to decrease urinary albumin excretion, independently of glucose control [ 147 , 148 ]. However, a few studies failed to demonstrate any positive effect of zinc supplementation in the metabolic control of T2D patients [ 146 ], also in the presence of long-term supplementation and low zinc levels at baseline [ 149 ]. Zinc supplementation might prove useful only in specific settings. In zinc-deficient patients with cirrhosis, independently of diabetes status, zinc treatment (zinc sulfate, 200 mg three times per day) was associated with improved non-insulin-mediated glucose disposal (so-called glucose effectiveness) [ 150 ], as well as improved alanine stimulated urea synthesis rate, a measure of amino acid utilization in tissues [ 151 ], also resulting in decreased ammonia levels and improved mental state. All these complementary effects might be important in subjects with T2D progressed to NAFLD-cirrhosis [ 152 ].

No relevant side effects of zinc supplements have been reported in chronic diseases [ 153 ].

4.5.2. Chromium

A possible role of deficient chromium levels as risk factor T2D has long been suggested based on its insulin-sensitising activity, but the effects on human disease remain uncertain. In a large case-control study involving 4443 Chinese individuals (nearly half with either newly diagnosed T2D or newly diagnosed pre-diabetes), plasma chromium levels were approximately 10% lower in the T2D and pre-diabetes groups vs. controls, and the risk of T2D and pre-diabetes decreased across quartiles of chromium [ 154 ]. This evidence fits with smaller studies reporting decreased chromium levels and/or increased chromium excretion in T2D [ 141 , 155 ].

The effects of chromium supplementation have been tested in multiple review articles with pooled analysis or metanalysis [ 156 , 157 , 158 , 159 ]. Based on 25 RCTs of chromium supplementation, Suksomboon et al., concluded for positive effects of chromium supplementation on glucose control in patients with diabetes, with no increased risks of adverse events compared with placebo [ 156 ]. On the contrary, Yin et al., in a meta-analysis of 14 trials (875 participants, mean age range: 30 to 83 years old, 8 to 24 weeks of follow-up) did not demonstrate any significant effect of chromium, either as Cr chloride, or Cr picolinate, or Cr yeast) on HbA1c levels [ 157 ]. In a review limited to patients with T2D, very few studies reached clinically meaningful goals, defined as fasting plasma glucose (FPG) ≤7.2 mmol/dL, a decline in HbA1c to values ≤7%, or a decrease of ≥0.5% in baseline levels [ 158 ]. Finally, in the most recent and largest analysis in T2D (28 studies, 1295 participants, heterogeneous chromium supplements with daily intake ranging up to 3000 µg for 6–24 weeks), the authors concluded for a positive effect of Cr supplements on glucose metabolism [ 159 ] and include chromium supplements into the treatment of T2D [ 159 ], despite uncertainty about long-term use. Treatment reduced fasting glucose (WMD, −0.99 mmol/L; 95% CI, −1.72 to −0.25), HbA1c (WMD, −0.54 %; 95% CI, −0.82 to −0.25), triglycerides and increased HDL-cholesterol. The effects were mainly reported using both chloride and picolinate formulations and were independent of treatment duration.

4.5.3. Magnesium

Insulin modulates the shift of magnesium from extracellular to intracellular space; in turn, intracellular Mg 2+ concentration modulates insulin action, as well as blood pressure [ 160 ]; thus, low magnesium induces insulin resistance, and insulin resistance further decreases magnesium levels [ 161 ]. In the past 20 years, several epidemiological and clinical studies have demonstrated the protective role of magnesium on the risk of diabetes. In U.S. women aged ≥45 years (Women’s Health Study) with no previous history of T2D, an inverse association was found between dietary magnesium and incident T2D, which was significant among women with increasing grades of overweight/obesity (P for trend, 0.02). It was associated with a progressive decline of insulin levels (P for trend, 0.03) [ 162 ]. Data were confirmed in 1122 individuals (20–65 years of age) enrolled between 1996 and 1997 and re-examined about 10 years later. The relative risk of new-onset prediabetes and T2D were increased in the presence of low magnesium levels at baseline [ 163 ].

Oral magnesium supplementation in subjects with T2D and low magnesium levels have been reported to improve insulin sensitivity and metabolic control [ 164 , 165 , 166 ]. In a meta-analysis of 40 prospective cohort studies enrolling more than 1 million participants and follow-up periods ranging from 4 to 30 years, dietary magnesium intake was associated with a 19% reduction in the relative risk of T2D (RR 0.81; 95% CI, 0.77–0.86 per 100 mg/day increment) [ 167 ]. In a different analysis of 28 studies involving 1694 subjects (834 in the treatment arm and 860 in the placebo arm), magnesium supplementation was demonstrated to produce favourable effects on blood glucose (WMD, −4.64 mg dL, 95% CI −7.60 to −1.68), as well as on HDL- and LDL-cholesterol, triglycerides and systolic blood pressure, also reducing cardiovascular risk [ 168 ].

Additionally, for magnesium supplements, no safety concerns have been raised; Verma and coll. argue that large trials should be performed to validate the use of magnesium supplements to prevent and treat T2D [ 168 ], but no consensus exists in the community [ 169 ].

5. Prevention and Treatment of Diabetes-Related Sarcopenia

Optimal energy intake, healthy food choices and sufficient protein intake, coupled with habitual physical activity, especially resistance training, are the cornerstones for metabolic control and the prevention of frailty in T2D. Despite the mounting evidence of the negative impact of sarcopenia on the natural history [ 170 ] and quality of life of T2D patients [ 171 ], there is a surprising dearth of intervention studies addressing T2D-related sarcopenia. Therefore, we must rely on findings from general intervention studies on sarcopenia and/or sarcopenic obesity.

Resistance training represents the most effective intervention for prevention and treatment and can be safely carried out even in fragile patients [ 172 ]. High protein (1.2–1.4 g/kg) hypocaloric diets—either exclusively food-based or including protein supplements, both as an adjunct to resistance training—have proven effective for preventing muscle mass loss during weight-reduction diets in women with obesity [ 173 ]. To reach the anabolic threshold, the protein supplement should be provided at meals rather than between meals in the elderly. The optimal protein dose (including food protein and proteins from supplements) should be 30–45 g of proteins per serving in the elderly [ 174 ]. However, high protein load cannot be recommended to T2D patients with chronic kidney disease (CKD) [ 175 ].

Whey proteins, rich in the anabolic amino acid leucine, represent the most frequently used protein supplements. Additionally, BCAA supplement or the leucine metabolite β-hydroxy-β-methyl butyrate have been proposed. These supplements are generally ineffective as sole treatment in patients without diabetes [ 173 , 176 , 177 ] and must be added to resistance training to improve already-established sarcopenia (associated or not to obesity). Leucine has strong insulinotropic properties, and leucine-rich supplements may increase the availability of amino acids for protein synthesis and reduce protein breakdown in the muscle, at the same time enhancing glucose disposal and glycaemic control, but solid data are lacking [ 178 ]. A noteworthy issue is that BCAA treatment has proven effective both in preventing and in improving sarcopenia in patients with liver cirrhosis, also independently of physical exercise/resistance training [ 179 , 180 ].

Finally, vitamin D was also proposed as a nutritional supplement to control sarcopenia. The activation of the vitamin D receptor present in muscle cells promotes their differentiation, proliferation and hypertrophy. Vitamin D deficiency is associated with reduced muscle mass and strength in the elderly [ 181 ], and vitamin D supplementation increased muscle strength, particularly in vitamin D-deficient cases and in the elderly [ 181 ]. Data were not confirmed by a Cochrane review in patients with liver disease; no data are available in T2D [ 182 ] and trials are eagerly warranted.

