From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.

The increasing prevalence of 'diabesity', a combination of type 2 diabetes and obesity, poses a significant global health challenge. Unhealthy lifestyle factors, including poor diet, sedentary behaviour, and high stress levels, combined with genetic and epigenetic factors, contribute to the diabesity epidemic. Diabesity leads to various significant complications such as cardiovascular diseases, stroke, and certain cancers. Incretin-based therapies, such as GLP-1 receptor agonists and dual hormone therapies, have shown promising results in improving glycaemic control and inducing weight loss. However, these therapies also come with certain disadvantages, including potential withdrawal effects. This review aims to provide insights into the cross-interactions of insulin, glucagon, and GLP-1, revealing the complex hormonal dynamics during fasting and postprandial states, impacting glucose homeostasis, energy expenditure, and other metabolic functions. Understanding these hormonal interactions may offer novel hypotheses in the development of 'anti-diabesity' treatment strategies. The article also explores the question of the antagonism of insulin and glucagon, providing insights into the potential synergy and hormonal overlaps between these hormones.

Improvement in Visceral Adipose Tissue and LDL Cholesterol by High PUFA Intake: 1-Year Results of the NutriAct Trial.

We assessed the effect of a dietary pattern rich in unsaturated fatty acids (UFA), protein and fibers, without emphasizing energy restriction, on visceral adipose tissue (VAT) and cardiometabolic risk profile. Within the 36-months randomized controlled NutriAct trial, we randomly assigned 502 participants (50-80 years) to an intervention or control group (IG, CG). The dietary pattern of the IG includes high intake of mono-/polyunsaturated fatty acids (MUFA/PUFA 15-20% E/10-15% E), predominantly plant protein (15-25% E) and fiber (≥30 g/day). The CG followed usual care with intake of 30% E fat, 55% E carbohydrates and 15% E protein. Here, we analyzed VAT in a subgroup of 300 participants via MRI at baseline and after 12 months, and performed further metabolic phenotyping. A small but comparable BMI reduction was seen in both groups (mean difference IG vs. CG: -0.216 kg/m2 [-0.477; 0.045], partial η2 = 0.009, p = 0.105). VAT significantly decreased in the IG but remained unchanged in the CG (mean difference IG vs. CG: -0.162 L [-0.314; -0.011], partial η2 = 0.015, p = 0.036). Change in VAT was mediated by an increase in PUFA intake (ß = -0.03, p = 0.005) and induced a decline in LDL cholesterol (ß = 0.11, p = 0.038). The NutriAct dietary pattern, particularly due to high PUFA content, effectively reduces VAT and cardiometabolic risk markers, independent of body weight loss.

Practical strategies to manage obesity in type 2 diabetes.

The rising phenomenon of obesity, a major risk factor for the development and progression of type 2 diabetes, is a complex and multifaceted issue that requires a comprehensive and coordinated approach to be prevented and managed. Although novel pharmacological measures to combat obesity have achieved unprecedented efficacy, a healthy lifestyle remains essential for the long-term success of any therapeutic intervention. However, this requires a high level of intrinsic motivation and continued behavioural changes in the face of multiple metabolic, psychological and environmental factors promoting weight gain, particularly in the context of type 2 diabetes. This review is intended to provide practical recommendations in the context of a holistic, person-centred approach to weight management, including evidence-based and expert recommendations addressing supportive communication, shared decision-making, as well as nutritional and pharmacological therapeutic approaches to achieve sustained weight loss.

Isomaltulose Enhances GLP-1 and PYY Secretion to a Mixed Meal in People With or Without Type 2 Diabetes as Compared to Saccharose.

SCOPE: Secretion of the gut hormones glucagon-like peptide (GLP-1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve ß-cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1 h before a standardized mixed meal test (MMT) on GLP-1, PYY, glucose-dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM). METHODS AND RESULTS: Fifteen healthy volunteers and 15 patients with T2DM consumed either 50 g ISO or SAC 1 h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50 g ISO as compared to SAC induced a significant increase in GLP-1, GIP, and PYY responses over 2 h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP-1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC. CONCLUSION: A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP-1 and enhances GIP release in response to a subsequent complex meal.

Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS).

BACKGROUND: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. METHODS: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. FINDINGS: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. INTERPRETATION: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. FUNDING: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.

The Regulation and Secretion of Glucagon in Response to Nutrient Composition: Unraveling Their Intricate Mechanisms.

Glucagon was initially regarded as a hyperglycemic substance; however, recent research has revealed its broader role in metabolism, encompassing effects on glucose, amino acids (AAs), and lipid metabolism. Notably, the interplay of glucagon with nutrient intake, particularly of AAs, and non-nutrient components is central to its secretion. Fasting and postprandial hyperglucagonemia have long been linked to the development and progression of type 2 diabetes (T2DM). However, recent studies have brought to light the positive impact of glucagon agonists on lipid metabolism and energy homeostasis. This review explores the multifaceted actions of glucagon, focusing on its regulation, signaling pathways, and effects on glucose, AAs, and lipid metabolism. The interplay between glucagon and other hormones, including insulin and incretins, is examined to provide a mechanistic understanding of its functions. Notably, the liver-α-cell axis, which involves glucagon and amino acids, emerges as a critical aspect of metabolic regulation. The dysregulation of glucagon secretion and its impact on conditions such as T2DM are discussed. The review highlights the potential therapeutic applications of targeting the glucagon pathway in the treatment of metabolic disorders.

Liver Fat Scores for Noninvasive Diagnosis and Monitoring of Nonalcoholic Fatty Liver Disease in Epidemiological and Clinical Studies.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and type 2 diabetes and independently contributes to long-term complications. Being often asymptomatic but reversible, it would require population-wide screening, but direct diagnostics are either too invasive (liver biopsy), costly (MRI) or depending on the examiner's expertise (ultrasonography). Hepatosteatosis is usually accommodated by features of the metabolic syndrome (e.g. obesity, disturbances in triglyceride and glucose metabolism), and signs of hepatocellular damage, all of which are reflected by biomarkers, which poorly predict NAFLD as single item, but provide a cheap diagnostic alternative when integrated into composite liver fat indices. Fatty liver index, NAFLD LFS, and hepatic steatosis index are common and accurate indices for NAFLD prediction, but show limited accuracy for liver fat quantification. Other indices are rarely used. Hepatic fibrosis scores are commonly used in clinical practice, but their mandatory reflection of fibrotic reorganization, hepatic injury or systemic sequelae reduces sensitivity for the diagnosis of simple steatosis. Diet-induced liver fat changes are poorly reflected by liver fat indices, depending on the intervention and its specific impact of weight loss on NAFLD. This limited validity in longitudinal settings stimulates research for new equations. Adipokines, hepatokines, markers of cellular integrity, genetic variants but also simple and inexpensive routine parameters might be potential components. Currently, liver fat indices lack precision for NAFLD prediction or monitoring in individual patients, but in large cohorts they may substitute nonexistent imaging data and serve as a compound biomarker of metabolic syndrome and its cardiometabolic sequelae.

The Effects of the Mediterranean Diet on Health and Gut Microbiota.

The Mediterranean Diet (MD) is plant-based and consists of multiple daily portions of vegetables, fruit, cereals, and olive oil. Although there are challenges with isolating the MD from the typical Mediterranean lifestyle and culture (including prolonged 'social' meals and siestas), much evidence supports the health benefits of the MD that include improved longevity, reduced metabolic risk of Diabetes Mellitus, obesity, and Metabolic Syndrome, reduced risk of malignancy and cardiovascular disease, and improved cognitive function. The MD is also associated with characteristic modifications to gut microbiota, mediated through its constituent parts (primarily dietary fibres, extra virgin olive oil, and polyunsaturated fatty acids [including ω-3]). These include enhanced growth of species that produce short-chain fatty acids (butyrate), such as Clostridium leptum and Eubacterium rectale, enhanced growth of Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii species, and reduced growth of Firmicutes and Blautia species. Such changes in gut microbiota are known to be associated favourably with inflammatory and oxidative status, propensity for malignancy and overall metabolic health. A key challenge for the future is to explore the extent to which the health benefits of the MD are mediated by such changes to gut microbiota. The MD confers both health and environmental benefits. Adoption of the MD should perhaps be encouraged and facilitated more generally and not just restricted to populations from Mediterranean regions. However, there are key challenges to this approach that include limited perennial availability of the constituent parts of the MD in some non-Mediterranean regions, intolerability of a high-fibre diet for some people, and potential cultural disconnects that juxtapose some traditional (including Western) diets with the MD.

