Frontiers in Endocrinology

IntroductionMetabolic flexibility, the ability to switch from glucose to fat as a fuel source, is considered a marker of metabolic health. Higher fat oxidation is often associated with greater flexibility and insulin sensitivity, while lower fat oxidation is linked to metabolic inflexibility and insulin resistance. However, our study challenges the universal validity of this relationship, uncovering a more nuanced understanding of the complex interplay between fuel source switching and fat oxida...

BackgroundThe glycemic-independent actions of glucagon-like peptide 1 (GLP-1) in the prandial state in humans are largely unknown. Protein ingestion stimulates beta-cell secretion without changing plasma glucose concentration. We examined the contribution of endogenous GLP-1 to glucose metabolism and beta-cell response to protein ingestion under basal glucose concentrations, and whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG). MethodsIns...

We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-m...

Background & AimsWeight loss is associated with an improvement of insulin sensitivity. Both, a negative energy balance and changes of body composition are integrative components of weight loss interventions. However, the individual impact of these two components on insulin sensitivity and energy metabolism is unclear. MethodsWe performed a randomized controlled trial including 80 overweight or obese post-menopausal women. Participants randomly assigned to the intervention group underwent an 800...

Aims/hypothesisWhile physical activity is clearly beneficial in combating type 2 diabetes, the underlying molecular mechanisms are incompletely understood. Moreover, there is a considerable degree of variability in the individual response to exercise-based lifestyle interventions that remains to be explained. We aimed to identify novel exercise-induced metabolites that could mediate the improvement in glycemic control and reduction of obesity and contribute to individual differences in the respo...

ObjectiveTo introduce and evaluate the clinical utility of the "adipo-B index" as a novel metric of the adipose tissue-pancreatic beta cell axis. To our knowledge, no prior clinical metric has integrated adipose tissue insulin resistance and pancreatic beta-cell function into a single index applicable across therapeutic classes. MethodsTreatment-naive subjects with T2DM received monotherapy with modified traditional diet for diabetes (MJDD, n=61), canagliflozin (n=67), pioglitazone (n=54), or s...

The Fasting for Brain and Heart Health Study was a prospective, single-center, observational study examining the effects of medically supervised, water-only fasting followed by an exclusively whole-plant-food refeeding diet on accepted measures of cardiovascular risk and metabolic health. The study enrolled 48 overweight/obese, non-diabetic participants of which 26 completed the full study protocol. The participants fasted according to an established protocol at an independent medical center tha...

ContextWomen with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can increase visceral adiposity (VAT) and impair vascular function. GH releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. ObjectiveWe tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. MethodsEighteen women with PCOS participated in a double-blinded, cross-over study. They received sitaglipt...

IntroductionPostbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics. Materials and methodsInsulin secretion, hepatic insulin ex...

Background/AimsPrandial hyperinsulinemia after Roux-en Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, {beta}-cell sensitivity to exogenous incretin is markedly reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and {beta}-cell response to increasing concentrations of endogenous incretins. MethodsGlucose kinetics, insuli...

Bariatric surgery enhances glucose metabolism, yet the detailed postprandial joint glucose and insulin responses, variability in individual outcomes, and differences in surgical approaches remain poorly understood. To address this, we used hierarchical multi-output Gaussian process (HMOGP) regression to reveal clinically relevant patterns between persons undergoing two types of bariatric surgery by modeling the individual postprandial glucose and insulin responses and estimating the average resp...

BackgroundThe prevalence of childhood obesity continues to rise worldwide. Obesity leads to major health risks already early in life, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The pathogenesis of these conditions includes mitochondrial alterations, however, data on mitochondrial health in pediatric populations are scarce to date. MethodsThe study evaluated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) from children and adolescents (6-18 yea...

Exercise is recommended in the treatment of Type 2 Diabetes and can improve insulin sensitivity [1]. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia [2]. Metformin is the most commonly prescribed initial pharmacological intervention in Type 2 Diabetes, and may alter adaptions to exercise [3]. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to i...

The timing of carbohydrate and fat intake modulates the metabolic status, yet the underlying mechanisms in humans remain poorly understood. In this crossover trial, we investigated the effects of two isocaloric 4-week dietary patterns - high carbohydrate in the morning and high fat in the afternoon (HC/HF) and the reverse (HF/HC) - on the subcutaneous adipose tissue (SAT) transcriptome in non-diabetic men. Analysis of SAT samples collected across the day identified 1386 genes exhibiting diurnal ...

Aims/hypothesisLipid metabolism might be compromised in type 1 diabetes and the understanding of their physiology is critically important. This study aimed to compare the change in plasma lipid concentrations during carbohydrate dietary changes in individuals with type 1 diabetes and identify predictive biomarkers and early-stage pathophysiology for dyslipidaemia. We hypothesized that: (1) the lipidomics profiles before and after ingesting low or high carbohydrate diet for 12 weeks would be diff...

AimDPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. MethodsSitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). ResultsThis ...

BackgroundAnagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels in plasma. Aim of studyThe objective of our study is to elucidate the mechanisms responsible for anagliptin-mediated improvements in high LDL-C levels (hyper-LDL-C-emia). MethodsWe prospectively examined the effects of anagliptin monotherapy on fasting plasma lathosterol, sitosterol, and campesterol levels in patients with type 2 diabetes mellitus and ...

BackgroundThe metabolic syndrome (MetS) is an obesity-driven disorder with pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered autonomic regulation, are important components of MetS pathophysiology. We recently reported that galantamine, an acetylcholinesterase inhibitor and an FDA-approved drug (for Alzheimers disease) alleviates the inflammatory state in MetS subjects. Here we examined the effects of galantamine on oxidative stress in parall...

ObjectiveTo test whether interventions with putative lipopolysaccharide (LPS)-lowering effects including sevelamer and a synbiotic (Bifidobacterium longum+oligofructose) improve insulin sensitivity in subjects with obesity. MethodsWe randomized 22 lean and 28 human subjects with obesity to receive sevelamer, synbiotic, or placebo orally for 4 weeks. Peripheral insulin sensitivity was measured with an insulin clamp. Plasma cholesterol, endotoxemia markers, intestinal permeability, stool bacteria...

The new generation of incretin-based therapies are potent anti-obesity medications (AOMs) that offer the first non-surgical treatment for 936 million patients globally suffering from being overweight or obese[1]. However, clinical data suggest that incretin-mimetics could cause a disproportionate decrease in lean body mass (LBM) [2, 3], raising a concern for deterioration of skeletal muscle and acceleration of sarcopenic obesity[4]. Unfortunately, muscle mass and function are not routinely asses...