6. Management of Other Comorbidity in Patients with T2D

6.1. cirrhosis.

Nutrition therapy in cirrhosis has already been discussed in this Special Issue of Nutrients. Nonetheless, its association with T2D deserves a special focus considering the high prevalence—up to two-thirds of patients with cirrhosis listed for liver transplantation have T2D [ 183 ]—and its importance as a risk factor for the development of complications (ascites, hepatic encephalopathy, bacterial infections, renal insufficiency, hepatocellular carcinoma) [ 184 ]. Nutrition treatment becomes extremely challenging since additional determinants of malnutrition may be present, including reduced food intake and/or defective absorption of nutrients and impaired albumin synthesis. Sarcopenia—accelerated by upregulation of myostatin due to hyperammonaemia—becomes a predictor of morbidity and mortality, aggravated by obesity (sarcopenic obesity) [ 185 , 186 ], and is difficult to treat. Bariatric surgery is frequently contraindicated [ 187 ]; also pharmacologic treatment with GLP-1 agonists favouring weight loss [ 188 ], such as liraglutide, may be contraindicated by the presence of varices at risk of bleeding [ 189 ], and dietary treatment remains the sole possibility.

Unfortunately, there are no specific guidelines for the nutritional treatment of T2D associated with cirrhosis, and individualized, structured nutritional programs are suggested to accomplish the need for restriction of sodium and fluids [ 190 ]. Due to the accelerated depletion of glycogen stores, it is important to provide frequent (3 to 5) meals containing carbohydrates, plus a late evening carbohydrate snack to prevent muscle protein catabolism [ 191 , 192 ].

Protein restriction is not systematically advocated, as these patients usually tolerate a normal protein intake. Besides hypoalbuminemia, potentially requiring a higher protein intake, albumin glycation is present in T2D [ 193 ]. The structurally damaged albumin molecule is also dysfunctional, and albumin administration may be required to reduce ascites. Although the specific indications for use are clearly defined by international guidelines [ 194 ], albumin is frequently administered outside evidence-based indications, including nutritional support [ 195 ]. At present, no studies showed a direct link between albumin administration and nutritional correction in decompensated cirrhosis; it can only be hypothesized that the clinical improvement seen with long-term albumin treatment could indirectly improve the nutritional status through different mechanisms, which include the control/resolution of ascites and whole body edema, or the reduction of systemic inflammation [ 196 ].

6.2. Renal Failure

In T2D patients with CKD, protein restriction may be advised; low protein diets (daily protein intake reduced to 0.8 g/kg b.w.) showed a beneficial impact on the trajectory of renal function leading to an attenuation in the progression of CKD and delayed initiation of dialysis treatment, an important goal for patients [ 197 , 198 , 199 ]. However, protein restriction may worsen sarcopenia and should be limited as long as possible. According to the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Guidelines, protein intake must actually be increased up to 1.2 g/kg body in patients undergoing maintenance dialysis due to important additional amino acid losses occurring in dialysate [ 200 , 201 ].

Different sources of dietary protein may have a different impact on CKD-related complications; meat intake increases the production of nitrogenous end products, worsens uraemia and may increase the risk of constipation with consequent hyperkalaemia associated with the low fibre intake [ 199 ]. A predominantly plant-based diet, fibre-rich and low in protein content (0.6–0.8 g/kg/day), can produce favourable changes in the intestinal microbiome, thus modulating the generation of uremic toxins and slowing down the progression of CKD, finally reducing cardiovascular risk [ 202 ]. Carbohydrates from sugars should be limited to less than 10% of the energy intake [ 203 ], and saturated fatty acids, trans fats, and cholesterol should be replaced by polyunsaturated and monounsaturated fats, associated with more favourable outcomes [ 204 ]. Dietary sodium restriction should be considered, but a deficient sodium intake (to less than 1.5–2.0 g/day) carries the risk of hyponatremia, leading to reduced insulin sensitivity and prediabetes [ 205 ]. T2D patients with advanced CKD progressing to end-stage renal disease may be prone to the “burnt-out diabetes” phenomenon (i.e., spontaneous resolution of hyperglycaemia and frequent hypoglycaemic episodes); further studies in this frail population in chronic hemodialysis treatment are particularly needed to determine the safety and the effectiveness of dietary manipulations [ 206 ].

7. Conclusions

T2D is the paradigm of conditions where genetic, behavioural and individual factors drive disease occurrence and severity. Despite decades of epidemiological studies and randomized trials, several unmet needs remain ( Table 4 ). The goal of optimal nutritional approach is to maintain or regain a body weight within the normal range, providing adequate intake of macronutrients and micronutrients to reduce the risk of sarcopenia. Various dietary approaches have been proposed to improve outcome, with the Mediterranean diet supported by solid evidence. However, as long-term adherence is the main goal to be achieved, the dietary plan and the calorie restriction that patients feel confident to maintain life-long should always be preferred. At present, supplementation with inositols, vitamin D and micronutrients (zinc, chromium, magnesium) is not systematically suggested, but might be considered in individual patients.

Principal unmet needs for optimal nutritional treatment of patients with type 2 diabetes.

Although advances in nutrigenomics and metabolomics offer the rationale for tailored precision medicine, a personalized meal plan, supported by continuous dietary counselling by registered dietitians remains at present the key strategy for long-term success in weight and glycaemic control [ 37 ], particularly in individual high-risk cases [ 38 ].

Acknowledgments

F.M. is supported by a contract financed by the Italian Ministry of Health and Italian Regions (NET-2016-02364191).

Author Contributions

Conceptualization, M.L.P., G.M. and F.R.; literature search, M.L.P., L.B., F.M., A.S.S., P.C., G.M. and F.R.; writing—original draft preparation, M.L.P., G.M. and F.R.; writing—review and editing, M.L.P., L.B., F.M., A.S.S., P.C., G.M. and F.R. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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Add antioxidants to your diet

Antioxidants are certain nutrients, such as vitamins C or E, or carotenoids, which may help protect cells against daily damage. As cells do their job, the way they process oxygen results in a molecule called a free radical. These molecules are unstable. As they regain stability, free radicals damage cells and DNA.

Disease and free radical damage

Over time, free radical damage can cause problems for tissues and organs in the body, potentially leading to disease. Research suggests that free radical molecules can add to the risk of health issues linked to aging. Some examples are heart disease, age-related macular degeneration, Alzheimer's disease and cancer.

The body's cells can fix or prevent free radical damage, for example, by making antioxidant enzymes. And some antioxidants, such as vitamin C, come from food and drink.

Eating antioxidants

Plant-based foods are the best source of antioxidants. These include fruits, vegetables, whole grains, nuts, seeds, herbs and spices, and even cocoa. Plants have naturally occurring antioxidants such as carotenoids, flavonoids, isothiocyanates, and phenolic acids.

As a bonus, many foods that have antioxidants also have other benefits. They are often high in fiber, low in saturated fat and cholesterol, and good sources of vitamins and minerals.

Artichokes are a good example.

They naturally have the fiber inulin. But artichokes also have plant chemicals called flavonoids and phenolic acids. Those phytonutrients have the potential to help manage free radicals.

Does cooking affect antioxidants?

Drying, cooking or freezing foods can affect its level of antioxidants. Sometimes cooking allows an antioxidant to be better absorbed. Lycopene in tomatoes is one example.

More lycopene is available in cooked tomatoes than raw ones. And for some foods, such as sweet potatoes, cooked is the only way we could eat them at all.

In addition to cooking, some antioxidants are more available when paired with another nutrient. One example is orange and yellow vegetables with beta carotene and vitamin E. Cooked with a bit of fat, those antioxidants are more available to the body.

