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.

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.

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.

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.

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.

Periodontitis, age-related diseases and diabetes in an endocrinological outpatient setting (PARADIES): a cross-sectional analysis on predictive factors for periodontitis in a German outpatient facility.

BACKGROUND: Diabetes mellitus (DM) is a risk factor for periodontitis. Data on risk-modifying factors for periodontitis in diabetes patients are limited. AIMS: We tested whether sex, age, type of diabetes, metabolic state, comorbidities, complications, measures of well-being and quality of life are predicting periodontitis in a German diabetes outpatient cohort. METHODS: In total, 1180 out of 1293 participating DM patients completed questionnaires on quality of life, dental hygiene and health. All patients also filled out a modified version of the periodontitis risk questionnaire by the American Association for Periodontology, from which the status of "assumed periodontitis" was deducted. In a subset of participants (n = 461), we measured or inquired the most recent Community Parodontal Index (CPI), providing an objective measure for clinically diagnosed periodontitis. For all subjects, DM history and phenotype, major metabolic parameters (HbA1c, BMI, LDL and total cholesterol levels), general health risk factors, comorbidities and medication were collected. RESULTS: Clinically diagnosed (CPI > 2) and assumed periodontitis was detected in 60-67% of our patients. Male sex and oral health-related quality of life were associated with clinically diagnosed periodontitis. Male sex, age, smoking, dental hygiene, dental control and diabetes-related quality of life independently predicted assumed periodontitis. CONCLUSION: In DM patients, quality of life and lifestyle factors which systemically alter microvascular and immunological functions seem to predict periodontitis. Further studies are needed for replication and for pathomechanistic clarification.

Insulin Directly Regulates the Circadian Clock in Adipose Tissue.

Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a "zeitgeber" aligning the clock in AT with the external time, but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes PER2, PER3, and NR1D1 in SAT were differentially changed upon insulin and saline infusion, suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells, and AT explants from mPer2Luc knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression, leading to the phase shift of circadian oscillations, with similar effects for Per1 Insulin effects were dependent on the region between -64 and -43 in the Per2 promoter but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes, thus representing a primary mechanism of feeding-induced AT clock entrainment.

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.

The Health Benefits of Dietary Fibre.

BACKGROUND: Dietary fibre consists of non-digestible forms of carbohydrate, usually as polysaccharides that originate from plant-based foods. Over recent decades, our diet within Westernised societies has changed radically from that of our hominid ancestors, with implications for our co-evolved gut microbiota. This includes increased ingestion of ultra-processed foods that are typically impoverished of dietary fibre, and associated reduction in the intake of fibre-replete plant-based foods. Over recent decades, there has been a transformation in our understanding of the health benefits of dietary fibre. OBJECTIVE: To explore the current medical literature on the health benefits of dietary fibre, with a focus on overall metabolic health. DATA SOURCES: We performed a narrative review, based on relevant articles written in English from a PubMed search, using the terms 'dietary fibre and metabolic health'. RESULTS: In the Western world, our diets are impoverished of fibre. Dietary fibre intake associates with overall metabolic health (through key pathways that include insulin sensitivity) and a variety of other pathologies that include cardiovascular disease, colonic health, gut motility and risk for colorectal carcinoma. Dietary fibre intake also correlates with mortality. The gut microflora functions as an important mediator of the beneficial effects of dietary fibre, including the regulation of appetite, metabolic processes and chronic inflammatory pathways. CONCLUSIONS: Multiple factors contribute to our fibre-impoverished modern diet. Given the plethora of scientific evidence that corroborate the multiple and varied health benefits of dietary fibre, and the risks associated with a diet that lacks fibre, the optimization of fibre within our diets represents an important public health strategy to improve both metabolic and overall health. If implemented successfully, this strategy would likely result in substantial future health benefits for the population.

Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men-A Randomized Controlled Trial.

SCOPE: Effective treatment for obesity associated non-alcoholic fatty liver disease (NAFLD) is limited. Dietary supplementation of n-3 polyunsaturated fatty acids, specifically alpha linolenic acid (ALA), can resolve intrahepatic lipid content (IHL). This study investigates the effect of daily supplementation of either refined rapeseed (RA), containing high amounts of ALA, or refined olive (OL) oil on IHL and glucose metabolism in NAFLD patients. METHODS AND RESULTS: 27 obese men consumed an isocaloric diet including either 50 g of RA or OL daily for 8 weeks. Hepatic proton magnetic resonance spectroscopy, hyperinsulinemic-euglycemic clamp studies and blood tests are performed before and at the end of the study. At 8 weeks a significant reduction in IHL is observed for RA (13.1 ± 1.6 before versus 11.1 ± 1.6% after intervention) versus OL (13.3 ± 2.5 before versus 15.7 ± 2.7% after intervention). For RA, a 21% reduction (P < 0.02) in serum free fatty acids (FFA) and a 1.68-fold increase (P = 0.03) of serum interleukin-6 (IL-6) is observed after 8 weeks. CONCLUSION: RA has a beneficial effect on hepatic lipid metabolism as shown by reduced IHL and serum FFA. RA induced IL-6 production seems to be liver protective confirming previous results.