Metabolic-Associated Fatty Liver Disease and Insulin Resistance: A Review of Complex Interlinks.

Metabolic-associated fatty liver disease (MAFLD) has now surpassed alcohol excess as the most common cause of chronic liver disease globally, affecting one in four people. Given its prevalence, MAFLD is an important cause of cirrhosis, even though only a small proportion of patients with MAFLD ultimately progress to cirrhosis. MAFLD suffers as a clinical entity due to its insidious and often asymptomatic onset, lack of an accurate and reliable non-invasive diagnostic test, and lack of a bespoke therapy that has been designed and approved for use specifically in MAFLD. MAFLD sits at a crossroads between the gut and the periphery. The development of MAFLD (including activation of the inflammatory cascade) is influenced by gut-related factors that include the gut microbiota and intactness of the gut mucosal wall. The gut microbiota may interact directly with the liver parenchyma (through translocation via the portal vein), or indirectly through the release of metabolic metabolites that include secondary bile acids, trimethylamine, and short-chain fatty acids (such as propionate and acetate). In turn, the liver mediates the metabolic status of peripheral tissues (including insulin sensitivity) through a complex interplay of hepatokines, liver-secreted metabolites, and liver-derived micro RNAs. As such, the liver plays a key central role in influencing overall metabolic status. In this concise review, we provide an overview of the complex mechanisms whereby MAFLD influences the development of insulin resistance within the periphery, and gut-related factors impact on the development of MAFLD. We also discuss lifestyle strategies for optimising metabolic liver health.

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins.

BACKGROUND: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. METHODS: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. RESULTS: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. CONCLUSION: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

Implication of sugar, protein and incretins in excessive glucagon secretion in type 2 diabetes after mixed meals.

AIMS: Amino acids powerfully release glucagon but their contribution to postprandial hyperglucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 inhibits, glucagon secretion in humans. However, their role in mixed meals is unclear, which we therefore characterized. METHODS: In three experiments, participants with type 2 diabetes and obese controls randomly received different loads of sugars and/or proteins. In the first experiment, participants ingested the rapidly cleaved saccharose (SAC) or slowly cleaved isomaltulose (ISO) which is known to elicit opposite profiles of GIP and GLP-1 secretion. In the second one participants received test meals which contained saccharose or isomaltulose in combination with milk protein. The third set of participants underwent randomized oral protein tests with whey protein or casein. Incretins, glucagon, C-peptide, and insulin were profiled by specific immunological assays. RESULTS: 50 g of the sugars alone suppressed glucagon in controls but slightly less in type 2 diabetes patients. Participants with type 2 diabetes showed excessive glucagon responses within 15 min and lasting over 3 h, while the obese controls showed small initial and delayed greater glucagon responses to mixed meals. The release of GIP was significantly faster and greater with SAC compared to ISO, while GLP-1 showed an inverse pattern. The glucagon responses to whey or casein were only moderately increased in type 2 diabetes patients without a left shift of the dose response curve. CONCLUSIONS: The rapid hypersecretion of glucagon after mixed meals in type 2 diabetes patients compared to controls is unaffected by endogenous incretins. The defective suppression of glucagon by glucose combined with hypersecretion to protein is required for the exaggerated response. CLINICAL TRIALS NUMBERS: NCT03806920, NCT02219295, NCT04564391.