Other foods with carotenes also may offer more nutrients cooked. Examples are carrots, red and green peppers, kale, spinach, and broccoli. Some of their phytochemicals may be better absorbed by the body after being cooked.

Other foods have more antioxidants when raw. In jam made of berries, for example, antioxidant levels were lower than in the raw, unprocessed berries.

Fresh or frozen, blueberries, blackberries, raspberries, strawberries and cranberries are among the top fruit sources of antioxidants.

Nuts, seeds and grains

Along with fruits and vegetables, nuts, seeds and grains add antioxidants to the diet. Whole grains, nuts and seeds are a source for selenium, vitamin E and antioxidant phytochemicals.

Unsalted nuts and seeds have protein and fats in addition to other phytochemicals. They are a nutrient dense food.

Nut and seed oils also may help people balance their healthy fat intake. Walnuts and pecans are some of the top nuts for antioxidant content. Not crazy about nuts? Try sunflower seeds.

And don't forget those grains. When made into flour, buckwheat, millet and barley seem to hold on to their phytochemicals best.

Antioxidants add up

Overall, antioxidants from foods taken in over a long period of time seem to support health. Individual antioxidants taken as supplements have less scientific support.

When it comes to adding antioxidants to the diet, no one food or food group can do it all. The best bet is to get a variety of fruits, vegetables, nuts and whole grains into the diet.

Adding foods with different colors can help meet that goal. A food's color hints at its antioxidants. Red, orange, yellow, green, and even blue or black fruits and vegetables provide different antioxidants.

Other things in the diet, such as tea, coffee and some fruit juices also have antioxidants. Some dark chocolate may have antioxidants as well, but it depends on the cocoa contents.

And it can be helpful to make sure to get some antioxidants every day. For example, vitamin C isn't stored in the body. So eating food with that vitamin every day can help make sure the body has enough.

Antioxidants and health. National Center for Complementary and Integrative Medicine. https://nccih.nih.gov/health/antioxidants/introduction.htm. Accessed March 11, 2024.
Antioxidants and cancer prevention. National Cancer Institute. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/antioxidants-fact-sheet. Accessed March 11, 2024.
Duyff RL. Vitamins and minerals. In: Academy of Nutrition and Dietetics Complete Food and Nutrition Guide. 5th ed. Houghton Mifflin Harcourt; 2017.
Aune D, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: A systematic review and dose-response meta-analysis of prospective studies. American Journal of Clinical Nutrition. 2018; doi:10.1093/ajcn/nqy097.
Carlsen MH, et al. The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide. Nutrition Journal. 2010; doi:10.1186/1475-2891-9-3.
Zeratsky KA (expert opinion). Mayo Clinic. March 11, 2024.
Izquierdo-Vega JA, et al. Evidence of some natural products with antigenotoxic effects. Part 1: Fruits and polysaccharides. Nutrients. 2017; doi:10.3390/nu9020102.
Lopez-Romero D, et al. Evidence of some natural products with antigenotoxic effects. Part 2: Plants, vegetables, and natural resin. Nutrients. 2018; doi:10.3390/nu10121954.
Rusu ME, et al. Health benefits of nut consumption in middle-aged and elderly population. Antioxidants (Basel). 2019; doi:10.3390/antiox8080302.
Artichoke. Natural Medicines. https://naturalmedicines.therapeuticresearch.com. Accessed Feb. 14, 2024.
Neri L. Antioxidant activity in frozen plant foods: Effect of cryoprotectants, freezing process and frozen storage. Foods. 2020; doi:10.3390/foods9121886.
2020-2025 Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agriculture. https://www.dietaryguidelines.gov. Accessed Feb. 13, 2024.

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ORIGINAL RESEARCH article

Association of exposure to multiple perfluoroalkyl and polyfluoroalkyl substances and glucose metabolism in national health and nutrition examination survey 2017–2018.

1 Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, China
2 MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, China
3 Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York at Buffalo, Buffalo, NY, United States

Objective: To investigate the relationships between perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure and glucose metabolism indices.

Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 waves were used. A total of 611 participants with information on serum PFASs (perfluorononanoic acid (PFNA); perfluorooctanoic acid (PFOA); perfluoroundecanoic acid (PFUA); perfluorohexane sulfonic acid (PFHxS); perfluorooctane sulfonates acid (PFOS); perfluorodecanoic acid (PFDeA)), glucose metabolism indices (fasting plasma glucose (FPG), homeostasis model assessment for insulin resistance (HOMA-IR) and insulin) as well as selected covariates were included. We used cluster analysis to categorize the participants into three exposure subgroups and compared glucose metabolism index levels between the subgroups. Least absolute shrinkage and selection operator (LASSO), multiple linear regression analysis and Bayesian kernel machine regression (BKMR) were used to assess the effects of single and mixed PFASs exposures and glucose metabolism.

Results: The cluster analysis results revealed overlapping exposure types among people with higher PFASs exposure. As the level of PFAS exposure increased, FPG level showed an upward linear trend ( p < 0.001), whereas insulin levels demonstrated a downward linear trend ( p = 0.012). LASSO and multiple linear regression analysis showed that PFNA and FPG had a positive relationship (>50 years-old group: β = 0.059, p < 0.001). PFOA, PFUA, and PFHxS (≤50 years-old group: insulin β = −0.194, p < 0.001, HOMA-IR β = −0.132, p = 0.020) showed negative correlation with HOMA-IR/insulin. PFNA (>50 years-old group: insulin β = 0.191, p = 0.018, HOMA-IR β = 0.220, p = 0.013) showed positive correlation with HOMA-IR/insulin, which was essentially the same as results that obtained for the univariate exposure-response map in the BKMR model. Association of exposure to PFASs on glucose metabolism indices showed positive interactions between PFOS and PFHxS and negative interactions between PFOA and PFNA/PFOS/PFHxS.

Conclusion: Our study provides evidence that positive and negative correlations between PFASs and FPG and HOMA-IR/insulin levels are observed, respectively. Combined effects and interactions between PFASs. Given the higher risk of glucose metabolism associated with elevated levels of PFAS, future studies are needed to explore the potential underlying mechanisms.

1 Introduction

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are a class of synthetic chemical that is widely used in various human production and daily life applications, such as paper, textiles, furniture, and foam fire extinguishers because of their thermal stability, hydrophobicity, and oil repellency ( 1 – 3 ). PFASs have high migration and contaminated ability and can be detected in environmental samples (such as water and soil), sera from various animal tissues, and human bodies ( 4 – 6 ). Additionally, PFASs have a significant bioaccumulation effect and a long half-life in the human body, making their degradation difficult ( 7 ). Animal experiments and epidemiological studies have demonstrated that PFASs have genotoxicity, reproductive toxicity, neurotoxicity, and developmental and endocrine-disrupting effects ( 8 , 9 ).

There is growing evidence that PFASs are associated with a variety of health problems, with glucose metabolism disorder among them ( 10 ). Glucose metabolism disorder can cause many diseases, with diabetes being the most common, and has become a major public health issue ( 11 ). FPG, Insulin and homeostasis model assessment for insulin resistance (HOMA-IR) are important detection indices of glucose metabolism. FPG level was highly correlated with the presence of diabetic complications ( 12 ). Insulin is secreted by pancreatic β-cells, and human blood insulin levels can assess pancreatic β-cell function ( 13 ). Insulin resistance refers to the target organs of insulin action, such as liver, muscle and other reduced sensitivity to insulin action, and the normal physiological response of insulin cannot be performed ( 14 ). The most widely used assessment of insulin resistance is HOMA-IR ( 15 ). Early identification and control of these indices can reduce the harm of glucose metabolism disorder to the body and improve the prognosis.