Intra-individual reproducibility of galectin-1, haptoglobin, and nesfatin-1 as promising new biomarkers of immunometabolism.

BACKGROUND: Galectin-1, haptoglobin, and nesfatin-1 have recently emerged as promising biomarkers implicated in immunometabolism. However, whether single blood measurements of these analytes could be suitable for large-scale human studies has not yet been evaluated. METHODS: The concentrations of galectin-1, haptoglobin, and nesfatin-1 were measured over a 4-month period in 207 healthy adults with median age of 56.7 years. Biomarker intra-individual reproducibility was assessed based on calculation of intraclass correlation coefficients (ICCs) and examining Bland-Altman plots. RESULTS: The overall ICCs were excellent for nesfatin-1 (ICC: 0.89 (95% CI: 0.86, 0.92), and good for galectin-1 and haptoglobin (ICCs: 0.70 (95% CI: 0.61, 0.77) and 0.67 (95% CI: 0.57, 0.74), respectively). Bland-Altman plots supported a high level of agreement between repeated biomarker measurements. CONCLUSIONS: Assay measurements of galectin-1, haptoglobin, and nesfatin-1 showed good to excellent within-subject reproducibility over a 4-month period, indicating that they may serve as feasible and reliable biomarkers for assessing metabolic inflammation in population research.

High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low- (LP) or high-protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved. METHODS: 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500-1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery. RESULTS: IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA-seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of ß-oxidation genes did not increase in the HP group. CONCLUSIONS: HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis.

Sexually dimorphic metabolic responses to exposure of a high fat diet during pregnancy, lactation and early adulthood in Gipr-/- mice.

Obesity has a multifactorial origin. It is known that alterations of the intra uterine milieu induce developmental programming effects leading to metabolic diseases in offspring. Obesity is diminished in mice lacking the glucose-dependent insulinotropic polypeptide receptor (Gipr-/-) when exposed to a high fat diet (HFD). We investigated whether Gipr-/- mice are still protected from obesity when additionally exposure to a HFD during pregnancy and lactation occurs. Male and female wild type (WT) and Gipr-/- offspring received either a control/ low fat diet or HFD during pregnancy and lactation and were then either left on this diet or placed on the opposite diet after weaning until 24 weeks of life. Female WT mice showed increased body weight and adiposity when exposed to a HFD during pregnancy and lactation and post-weaning compared to female WT that received the HFD after weaning only. This exacerbated effect of a HFD during pregnancy and lactation was abolished in female Gipr-/- mice. Male Gipr-/- mice were protected from obesity to a much lesser extent. Male Gipr-/- mice exposed to a HFD during pregnancy and lactation and after weaning exhibited significantly increased fed serum glucose compared to Gipr-/- mice exposed to a HFD after weaning only. In female Gipr-/- mice no differences in fed blood glucose were observed between these groups. Our data indicate that female Gipr-/- mice are more protected from obesity. This protection is preserved in female Gipr-/- mice when additional deleterious effects of a HFD occur during fetal development.

Arachidonic acid inhibits the production of angiotensin-converting enzyme in human primary adipocytes via a NF-κB-dependent pathway.

BACKGROUND: The modulating mechanism of fatty acids on angiotensin-converting enzyme production (ACE) in human adipocytes is still elusive. Diet-induced regulation of the renin angiotensin system is thought to be involved in obesity and hypertension, and several previous studies have used mouse cell lines such as 3T3-L1 to investigate this. This study was carried out in human subcutaneous adipocytes for better understanding of the mechanism. METHODS: Human adipose stem cells were isolated from subcutaneous adipose tissue biopsies collected from four patients during bariatric surgery and differentiated into mature adipocytes. The mRNA expression and the activity of ACE were measured under different stimuli in cell cultures. RESULTS: Arachidonic acid (AA) decreased ACE mRNA expression and ACE activity in a dose-dependent manner while palmitic acid had no effect. The decrease of ACE by 100 µM AA was reversed by the addition of 5 µM nuclear factor-κB (NF-κB) inhibitor. Furthermore, when the production of 20-hydroxyeicosatetraenoic acid, a metabolite of AA, was stopped by the specific inhibitor HET0016 (10 µM) in the culture media, the effect of AA was blocked. CONCLUSIONS: This study indicated that AA can decrease the expression and activity of ACE in cultured human adipocytes, via an inflammatory NF-κB-dependent pathway. Blocking 20-hydroxyeicosatetraenoic acid attenuated the ACE-decreasing effects of AA.