Acute and long-term exercise adaptation of adipose tissue and skeletal muscle in humans: a matched transcriptomics approach after 8-week training-intervention.

BACKGROUND: Exercise exerts many health benefits by directly inducing molecular alterations in physically utilized skeletal muscle. Molecular adaptations of subcutaneous adipose tissue (SCAT) might also contribute to the prevention of metabolic diseases. AIM: To characterize the response of human SCAT based on changes in transcripts and mitochondrial respiration to acute and repeated bouts of exercise in comparison to skeletal muscle. METHODS: Sedentary participants (27 ± 4 yrs) with overweight or obesity underwent 8-week supervised endurance exercise 3×1h/week at 80% VO2peak. Before, 60 min after the first and last exercise bout and 5 days post intervention, biopsies were taken for transcriptomic analyses and high-resolution respirometry (n = 14, 8 female/6 male). RESULTS: In SCAT, we found 37 acutely regulated transcripts (FC > 1.2, FDR < 10%) after the first exercise bout compared to 394, respectively, in skeletal muscle. Regulation of only 5 transcripts overlapped between tissues highlighting their differential response. Upstream and enrichment analyses revealed reduced transcripts of lipid uptake, storage and lipogenesis directly after exercise in SCAT and point to ß-adrenergic regulation as potential major driver. The data also suggest an exercise-induced modulation of the circadian clock in SCAT. Neither term was associated with transcriptomic changes in skeletal muscle. No evidence for beigeing/browning was found in SCAT along with unchanged respiration. CONCLUSIONS: Adipose tissue responds completely distinct from adaptations of skeletal muscle to exercise. The acute and repeated reduction in transcripts of lipid storage and lipogenesis, interconnected with a modulated circadian rhythm, can counteract metabolic syndrome progression toward diabetes.

Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P < 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction < 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.

Predicting Factors for Metabolic Non-Response to a Complex Lifestyle Intervention-A Replication Analysis to a Randomized-Controlled Trial.

BACKGROUND: T2DM heterogeneity affects responsiveness to lifestyle treatment. Beta-cell failure and nonalcoholic fatty liver disease (NAFLD) independently predict T2DM, but NAFLD inconsistently predicts metabolic response to lifestyle intervention. AIM: We attempt to replicate a prediction model deducted from the Tübinger Lifestyle Intervention Program by assessing similar metabolic factors to predict conversion to normal glucose regulation (NGR) in a comparable lifestyle intervention trial. METHODS: In the Optimal Fiber Trial (OptiFiT), 131 Caucasian participants with prediabetes completed a one-year lifestyle intervention program and received a fiber or placebo supplement. We compared baseline parameters for responders and non-responders, assessed correlations of major metabolic changes and conducted a logistic regression analysis for predictors of remission to NGR. RESULTS: NGR was achieved by 33 participants, respectively. At baseline, for the placebo group only, 1 h and 2 h glucose levels, glucose AUC and Cederholm index predicted conversion to NGR. HOMA-beta, HOMA-IR or liver fat indices did not differ between responders and non-responders of the placebo or the fiber group. Changes in waist circumference or fatty liver index correlated with changes in glycemia and insulin resistance, but not with changes in insulin secretion. Insulin-resistant NAFLD did not predict non-response. Differences in compliance did not explain the results. CONCLUSIONS: Higher post-challenge glucose levels strongly predicted the metabolic non-response to complex lifestyle intervention in our cohort. Depending on the specific intervention and the investigated cohort, fasting glucose levels and insulin sensitivity might contribute to the risk pattern. Beta-cell function did not improve in accordance with other metabolic improvements, qualifying as a potential risk factor for non-response. We could not replicate previous data suggesting that an insulin-resistant fatty liver is a specific risk factor for treatment failure. Replication studies are required.

The role of cereal soluble fiber in the beneficial modulation of glycometabolic gastrointestinal hormones.