Currently, epidemiological studies on the effects of PFASs on glucose metabolism have yielded conflicting and inconclusive results. The Diabetes Prevention Project analyzed the relationship between serum PFASs concentrations and blood glucose indices and found that perfluorooctane sulfonates acid (PFOS) and perfluorooctanoic acid (PFOA) concentrations were positively associated with the function of HOMA-IR, fasting blood glucose and β cells function ( 1 ). The level of serum PFASs 1871 adults was measured in the 2013–2014 National Health and Nutrition Examination Survey (NHANES) in the United States revealed that branched-chain PFOA level was positively correlated with increased FPG ( 10 ). However, a study on obese children in Ohio found no statistical significance between PFASs and blood glucose levels ( 16 ). Nelson et al. analyzed data from NHANES (2003–04) and found no significant association between the PFASs (PFOA, perfluorononanoic acid (PFNA), PFOS, and perfluorohexane sulfonic acid (PFHxS)) and HOMA-IR ( 2 ). Although several studies demonstrated a positive association between serum PFASs levels and glucose metabolism indices, various studies have also determined there to be a non-significant or inverse association. Therefore, further investigation into the relationships between PFASs exposure and glucose metabolism is warranted.

At present, the mechanism of PFASs affecting glucose metabolism is also not clear, and some researchers believe that it may be related to the activation of Peroxisome proliferator activated receptors (PPAR) ( 17 , 18 ). PPAR belongs to the nuclear hormone receptor superfamily that regulates lipid, hormonal, and glucose metabolism and is considered possibly the major target of PFASs ( 19 ). PFASs can activate signaling pathways mediated by all PPAR isoforms (PPARα, PPARβ, PPARγ) ( 20 ). Moreover, PPARα may be a preferential target for PFAS above the other PPAR isoform ( 21 ). Toxicological studies have found that PFOA can also increase insulin sensitivity and glucose tolerance in mice by affecting the PI3K-AKT signaling pathway in the liver, causing an increase in fasting blood glucose level and a decrease in liver glycogen content in mice ( 22 ).

Additionally, most of the previous studies have focused on the biological toxicity of individual PFASs; however, in real-life settings, multiple PFASs often co-exist and interact during exposure, uptake, and metabolism processes, and this interaction can result in complex effects on body glucose metabolism. Currently, the specific effects of combined exposure to multiple PFASs on glucose metabolism remain unknown. Therefore, to provide new evidence on the relationships of PFASs exposure and glucose metabolism, we aimed to examine the relationships between exposure to multiple PFASs and glucose metabolism indices in this study by analyzing the NHANES data from 2017 to 2018, using the Least absolute shrinkage and selection operator (LASSO) and multiple linear regression analysis and Bayesian kernel machine regression (BKMR) models.

2 Materials and methods

2.1 study population.

Data on the study participants were obtained from the NHANES databases. NHANES is a unique 2 years cross-sectional survey of the health and nutrition status of the U.S. population that collects data on demographic, socioeconomic, and health-related issues through interviews, standardized exams, and biometric specimen collection. The health screening was conducted at a mobile Screening Center (MEC) after the participants had already participated in a household interview. The methods and processes used by NHANES for data collection are available on NHANES website 1 . In the current study, we used data from 2017–2018 wave which is the latest test data on PFASs in NHANES.

The total sample size in 2017–2018 was 9,254, of which 1929 were tested for serum PFASs. Considering that type 1 diabetes mellitus accounts for about 90% of total diabetes in children and adolescents and is the most common form of childhood diabetes in most parts of the world ( 23 ); at the same time, pregnant women are at risk of gestational diabetes mellitus. 14% of pregnant women worldwide are affected by gestational diabetes mellitus which is a global health problem, affecting a considerable number of pregnant women ( 24 ). Therefore, 313 individuals <20 years old, 1,005 individuals who were pregnant, taking anti-hyperglycemic drugs or missed main research indices were excluded. Finally, a total of 611 individuals were included in this study. The National Center for Health Statistics Research Ethics Review Board approved NHANES, and all participants provided written informed consent. The selection process of research participants is summarized in Figure 1 .

Figure 1 . NHANES database research participants screening flow chart. (Data screening from top to bottom as indicated by the arrow).

2.2 Covariates

The demographic database provided information on the gender (male, female), age, race (mexican-American, other Hispanic, non-Hispanic white, non-Hispanic blacks, other races), marital status (married, bereaved spouse, divorce, separation, unmarried, cohabitation), poverty, and education level (less than high school education, high School Degree, university and above). Information on weight and body mass index (BMI) were obtained from obtained from Examination database. Information on smoking, alcohol and leisure-time physical activity were obtained from Questionnaire database. Smoking status was classified as never smoking (fewer than 100 cigarettes or other tobacco products in their life), previously smoking (over 100 cigarettes or other cigarettes in their life but now quit smoking), and currently smoking (100 cigarettes or other cigarettes in their life and still smoking). Drinking status was classified as never drinking (no kind of alcohol in their life), previously smoking (drinking previously, but not in the past 12 months), and now smoking (drinking in the past 12 months). Leisure-time physical activity for each participant was categorized based on the recommended weekly amount of moderate-intensity to vigorous-intensity activity as follows: (1) below, indicating less than 150 min per week; (2) meet, indicating 150 to 300 min per week; (3) exceed, indicating more than 300 min per week.

2.3 Laboratory measurement methods

2.3.1 blood specimen collection.

Each study participants need to meet the 8 to less than 24 h fasting criteria and draw venous blood in a fasting state. The phlebotomist collected study participant’s peripheral venous blood into 2 mL gray tubes for FPG and into 15 mL red top tubes for PFASs and insulin. Centrifuge the 2 mL gray tube to yield plasma and transfer at least 0.5 mL plasma from this tube into 2 mL vessels. Centrifuge the red top tubes to yield serum and remove serum into 5 mL sterile cryovials for PFASs and 2 mL vessels for insulin. Store under appropriate frozen (−30°C) conditions until they are tested.

2.3.2 Measurement of serum PFASs concentration

Online solid phase extraction coupled to high-performance liquid chromatography-turbo ion spray ionization-tandem mass spectrometry was used for the quantitative detection of the PFASs. A total of six perfluorinated compounds, including PFOA, PFOS, perfluorodecanoic acid (PFDeA), PFHxS, PFNA, and perfluoroundecanoic acid (PFUA), were analysed in this study. Notably, the PFOA and PFOS used in this manuscript refer to the sum of linear and branched. (The description of measurements of PFASs for NHANES 2017–2018 presents n-perfluorooctanoic acid (n-PFOA), Branch perfluorooctanoic acid isomers (Sb-PFOA), n-perfluorooctane sulfonic acid (n-PFOS), Perfluoromethylheptane sulfonic acid isomers (Sm-PFOS)). The limits of detection (LOD) of the six PFASs were all 0.1 ng/mL. Following NHANES analysis guidelines, PFASs below the LOD were expressed using LOD/ 2 . Details on the analytical methodology can be found on the NHANES website 2 .

2.3.3 Measurement of glucose metabolism indices

FPG were determined by hexokinase initiation using the Roche/Hitachi cobas c system (c311). Insulin was measured using the Tosoh AIA system analyzer. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated as follows: HOMA-IR = FPG (mmol/L) × insulin (mIU/L)/22.5.

2.4 Statistical analysis

We calculated weighted means (±standard deviation [SD]) using the NHANES primary sampling unit, strata, and weights of environmental samples for continuous variables and frequencies (proportions) for categorical variables. Means and standard deviations (SDs) for continuous variables with normally distributed distribution, medians and interquartile ranges (IQRs) for continuous variables with non-normally distributed distribution, and proportions for binary or categorical variables were displayed. The distributions of serum PFAS were generally right-skewed, therefore, were ln-transformed was conducted. Spearman correlation analysis were presented using correlation heat maps.