Effects of plant and animal high protein diets on immune-inflammatory biomarkers: A 6-week intervention trial.

BACKGROUND & AIMS: Pro-inflammatory biomarkers are well-established contributors to insulin resistance and represent valid targets for diabetes management and prevention. Yet, little is known whether nutrition could play a role in modulating various aspects of immune-inflammatory responses. Our aim is to assess the effect of isocaloric animal and plant protein dietary interventions on selected biomarkers representing various immune-inflammatory pathways. METHODS: We enrolled 37 participants with type 2 diabetes (age 64 ± 6 years, body mass index 30.2 ± 3.6 kg/m2, glycated hemoglobin 7.0 ± 0.6%) who underwent an either high-animal protein (AP) or high-plant protein (PP) diet (30 E% protein, 40 E% carbohydrates, 30 E% fat) for 6-weeks. Clinical examinations were performed at beginning and end of the study. Levels of pro-inflammatory adipokines [chemerin, progranulin], cytokines [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), soluble urokinase-type plasminogen activator receptor (suPAR), transforming growth factor beta 1 (TGF-ß1)], and proteins [calprotectin, lactoferrin and growth differentiation factor 15 (GDF-15)] were determined in blood serum using enzyme-linked immunosorbent assay. RESULTS: Chemerin and progranulin concentrations decreased following AP and PP diets. TGF-ß1 increased in AP and decreased in PP, whereas calprotectin increased in PP and decreased in AP. No statistically significant differences in the concentrations of IL-6, TNF-α, suPAR, lactoferrin and GDF-15 could be seen in either of the protein diet arms. CONCLUSIONS: These results suggest that both AP and PP diets may effectively reduce the levels of the pro-inflammatory adipokines chemerin and progranulin. The effects on the additional immune-inflammatory biomarkers seem to be more complex. CLINICAL TRIAL REGISTRY NUMBER: NCT02402985 (ww.clinicaltrials.gov).

Endogenously released GIP reduces and GLP-1 increases hepatic insulin extraction.

GIP was proposed to play a key role in the development of non- alcoholic fatty liver disease (NAFLD) in response to sugar intake. Isomaltulose, is a 1,6-linked glucose-fructose dimer which improves glucose homeostasis and prevents NAFLD compared to 1,2-linked sucrose by reducing glucose-dependent insulinotropic peptide (GIP) in mice. We compared effects of sucrose vs. isomaltulose on GIP and glucagon-like peptide-1 (GLP-1) secretion, hepatic insulin clearance (HIC) and insulin sensitivity in normal (NGT), impaired glucose tolerant (IGT) and Type 2 diabetes mellitus (T2DM) participants. A randomized crossover study was performed in 15 NGT, 10 IGT and 10 T2DM subjects. In comparison to sucrose, peak glucose concentrations were reduced by 2.3, 2.1 and 2.5 mmol/l (all p < 0.05) and insulin levels were 88% (p < 0.01, NGT), 32% (p < 0.05, IGT) and 55% (T2DM) lower after the isomaltulose load. Postprandial GIPiAUC concentrations were decreased (56%, p < 0.01 in NGT; 42%, p < 0.05 in IGT and 40%,p < 0.001 in T2DM) whereas GLP-1iAUC was 77%, 85% and 85% higher compared to sucrose (p < 0.01), respectively. This resulted in ∼35 - 50% improved insulin sensitivity and reduced insulinogenic index after isomaltulose, which correlated closely with improved HIC, respectively (r = 0.62, r=-0.70; p < 0.001). HIC was inversely related to GIP (r=-0.44, p < 0.001) and positively related to GLP-1 levels (r = 0.40, p = 0.001). CONCLUSION: Endogenously released GIP correlated with reduced, and GLP-1 with increased hepatic insulin extraction. Increased peripheral insulin levels may contribute to insulin resistance and obesity. We propose that the unfavorable effects of high glycemic index Western diets are related to increased GIP-release and reduced HIC.

Predictive effect of GIPR SNP rs10423928 on glucose metabolism liver fat and adiposity in prediabetic and diabetic subjects.