According to cohort studies, cereal fiber, and whole-grain products might decrease risk for type 2 diabetes (T2DM), inflammatory processes, cancer, and cardiovascular diseases. These associations, mainly affect insoluble, but not soluble cereal fiber. In intervention studies, soluble fiber elicit anti-hyperglycemic and anti-inflammatory short-term effects, partially explained by fermentation to short-chain fatty acids, which acutely counteract insulin resistance and inflammation. ß-glucans lower cholesterol levels and possibly reduce liver fat. Long-term benefits are not yet shown, maybe caused by T2DM heterogeneity, as insulin resistance and fatty liver disease - the glycometabolic points of action of soluble cereal fiber - are not present in every patient. Thus, only some patients might be susceptive to fiber. Also, incretin action in response to fiber could be a relevant factor for variable effects. Thus, this review aims to summarize the current knowledge from human studies on the impact of soluble cereal fiber on glycometabolic gastrointestinal hormones. Effects on GLP-1 appear to be highly contradictory, while these fibers might lower GIP and ghrelin, and increase PYY and CCK. Even though previous results of specific trials support a glycometabolic benefit of soluble fiber, larger acute, and long-term mechanistic studies are needed in order to corroborate the results.

Dietary protein and the glycemic index handle insulin resistance within a nutritional program for avoiding weight regain after energy-restricted induced weight loss.

BACKGROUND AND AIM: The role of dietary protein and glycemic index on insulin resistance (based on TyG index) within a nutritional program for weight loss and weight maintenance was examined. METHODS: This study analyzed 744 adults with overweight/obesity within the DIOGenes project. Patients who lost at least 8% of their initial weight (0-8 weeks) after a low-calorie diet (LCD) were randomly assigned to one of five ad libitum diets designed for weight maintenance (8-34 weeks): high/low protein (HP/LP) and high/low glycemic index (HGI/LGI), plus a control. The complete nutritional program (0-34 weeks) included both LCD plus the randomized diets intervention. The TyG index was tested as marker of body mass composition and insulin resistance. RESULTS: In comparison with the LP/HGI diet, the HP/LGI diet induced a greater BMI loss (p < 0.05). ∆TyG was positively associated with resistance to BMI loss (ß = 0.343, p = 0.042) during the weight maintenance stage. In patients who followed the HP/LGI diet, TyG (after LCD) correlated with greater BMI loss in the 8-34 weeks period (r = -0.256; p < 0.05) and during the 0-34 weeks intervention (r = -0.222, p < 0.05) periods. ΔTyG1 value was associated with ΔBMI2 (ß = 0.932; p = 0.045) concerning the HP/LGI diet. CONCLUSIONS: A HP/LGI diet is beneficial not only for weight maintenance after a LCD, but is also related to IR amelioration as assessed by TyG index changes. Registration Clinical Trials NCT00390637.

Low IGF1 and high IGFBP1 predict diabetes onset in prediabetic patients.

Objectives: Some individuals develop type 2 diabetes mellitus (T2DM) despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that insulin growth factor 1 (IGF1) and its binding proteins 1 and 2 predict the onset of T2DM in prediabetes patients and determine the capacity for metabolic regeneration. Design: We measured fasting serum IGF1, insulin growth factor-binding protein 1 (IGFBP1) and IGFBP2 in three randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up. Methods: Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. Three hundred and forty-five subjects finished the first year of intervention. Results: The interventions significantly improved body weight (BMI: -3.24%, P < 0.001), liver fat (-36.8%, P < 0.001), insulin sensitivity (IS) (homeostatic model assessment-insulin resistance: -6.3%, P < 0.001) and insulin secretion (disposition index: +35%, P < 0.001) in the cohort. Fourteen percent developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and nonalcoholic fatty liver disease had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs 146.6 µg/L) and IGFBP1 was higher (3.32 vs 2.09 µg/L) in subjects who developed T2DM (n = 57), resulting in a significant prediction of diabetes incidence (hazard ratio (HR) IGF1: 0.991 µg/L, P = 0.003; HR IGFBP1: 1.061 µg/L, P = 0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral fat and hepatic fat in response to 1 year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1. Conclusions: Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention.