Cluster analysis was performed based on the concentration of PFASs. K-means algorithm is the most used clustering method, which is simple to operate, computationally efficient, so K-means algorithm was used in this study ( 25 ). First, the logarithmic transformation of PFASs concentration was performed to achieve an approximate normal distribution. After the data was standardized, the index of sum of squared error provided by Factoextra package in R 4.2.2 was used to determine the optimal number of clusters. The overall population was divided into separate subgroups using the k-means algorithm. The ratio of the average concentration in each subgroup to the average concentration in the total participants of each PFASs was calculated to further assess the exposure level. The Kruskal–Wallis H and Chi-square tests were used to compare differences in baseline information and the levels of glucose metabolism indices between subgroups. Variables showing significant differences ( p < 0.05) were used as covariates for multiple liner regression analysis to control for potential confounding factors.

Since diabetes is often diagnosed before the age of 50 ( 26 ); people under the age of 50 are the most active workforce, the working group affected by diabetes imposes a high economic burden on the country, so the study of glucose metabolism in people under 50 is significant ( 27 ); considering that glucose metabolism indices are easily influenced by age and the age range of the study population was large, the study participants were categorized into two groups: ≤50 years old and >50 years old for correlation and regression analyses. Next, The Kruskal–Wallis H test was used to compare differences in PFASs levels between different age groups. Then, the mixed effects of PFASs were analyzed using LASSO and BKMR models.

To explore the association of single PFASs with glucose metabolism indices in the mixture of PFASs exposure, and to avoid the potential collinearity among the variables included in the regression model, the multi-PFASs exposure model was established using LASSO regression for the six PFASs based on adjusting the confounding factors of sex, age, alcohol consumption, race, leisure-time physical activity, BMI, weight and poverty ratio. The coefficient distribution of these six PFASs was used as the penalty parameter for LASSO regression path selection, and the PFASs related to glucose metabolism indices were screened using five cross-validations. Subsequently, the selected elements of PFASs were included in the multiple linear regression model and analyzed the regression coeffcients and 95% confidence intervals (95% CI). The variance inflation factor (VIF) was calculated to evaluate the multicollinearity of PFASs in the model. It is generally believed that if the VIF of an independent variable is >10, there is a multicollinearity problem between the independent variable and other independent variables.

Furthermore, we used the BKMR model as part of the sensitivity analysis and further explored the mixed effects of multiple PFASs exposure on glucose metabolism indices. BKMR utilizes a flexible non-parametric approach to assess dose–response relationships, overcoming the disadvantage that conventional methods may be limited by multicollinearity and model selection error, to more reliably assess the health effects of environmental chemical mixtures ( 28 ). This study used the BKMR model to present the cumulative effect of the mixture of the six PFASs, the univariate expose-response relationships between PFASs and glucose metabolism indices and the interactions among individual PFASs. The BKMR analysis included the same covariates as the LASSO regression and calculated the posterior inclusion probability (PIP) to quantify the relative importance of each element to glucose metabolism, with values ranging from 0 to 1. The “BKMR” and “ggplot2” packages of R4.2.2 were used to build the BKMR model and present the results. The data were combined and analyzed using R4.2.2 software, and p < 0.05 was presented at the significance level.

3.1 General condition of the study participants and distribution of blood PFASs

As shown in Table 1 , 611 participants were included in this study comprising 308 males and 303 females, which accounted for 50.4 and 49.6% participants, respectively. Never smokers and individuals with a history of alcohol consumption accounted for 56.3 and 91.3%, respectively, and the median age was 53 years.

Table 1 . Basic characteristics of study participants, grouped by gender ( N (%)/M (P25, P75)).

Except for PFUA, the blood detection rate of the other five PFASs exceeded 85%. The detection rate and concentration of PFASs in the blood of the study participants are presented in Table 2 . Figure 2 illustrates that the correlation coefficients between PFDeA and PFUA, PFNA and PFUA, and PFNA and PFDeA were 0.85, 0.71, and 0.72, respectively. This suggests a strong correlation between some PFASs ( r s > 0.7).

Table 2 . Detection rate and concentration of PFASs (ng/mL) in the population (median [IQR]).

Figure 2 . Heat map of PFAS correlation in blood. (The values in the box are the correlation coefficient, with values ranging from −1 to 1).

3.2 Subgroup analysis of the relationship between PFASs and glucose metabolism indices

3.2.1 cluster analysis based on pfass exposure.

By observing the the cluster heatmap ( Figure 3 ), we found that individuals highly exposed to one type of PFASs were also likely to be exposed to other PFASs simultaneously. As can be seen in the Figure 4 , the exposure levels of the six PFASs in subgroup 3 were significantly higher than those in subgroups 2 and 1, while subgroup 2 was significantly higher than subgroup 1. From this, we identified subgroups 1, 2, and 3 as low, medium, and high exposure subgroups, respectively. Figure 5 shows the comparison results of glucose metabolism indices among the three subgroups, with statistically significant differences in FPG among all subgroups and insulin between the high-exposure and low-exposure groups. The trend of FPG and insulin levels showed statistical significance ( p < 0.05, Table 3 ), indicating a linear trend between exposure and these two glucose metabolism indices. Combined with the box plots ( Figure 5 ), it was found that FPG levels showed an elevated trend with increasing exposure to PFASs. However, insulin demonstrated a decreasing trend with increasing exposure to PFASs, indicating an association between PFASs exposure and changes in glucose metabolism levels. The weighted basic characteristics of the three subgroups determined based on cluster analysis are presented in Table 4 . Statistically significant differences were observed between the groups in terms of gender, age, alcohol consumption, race, and poverty ratio.

Figure 3 . Heat map of clustering based on the concentration of PFASs in blood. (The vertical axis represents different PFASs. The horizontal axis represents the sample).

Figure 4 . Comparison of PFASs concentrations among three exposure subgroups. (Data are expressed as the ratio of the mean concentration of PFASs in subgroups to the population mean; all groups ( n = 6). The horizontal coordinates indicate the relative levels of the mean concentrations of the subgroup PFASs to the overall mean, and the vertical coordinates are the six PFASs).

Figure 5 . Comparison of glucose metabolism indices between the three exposure subgroups. (Blue, yellow, and gray represent the high, medium, and low exposure groups, respectively. (Data are expressed as mean ± SD; all groups ( n = 3)). The ordinate represents the logarithmic concentration of glucose metabolism indices, and the horizontal coordinate is the exposure subgroup).

Table 3 . Trend test of glucose metabolism indices in three exposure subgroups.

Table 4 . Characteristics of the high-, medium-, and low-exposure groups ( N (%)/M (P25, P75)).

3.2.2 Comparison of PFASs levels between the two age groups

As shown in Table 5 , the differences in serum levels of six PFASs were statistically significant between the two groups with all p < 0.001. Except for PFUA and PFDeA, the remaining four PFASs levels were significantly higher in ≤50 year old group than in >50 year old group.

Table 5 . Comparison of PFASs levels between the two age groups.