The gastric inhibitory polypeptide receptor (GIPR) regulates postprandial metabolism. In this context GIPR SNP rs10423928 seems toplay an important role in modulating glucose metabolism and insulinsensitivity. However, evidence regarding thisparticular SNP is still vague. In this study, we collected baseline data from four different dietaryintervention studies. We genotyped 424 subjects with prediabetes and 73with diabetes for GIPR SNP rs10423928 and examined its impact on glucosemetabolism, insulin sensitivity and body fat accumulation. We extended previous data by showing that carriers of the A allele withprediabetes displayed increased fasting glucose (p = 0.015). Unexpectedly,A allele carriers showed lower glucose levels 2 h (p = 0.021) after anoral glucose challenge compared to T/T homozygous individuals. A allelecarriers also showed significantly higher insulin sensitivity (p < 0.001)(assessed by Cederholm Index), indicating an enhanced ß-cell response. This study points to a potential protective role for rs10423928 inglucose metabolism and insulin sensitivity in subjects with prediabetes.Further studies are necessary to confirm these results.

Diverse Excretion Pathways of Benzyl Glucosinolate in Humans after Consumption of Nasturtium (Tropaeolum majus L.)-A Pilot Study.

SCOPE: Different metabolic and excretion pathways of the benzyl glucosinolate breakdown products benzyl isothiocyanate and benzyl cyanide are investigated to obtain information about their multiple fate after ingestion. Detailed focus is on the so far underestimated transformation/excretion pathways-protein conjugation and exhalation. METHODS AND RESULTS: Metabolites, protein conjugates, and non-conjugated isothiocyanates are determined in plasma, urine, and breath of seven volunteers after consuming freeze-dried nasturtium or bread enriched with nasturtium. Samples are collected up to 48 h at selected time points. The metabolites of the mercapturic acid pathway are detectable in plasma up to 24 h after consumption. Additionally, mercapturic acid is the main metabolite in urine, but non-conjugated benzyl isothiocyanate is detectable as well. Protein conjugates show high amounts in plasma even 48 h after consumption. In breath, benzyl isothiocyanate and benzyl cyanide are detectable up to 48 h after consumption. CONCLUSION: Isothiocyanates are not only metabolized via the mercapturic acid pathway, but also form protein conjugates in blood and are exhaled. To balance intake and excretion, it is necessary to investigate all potential metabolites and excretion routes. This has important implications for the understanding of physiological and pharmacological effects of isothiocyanate-containing products.

Rate of appearance of amino acids after a meal regulates insulin and glucagon secretion in patients with type 2 diabetes: a randomized clinical trial.

Background: Meal composition regulates the postprandial response of pancreatic and gastrointestinal hormones and plays an important role in patients with type 2 diabetes (T2D). Proteins have glucagon and insulinotropic effects, which may differ depending on amino acid composition, form of intake, and rate of digestibility and absorption. Objective: The aim of this study was to test effects of isolated pea protein-based (PP) compared with casein protein-based (CP) meals differing in amino acid compositions on endocrine responses to meal tolerance tests (MTTs) in patients with T2D. Design: Thirty-seven individuals with T2D [mean ± SD age: 64 ± 6 y; mean ± SD body mass index (kg/m2): 30.2 ± 3.6; mean ± SD glycated hemoglobin: 7.0% ± 0.6%] were randomly assigned to receive either high-animal-protein (∼80% of total protein) or high-plant-protein (∼72% of total protein) diets (30% of energy from protein, 40% of energy from carbohydrate, 30% of energy from fat) for 6 wk. MTTs were performed at study onset and after 6 wk. Participants received standardized high-protein (30% of energy) meals 2 times/d containing either CP-rich (∼85% wt:wt) or PP-rich (∼95% wt:wt) foods. Results: The CP and PP meals produced differences in insulin, C-peptide, glucagon, and glucose-dependent insulinotropic peptide (GIP) release. Total areas under the curve after CP were significantly lower than after the PP lunch by 40% for insulin and 23% for glucagon. Indexes of insulin sensitivity and secretion were significantly improved for the second CP MTT. This was accompanied by differential rates of appearance of amino acids. The ingestion of PP resulted in significant increases in amino acids after both meals, with a decline between meals. By contrast, CP intake resulted in increases in most amino acids after breakfast, which remained elevated but did not increase further after lunch. Conclusions: PP elicits greater postprandial increases in glucagon than does CP and consequently requires higher insulin to control glucose metabolism, which appears to be related to the rate of amino acid appearance. The metabolic impact of protein quality could be used as a strategy to lower insulin needs in patients with T2D. This trial was registered at www.clinicaltrials.gov as NCT02402985.