Implications of Resveratrol in Obesity and Insulin Resistance: A State-of-the-Art Review.

Background: Resveratrol is a polyphenol chemical that naturally occurs in many plant-based dietary products, most notably, red wine. Discovered in 1939, widespread interest in the potential health benefits of resveratrol emerged in the 1970s in response to epidemiological data on the cardioprotective effects of wine. Objective: To explore the background of resveratrol (including its origins, stability, and metabolism), the metabolic effects of resveratrol and its mechanisms of action, and a potential future role of dietary resveratrol in the lifestyle management of obesity. Data sources: We performed a narrative review, based on relevant articles written in English from a Pubmed search, using the following search terms: "resveratrol", "obesity", "Diabetes Mellitus", and "insulin sensitivity". Results: Following its ingestion, resveratrol undergoes extensive metabolism. This includes conjugation (with sulfate and glucuronate) within enterocytes, hydrolyzation and reduction within the gut through the action of the microbiota (with the formation of metabolites such as dihydroresveratrol), and enterohepatic circulation via the bile. Ex vivo studies on adipose tissue reveal that resveratrol inhibits adipogenesis and prevents the accumulation of triglycerides through effects on the expression of Peroxisome Proliferator-activated Receptor γ (PPARγ) and sirtuin 1, respectively. Furthermore, resveratrol induces anti-inflammatory effects, supported by data from animal-based studies. Limited data from human-based studies reveal that resveratrol improves insulin sensitivity and fasting glucose levels in patients with Type 2 Diabetes Mellitus and may improve inflammatory status in human obesity. Although numerous mechanisms may underlie the metabolic benefits of resveratrol, evidence supports a role in its interaction with the gut microbiota and modulation of protein targets, including sirtuins and proteins related to nitric oxide, insulin, and nuclear hormone receptors (such as PPARγ). Conclusions: Despite much interest, there remain important unanswered questions regarding its optimal dosage (and how this may differ between and within individuals), and possible benefits within the general population, including the potential for weight-loss and improved metabolic function. Future studies should properly address these important questions before we can advocate the widespread adoption of dietary resveratrol supplementation.

High Protein Diets Improve Liver Fat and Insulin Sensitivity by Prandial but Not Fasting Glucagon Secretion in Type 2 Diabetes.

Glucagon (GCGN) plays a key role in glucose and amino acid (AA) metabolism by increasing hepatic glucose output. AA strongly stimulate GCGN secretion which regulates hepatic AA degradation by ureagenesis. Although increased fasting GCGN levels cause hyperglycemia GCGN has beneficial actions by stimulating hepatic lipolysis and improving insulin sensitivity through alanine induced activation of AMPK. Indeed, stimulating prandial GCGN secretion by isocaloric high protein diets (HPDs) strongly reduces intrahepatic lipids (IHLs) and improves glucose metabolism in type 2 diabetes mellitus (T2DM). Therefore, the role of GCGN and circulating AAs in metabolic improvements in 31 patients with T2DM consuming HPD was investigated. Six weeks HPD strongly coordinated GCGN and AA levels with IHL and insulin sensitivity as shown by significant correlations compared to baseline. Reduction of IHL during the intervention by 42% significantly improved insulin sensitivity [homeostatic model assessment for insulin resistance (HOMA-IR) or hyperinsulinemic euglycemic clamps] but not fasting GCGN or AA levels. By contrast, GCGN secretion in mixed meal tolerance tests (MMTTs) decreased depending on IHL reduction together with a selective reduction of GCGN-regulated alanine levels indicating greater GCGN sensitivity. HPD aligned glucose metabolism with GCGN actions. Meal stimulated, but not fasting GCGN, was related to reduced liver fat and improved insulin sensitivity. This supports the concept of GCGN-induced hepatic lipolysis and alanine- and ureagenesis-induced activation of AMPK by HPD.