3.3 The relationships of single PFASs and glucose metabolism indices

As shown in Table 6 , among aged ≤50 years group, PFHxS (Insuliu: β = −0.194, p < 0.001; HOMA-IR: β = −0.132, p = 0.020) was found to be correlated with insulin and HOMA-IR. In the >50 years old population, PFNA exhibited a positive correlation with FPG ( β = 0.059, p < 0.001); insulin and HOMA-IR were negatively correlated with PFUA (Insulin: β = −0.133, p = 0.037; HOMA-IR: β = −0.141, p = 0.041), and PFOA (Insulin: β = −0.159, p = 0.047; HOMA-IR: β = −0.163, p = 0.042) but positively associated with PFNA (Insulin: β = 0.191, p = 0.018; HOMA-IR: β = 0.220, p = 0.013). Additionally, the multiple linear regression models indicated that the VIF of all PFASs was less than 10, indicating no multicollinearity among the PFASs variables in the regression process.

Table 6 . Regression coefficients of population glucose metabolism indices and blood PFASs concentrations (95% CI).

3.4 The effects of multiple PFASs on glucose metabolism indices

As shown in Figure 6 , in the ≤50 years-old group, the level of FPG showed an increasing trend with the increase of the total level of PFASs mixture. PFOS showed a positive expose-response relationship with FPG. Negative interaction between PFOS and PFHxS may exist. Insulin and HOMA-IR decreased with the increase of the total level of PFASs mixture. Further, PFHxS demonstrated a clear negative linear relationships with these two indices in the expose-response relationship plot, which was consistent with the LASSO regression screening results. As PFNA concentration percentiles changed from low to high, the negative effect of PFOA on insulin/HOMA-IR decreased, indicating the possibility of negative interactions between PFNA and PFOA. The results presented in Table 7 highlight the significant role of PFHxS in the relationships of PFASs on both insulin and HOMA-IR, with the highest PIPs (0.990 and 0.796, respectively).

Figure 6 . BKMR study the correlation of FPG, HOMA-IR and Insulin with PFASs in the ≤50 years-old group. (A–C) : overall effect (95%CI) of PFASs. h ( Z ) can be interpreted as the correlations of FPG, HOMA-IR and insulin with blood PFASs. (D–F) : exposure-response plots of FPG, HOMA-IR and Insulin against each PFAS, with other PFASs held at the median. h ( Z ) can be interpreted as the correlations of FPG, HOMA-IR and Insulin with blood PFASs. (G–I) : bivariate expose-response relationship. Each cell represented the exposure-response curve for the column PFASs when the row PFASs was fixed at 25th, 50th, or 75th percentile and the remaining PFASs were fixed at their medians.

Table 7 . A posteriori inclusion probability (PIPs) of the effect of PFASs on glucose metabolism indices.

As shown in Figure 7 , in the >50 years-old group, the level of FPG also showed an increasing trend, corresponding to the total PFASs mixture levels. The univariate expose-response diagram showed a linear relationships between the six PFASs and the level of FPG. No interactions were observed between the PFASs. The insulin and HOMA-IR results were similar-both levels demonstrated a downward trend with the increase in the overall level of the PFASs mixture. Furthermore, the univariate expose-response relationships showed that all PFASs had linear relationship with these two indices. PFOA, PFUA and PFHxS showed a negative expose-response relationship with these two indices while PFOS and PFNA demonstrated a positive relationship, which was consistent with the LASSO regression screening results. In the bivariate exposed-response relationship plots of insulin or HOMA-IR, negative interactions were found between PFOA and PFNA/PFOS, and positive interaction was observed between PFOA and PFHxS in the bivariate exposed-response relationship plots of HONA-IR. The results presented in Table 5 highlight the significant role of PFNA in the relationships of PFASs on FPG, with the highest PIPs (0.356).

Figure 7 . BKMR study the correlation of FPG, HOMA-IR and Insulin with PFASs in the >50 years-old group. (A–C) : overall effect (95%CI) of PFASs. h ( Z ) can be interpreted as the correlations of FPG, HOMA-IR and Insulin with blood PFASs. (D–F) : exposure-response plots of FPG, HOMA-IR and Insulin against each PFAS, with other PFASs held at the median. h ( Z ) can be interpreted as the correlations of FPG, HOMA-IR and insulin with blood PFASs. (G–I) : bivariate expose-response relationship. Each cell represented the exposure-response curve for the column PFASs when the row PFASs was fixed at 25th, 50th, or 75th percentile and the remaining PFASs were fixed at their medians.

As shown in Figure 8 , all possible interactions between PFASs were summarized, and it was found that PFOA could interact with multiple PFASs, and PFOA played an important role in the combined influence of multiple PFASs on glucose metabolism.

Figure 8 . Summary of PFASs interactions. (A line between PFASs indicates possible interaction, with a black line indicating negative interaction and a red line indicating a positive interaction).

4 Discussion

In this study, 611 participants from the 2017–2018 NHANES cohort were selected. Cluster analysis, LASSO regression, and BKMR regression models were used to explore the relationships between the six PFASs and glucose metabolism indices. The results showed that with the increase of PFASs exposure, the FPG level showed an upward trend, while HOMA-IR/insulin demonstrated a downward trend. PFNA and FPG had a positive relationship. PFOA, PFUA, and PFHxS showed negative correlations with HOMA-IR/insulin, whereas PFNA mainly had positive correlation. Negative interactions were observed between PFOA and PFNA/PFOS, PFOS and PFHxS, while positive interactions were found between PFOA and PFHxS. Notably, PFOA can combine with various PFASs (PFOS/PFNA/PFHxS) to affect glucose metabolism indices.

PFASs exposure was closely associated with the level of FPG. The results of this study revealed that higher exposure to PFASs corresponded to a higher level of FPG, with PFNA having the greatest influence. A cross-sectional studies for adolescents and adults demonstrated that elevated serum PFNA concentration was associated with hyperglycemia (95% CI: 1.39–7.16) ( 29 , 30 ). A nested case-control study also found that mixed PFASs homologs could affect glucose homeostasis by increasing 1 h glucose levels, with PFNA being the main contributor ( 31 ). The reason may be that PFNA is a kind of long-chain PFASs that is difficult to degrade and can lead to higher PPARα activation ( 32 ), which also explains the prominent position of PFNA in the relationship between PFASs and FPG.

Insulin is a protein hormone synthesized and secreted by islet β cells, which binds to target cell receptors and activates signaling pathways leading to various metabolic changes, most notably increasing glucose uptake and lowering blood glucose levels ( 33 ). Another marker of diabetes is insulin resistance that is measured using HOMA-IR. The results of this study demonstrated that exposure to mixed PFASs was associated with lower insulin and HOMA-IR levels, while PFOA, PFUA, and PFHxS were negatively correlated with both. Another study of the NHANES database also found PFASs mixture exposure were associated with decreased INS and HOMA-IR ( 34 ). Studies conducted in Cincinnati found a marginal negative correlation between PFOA levels and insulin/HOMA-IR, and another study in the New York reported a negative correlation between PFHxS and both ( 35 , 36 ), which were consistent with the present study. In addition, we also found that PFNA was positively associated with both insulin and HOMA-IR levels. Zeeshan et al. analyzed data from the “Isomers of C8 Health Project in China,” and also found that PFNA was significant positive associations with insulin and HOMA-IR ( 37 ). However, there were some studies with opposite results to the present study. For example, Zeeshan et al. found significant positive correlations between PFOA, PFUA, PFHxS, and both insulin and HOMA-IR ( 37 ); some researchers found no significant correlations between PFOA/PFNA/PFHxS and HOMA-IR ( 2 , 38 ). The analysis of similar and contradictory epidemiological results with this study found that different overall exposure levels in the study population may influence the association of PFASs with indicators of glucose metabolism. The results of studies analyzing populations or countries with lower concentrations of serum PFASs were more consistent with this study, concluding that there was a negative or nonsignificant correlation between PFASs exposure and insulin and HOMA-IR. For instance, the median serum concentration of PFOA was 3.8 ng/mL in NHANES (2003–2004) ( 2 ), 2.46 ng/mL in the Canadian Health Measures Survey (2007–2009) ( 38 ), and 1.47 ng/mL in this study. In studies where there were significant positive correlations, participants had a higher median PFOA concentration, such as the European Young Heart Study, which measured a median PFOA concentration of 9.7 ng/mL and 9.0 ng/mL in men and women, respectively ( 39 ). The biological mechanisms associated with PFASs and insulin resistance are unclear. Animal studies have shown that in mice exposed to PFAS, PFAS negatively regulates the protein kinase B (PKB) pathway in white adipose tissue, resulting in increased glucose and decreased insulin and insulin resistance ( 40 ). PFASs also have affinity to PPAR-γ and exposure to PFASs may also trigger expression of store free fatty acids and regulate the transcription of various insulin-related genes through activation of PPAR-γ and ultimately enhance insulin sensitivity ( 17 , 34 , 41 ). Although the findings from toxicology studies provide valuable insights, population data are lacking, so further research is needed to clarify the underlying mechanisms.

The results of this study showed that PFASs had different interactions in different age groups, for example, in terms of the relationships of PFASs and FPG, a negative interaction was observed between PFOS and PFHxS in ≤50 years old groups, while no interaction was found in >50 years old groups. At the same time, the differences in the serum levels of the six PFASs were all statistically significant between the two age groups in this study. Some researchers found that the combined toxic effects between PFASs may vary with the concentration ( 42 ). A study found that the toxic effect of high dose PFASs exposure experiment is not the same as that of low dose PFASs exposure experiment, that is, no effect under high dose exposure does not mean that there is no effect under low dose exposure ( 43 , 44 ). Therefore, different concentrations may explain the different interaction of PFASs in different age groups. Furthermore, the results of the BKMR model indicate that there is an interaction between PFASs, especially between PFOA and multiple PFASs (PFOS/PFUA/PFHxS). PFASs are a large family containing thousands of compounds, of which PFOA is the most typical and most widely used ( 45 ). Studies show that PFOA is the final metabolite of various PFASs in the environment ( 46 ). Activation of PPAR-α is thought to play a key role in the production of toxic effects by PFASs, and PFOA is a potent agonist of PPAR-α ( 47 ). The above may be the reason for the interaction of PFOA and multiple PFASs.

Previous studies have primarily focused on the effects of a single PFAS on glucose metabolism, with limited analysis of mixed exposures, and the toxic mechanism of mixed exposure of PFASs is currently unknown. A study found that the six PFASs (PFHxS, PFOA, PFNA, PFDA, PFUA, and PFDeA) can bind to human G protein-coupled receptor 40 (GPR40), and the increase in intracellular calcium level mediated by GPR40 can promote the fusion of insulin-containing vesicles with plasma, leading to insulin secretion, disrupting glucose homeostasis and ultimately aggravating insulin resistance ( 48 , 49 ). An animal study found tha the PFAS mixture could cause mitochondrial dysfunction and further disrupt glucose and lipid metabolic pathways, ultimately causing metabolic disorders ( 50 ). Further studies are needed to clarify the combined mechanism of action of PFASs in the future.

The strengths of this study are as follows: this study first used the method of cluster analysis to automatically categorize the study participants into three groups based on PFASs exposure levels. By comparing the differences in glucose metabolism levels among these exposure groups, the distribution of PFASs among the participants and the influence of PFASs exposure levels on glucose metabolism indices were effectively presented. Further, unlike previous studies on the health effects of exposure to a single PFAS, this study explores the relationship between exposure to multiple PFASs and glucose metabolism indices. This study used LASSO regression to screen PFASs variables and used the BKMR model to evaluate the overall mixed effects and interactions of multiple PFASs. These two approaches complemented each other.

However, some limitations should be recognized. First, we cannot rule out residual and unmeasured confounders (for example, total fat or high fructose dietary intake), or consumption of foods packaged with food contact materials containing PFASs, which could lead to more PFAS exposure. Additionally, the cross-sectional design could not tell the causal relationship between PFAS exposure and glucose metabolism and biological mechanisms linking PFASs exposure to glucose metabolism have yet to be established. Therefore, further experimental studies are required to explore the relevant mechanisms underlying the association of serum PFASs with glucose homeostasis and metabolic indices.

5 Conclusion

In this study, we analyzed 2017–2018 United States NHANES data to assess the relationships between serum concentrations of the six PFASs and glucose metabolism indices. It was found that PFOA, PFOS, PFUA, PFNA, and PFHxS could play a significant role in the relationships of PFASs and glucose metabolism. Moreover, interactions were observed between PFOS and PFHxS, and PFOA and PFOS/PFHxS/PFNA. Our study provides new evidence for the harmful effects of PFASs exposure; however, further longitudinal studies are needed to confirm these findings and clarify the underlying mechanisms.

Data availability statement

Publicly available datasets were analyzed in this study. This data can be found at: https://www.cdc.gov/nchs/nhanes/ .

Ethics statement

The studies involving human participants were reviewed and approved by National Center for Health Statistics Research Ethics Review Board. The participants provided their written informed consent to participate in this study.

Author contributions

QT: Writing – original draft, Visualization, Software, Methodology, Formal analysis, Conceptualization. YY: Writing – review & editing, Visualization, Software, Resources, Data curation, Conceptualization. QA: Writing – review & editing, Software, Methodology. YL: Software, Methodology, Writing – review & editing. QW: Writing – review & editing, Validation, Resources. PZ: Writing – review & editing. YuZ: Writing – review & editing. YiZ: Writing – review & editing, Funding acquisition. LM: Project administration, Writing – review & editing, Supervision, Data curation. LL: Project administration, Writing – review & editing, Supervision, Funding acquisition.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China [grant numbers 81872701, 81273040] and National Natural Science Foundation of China [grant number 82103938].

Acknowledgments

We acknowledge the financial support for this study and the participation of all individuals.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

PFASs, perfluoroalkyl and polyfluoroalkyl substances; NHANES, National Health and Nutrition Examination Survey; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment for insulin resistance; LASSO, least absolute shrinkage and selection operator; BKMR, Bayesian kernel machine regression; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFUA, perfluoroundecanoic acid; PFHxS, perfluorohexane sulfonic acid; PFOS, perfluorooctane sulfonates acid; PFDeA, perfluorodecanoic acid; PPAR, peroxisome proliferator activated receptors; IQR, interquartile range; VIF, variance inflation factor; PIP, posterior inclusion probability; GPR40, human G protein-coupled receptor 40; PPAR-α, peroxisome proliferator-activated receptor alpha; n-PFOA, n-perfluorooctanoic acid; Sb-PFOA, branch perfluorooctanoic acid isomers; n-PFOS, n-perfluorooctane sulfonic acid; Sm-PFOS, perfluoromethylheptane sulfonic acid isomers.

1. ^ https://www.cdc.gov/nchs/nhanes/

2. ^ https://wwwn.cdc.gov/Nchs/Nhanes/2017-2018/PFAS_J.htm

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Keywords: perfluoroalkyl and polyfluoroalkyl substances, National Health and Nutrition Examination Survey, glucose metabolism, least absolute shrinkage and selection operator, Bayesian kernel machine regression

Citation: Tian Q, Yang Y, An Q, Li Y, Wang Q, Zhang P, Zhang Y, Zhang Y, Mu L and Lei L (2024) Association of exposure to multiple perfluoroalkyl and polyfluoroalkyl substances and glucose metabolism in National Health and Nutrition Examination Survey 2017–2018. Front. Public Health . 12:1370971. doi: 10.3389/fpubh.2024.1370971

Received: 15 January 2024; Accepted: 13 March 2024; Published: 03 April 2024.

Reviewed by:

Copyright © 2024 Tian, Yang, An, Li, Wang, Zhang, Zhang, Zhang, Mu and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lijian Lei, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Nutrients exert potent effects on metabolism through a variety of regulatory mechanisms, resulting in local and systemic changes in metabolite levels. Numerous studies have focused on mechanisms by which nutrients and disease states regulate metabolism at the gene or protein levels using genomic and proteomic approaches, respectively. However, few studies have investigated nutritional ...
Creating the Future of Evidence-Based Nutrition Recommendations: Case
Case studies on ω-3 (n-3) fatty acids (FAs) and industrial trans-FAs illustrate key factors vital to relevance and translational impact, including choice of a relevant population (e.g., healthy, at risk, or diseased subjects; general population or high-performance soldiers); dose and form of the intervention (e.g., food or supplement); use ...
Journal of Health, Metabolism and Nutrition Studies
About the Journal. Journal of Health, Metabolism and Nutrition Studies is a peer-reviewed journal that publishes original research articles, reviews, and case studies covering the broad and multidisciplinary field of health sciences, metabolism and human nutrition. This interdisciplinary journal serves as a platform for researchers, healthcare ...
Full article: Case study: nutritional considerations in the head and
Nathaniël Van Wyk. Head and neck squamous cell cancer (HNSCC) involves cancer of the oral cavity, oropharynx, hypopharynx and larynx. By virtue of the tumour location, nutrition support in this patient cohort can be extremely challenging. A 48-year-old male presented with a two-month history of progressive dysphagia, significant loss of weight ...
Case studies and realist review of nutrition education innovations
Apart from lectures related to nutrition metabolism, the students had had no previous teaching on nutrition. An initial meeting with medical school representatives from the GP academic department and Bags of Taste had established joint educational aims. ... Case study 3: development of a nutrition online learning module at Barts and The London ...
WK 3 CASE Study
Week 3 Case Study: Metabolism and Nutrition. Identify 2 potential causes of ketonuria. Two potential causes of ketonuria are fasting diets, such as keto, and physiologic circumstances, such as excessive alcohol. Identify the nutrient involved in the formation of ketones. When the glucose supply is short, the body utilizes fats and proteins.
Medical Nutrition Therapy in Chronic Renal Disease: A Case S
y the progression of the disease and improve the quality of life. Patient education was emphasized during every diet counseling session. The patient progressed through nutrition care as indicated in the plan of care, with improvement. NCP was used to document and manage nutrition care and involves four steps: nutrition assessment and reassessment, nutrition diagnosis, nutrition intervention ...
Introduction to Metabolism and Nutrition
By the end of this section, you will be able to: Figure 1. Metabolism is the sum of all energy-requiring and energy-consuming processes of the body. Many factors contribute to overall metabolism, including lean muscle mass, the amount and quality of food consumed, and the physical demands placed on the human body. (credit: "tableatny ...
Nutritional Biochemistry and Metabolism, BS
Degree: Bachelor of Science (BS) Major: Nutritional Biochemistry and Metabolism Program Overview. Nutritional Biochemistry and Metabolism is the study of nutrients and their metabolic functions. This degree program also prepares the students for graduate studies in nutrition or metabolic research or for further training for careers in medicine, dentistry, and other allied health professions.
PDF Case Study: Nutrition and Training Periodization in Three Elite
tion approaches with the same physiology/nutrition practitioner. Each athlete/coach has read, approved, and provided written permission for this publication, which conforms to the principle approval for case studies in the International Journal of Sports Nutrition and Exercise Metabolism by the ethics committee of the Australian Institute of Sport.
Week 3 Case Study Metabolism and Nutrition.docx
View Week 3 Case Study Metabolism and Nutrition.docx from BIO 256 at Chamberlain College of Nursing. History: BT is a 36-year-old female experiencing pain during urination over the course of two days
Bios256 case study week 3
Case Study: Week 3 Metabolism and Nutrition. BIOS 256. Professor: Hannah Gocinski. 24 th July 2023. Week 3: Metabolism and Nutrition. Identify 2 potential causes of ketonuria. There are two different etiologies that may lead to the occurrence of ketonuria. One potential dietary approach that has gained attention is fasting for extended ...
JCM
This comprehensive review explores the dynamic relationship between sports, nutrition, and neurological health. Focusing on recent clinical advancements, it examines how physical activity and dietary practices influence the prevention, treatment, and rehabilitation of various neurological conditions. The review highlights the role of neuroimaging in understanding these interactions, discusses ...
Nutrition in Patients with Type 2 Diabetes: Present Knowledge and
In a large case-control study involving 4443 Chinese individuals (nearly half with either newly diagnosed T2D or newly diagnosed pre-diabetes), plasma chromium levels were approximately 10% lower in the T2D and pre-diabetes groups vs. controls, and the risk of T2D and pre-diabetes decreased across quartiles of chromium .
Add antioxidants to your diet
In: Academy of Nutrition and Dietetics Complete Food and Nutrition Guide. 5th ed. Houghton Mifflin Harcourt; 2017. Aune D, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: A systematic review and dose-response meta-analysis of prospective studies.
Case Study Metabolism and Nutrition.docx
View Case Study Metabolism and Nutrition.docx from BIO 256 at Chamberlain University College of Nursing. Case Study: Metabolism and Nutrition July 20, 2022 Tashondra Smith Bio 256 Human Anatomy &
Nutrients
Many countries are facing the advent of super-aging societies, where sarcopenia and frailty will become pertinent problems. The prevalence of comorbidities is a major problem in countries with aged populations as elderly people suffer from various diseases, such as diabetes, heart failure, chronic kidney disease and dementia. All of these diseases are associated with sarcopenia and frailty ...
Frontiers
A nested case-control study also found that mixed PFASs homologs could affect glucose homeostasis by increasing 1 ... Association of exposure to multiple perfluoroalkyl and polyfluoroalkyl substances and glucose metabolism in National Health and Nutrition Examination Survey 2017-2018. Front. Public Health. 12:1370971. doi: 10.3389/fpubh ...
Solved Week 3 Case Study: Metabolism and Nutrition Start
Week 3 Case Study: Metabolism and Nutrition Start Assignment Due Sunday by 11.59pm Points 15 Submitting a file upload Week 3 Case Study: Metabolism and Nutrition Required Resources Read/review the following resources for this activity • Textbook • Weekly Concepts • Minimum of 1 scholarly source Scenario/Summary History: BT is a 36 year old female experiencing pain during urination over ...
How Many Calories Should You Eat in a Day?
Many factors go into determining your calorie needs. Your age, weight, gender/sex, height and activity level all play a role. According to dietary guidelines in the United States, adults 21 years ...
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Week 3 Case Study Metabolism and Nutrition.docx
1 Week 3 Case Study on Metabolism and Nutrition Chamberlain University College of Nursing BIOS256: Anatomy and Physiology IV Week 3 Case Study on Metabolism and Nutrition. 2 According to the text, the abnormal presence of ketones in the urine is known as ketonuria. This condition is a common sign of diabetes mellitus.
Measuring the value of using social protection for ...
Assessment in English on Bangladesh about Food and Nutrition, Protection and Human Rights, ... Three light-touch case studies examine the use of social protection systems and programmes in recent ...
Week 3 Case Study Metabolism and Nutrition.docx
Week 3 Case Study: Metabolism and Nutrition Ban Ahmed 1. Identify 2 potential causes of ketonuria. Ketonuria is a condition in which the body produces energy from fat rather than carbohydrates. Infection and corticosteroid use are two probable causes of ketonuria. 2. Identify the nutrient involved in the formation of ketones.