Insulin Sensitivity In Individuals Research Articles

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

β-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity

BackgroundImproving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases. ObjectivesThis study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity. MethodsIn a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m2) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed. ResultsBody weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: −4.5 ± 4.7 mL/100 g/min; P < 0.001; −4.6 ± 4.8 mL/100 g/min; P < 0.001; and −4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (−4.3 ± 5.6 mL/100 g/min; and −3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (−5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (−0.7%-point; 95% CI: −1.3%-point to −0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (−0.24 mmol/L; 95% CI: −0.44 to −0.04 mmol/L; P = 0.019), and systolic blood pressure (−5 mm Hg; 95% CI: −8 to −1 mm Hg; P = 0.006) were lower after the mixed nut intervention. ConclusionsLonger-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected.This trial was registered at clinicaltrials.gov as NCT04210869.

Mediterranean versus Western diet and the gut‐brain axis: Diet‐induced links between gut Oscillospira abundance, plasma branched‐chain amino acid concentrations and insulin resistance, and change in white matter volumes in nonhuman primates

AbstractBackgroundWestern vs. Mediterranean patterned diets have been associated with divergent effects on neurodegenerative diseases including Alzheimer’s Disease (AD). Such effects may be mediated through the gut microbiome, although the exact mechanisms linking diet, microbiome, and brain outcomes remain unclear. Oscillospira, a genus of gut‐dwelling bacteria, appears to be a good candidate which may help explain the mechanistic underpinnings of this relationship. Previous studies have shown associations between Oscillospira abundance, blood biomarkers, and brain physiology in rodents, and patients with neurodegenerative diseases including AD exhibit decreased gut Oscillospira abundances. Notably, Oscillospira may alter myelination by modifying branched‐chain amino acid (BCAA) concentrations in blood and preventing or minimizing insulin resistance.MethodIn the present study, we test a mechanistic role for Oscillospira on white matter volumes in cynomolgus monkeys (Macaca fascicularis) experimentally fed either a Mediterranean or Western‐type diet. We analyzed associations between gut Oscillospira abundances, plasma BCAA concentrations (i.e., leucine, isoleucine, and valine), plasma insulin, beta‐amyloid (Aβ) 42 to 40 ratio in cerebrospinal fluid (CSF), and magnetic resonance imaging‐derived white matter volumes.ResultWe found that Oscillospira abundance was significantly higher in the Mediterranean diet cohort than in the Western cohort (β = 0.258, SE = 0.084, p = 0.004). Oscillospira abundance was significantly negatively associated with plasma leucine (β = ‐0.169, SE = 0.059, p = 0.007) and valine concentrations (β = ‐0.206, SE = 0.069, p = 0.005); a similar, non‐significant (p = 0.066) trend was observed for isoleucine. Similarly, Oscillospira abundance was negatively associated with insulin area under the curve (AUC) at 26 months (β = ‐0.282, SE = 0.125, p = 0.031) and change in insulin AUC from baseline to 26 months (β = ‐14.6, SE = 6.97, p = 0.044), suggesting better insulin sensitivity in individuals with higher Oscillospira abundance. Oscillospira abundance was also positively associated with CSF Aβ42:40 ratio (β = 0.013, SE = 0.004, p = 0.007). Furthermore, the percent change in white matter volume over the study period was positively associated with Oscillospira abundance (β = 2.45, SE = 0.915, p = 0.012) and negatively associated with leucine (β = ‐2.39, SE = 0.920, p = 0.014), isoleucine (β = ‐2.67, SE = 0.895, p = 0.005), and valine concentrations (β = ‐2.28, SE = 0.929, p = 0.020) as well as change in insulin AUC (β = ‐2.04, SE = 0.947, p = 0.039).ConclusionThese results suggest that diet impacts the central nervous system by altering gut microbiome composition and highlight the complexity of relationships between BCAAs and brain health.

Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common sleep disorder associated with increased risk for the development of type 2 diabetes. While studies have examined the effects of sleep on whole-body insulin sensitivity, little is known about the effects of sleep on adipose tissue insulin sensitivity in patients with OSA. We analyzed if the severity of OSA, measured by apnea-hypopnea index (AHI), is associated with adipose tissue insulin sensitivity. We examined the relationship between sleep parameters and adipose tissue insulin sensitivity in non-diabetic participants with obesity and newly diagnosed OSA who underwent overnight polysomnography and a 2 h oral glucose tolerance test during which circulating free fatty acids were measured. In total, 16 non-diabetic participants with obesity and newly diagnosed OSA (sex, 81.3% males; mean age, 50.9 ± 6.7 y; BMI, 36.5 ± 2.9 kg/m2; AHI, 43 ± 20 events/h) were included in the analysis. In our study participants, AHI is inversely associated with free-fatty acid suppression during oral glucose challenge (R = -0.764, p = 0.001). This relationship persisted even after statistical adjustment for age (R = -0.769, p = 0.001), body mass index (R = -0.733, p = 0.002), waist-to-hip ratio (R = -0.741, p = 0.004), or percent body fat mass (R = -0.0529, p = 0.041). Furthermore, whole-body insulin sensitivity as determined by the Matsuda index was associated with percent REM sleep (R = 0.552, p = 0.027) but not AHI (R = -0.119, p = 0.660). In non-diabetic patients with OSA, the severity of sleep apnea is associated with adipose tissue insulin sensitivity but not whole-body insulin sensitivity. The impairments in adipose tissue insulin sensitivity may contribute to the development of type 2 diabetes.

Molecular regulators of exercise-mediated insulin sensitivity in non-obese individuals.

Insulin resistance is a significant contributor to the development of type 2 diabetes (T2D) and is associated with obesity, physical inactivity, and low maximal oxygen uptake. While intense and prolonged exercise may have negative effects, physical activity can have a positive influence on cellular metabolism and the immune system. Moderate exercise has been shown to reduce oxidative stress and improve antioxidant status, whereas intense exercise can increase oxidative stress in the short term. The impact of exercise on pro-inflammatory cytokine production is complex and varies depending on intensity and duration. Exercise can also counteract the harmful effects of ageing and inflamm-ageing. This review aims to examine the molecular pathways altered by exercise in non-obese individuals at higher risk of developing T2D, including glucose utilization, lipid metabolism, mitochondrial function, inflammation and oxidative stress, with the potential to improve insulin sensitivity. The focus is on understanding the potential benefits of exercise for improving insulin sensitivity and providing insights for future targeted interventions before onset of disease.

Metformin and exercise effects on postprandial insulin sensitivity and glucose kinetics in pre-and-diabetic adults.

The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre- and - type 2 diabetes (T2D). Eight T2D adults (60±4 years) with overweight/obesity (32±4 kg·m-2) under chronic metformin treatment (9±6 years; 1281±524 mg·day-1) underwent four trials; a) taking their habitual metformin treatment (MET), b) substituting during 96 h their metformin medication by placebo (PLAC), c) placebo combined with 50 min bout of high-intensity interval exercise (PLAC+EX), and d) metformin combined with exercise (MET+EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (i.e., OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET+EX lower than PLAC and PLAC+EX, respectively; P=0.023). MET+EX increased MATSUDAindex above PLAC (4.8±1.4 vs 3.3±1.0, respectively; P=0.018) and OGISindex above PLAC (358±52 vs 306±46 mL·min-1·m-2, respectively; P=0.006). Metformin decreased plasma appearance of the ingested glucose (Ra OGTT; MET vs PLAC, -3.5; 95% CI -0.1 to -6.8 µmol·kg-1·min-1; P=0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre- and - type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise.

Exploring the Impact of Intermittent Fasting on Metabolic Syndrome, Prediabetes and Type 2 Diabetes: a systematic review

Introduction: Metabolic syndrome, prediabetes and type 2 diabetes mellitus represent a growing and interconnected health challenge, gaining significant attention due to their high prevalence and impact they have on individuals' well-being. Intermittent Fasting (IF), involving cycling between periods of fasting and eating, has emerged as a promising dietary approach garnering substantial attention for its potential therapeutic effects on metabolic health.&#x0D; Purpose: This review aims to explore the impact of intermittent fasting on metabolic disease by examining recent studies.&#x0D; Methods: A review of the recent literature was conducted to explore potential positive effects of IF on relevant metabolic parameters.&#x0D; Results: The findings from the reviewed studies demonstrated favorable effects of IF associated with improvements in glycemic control as improved insulin sensitivity and decreased HbA1c levels. Additionally, it led to significant reductions in body weight and waist circumference. Beneficial effects on lipid profiles, such as reduced triglyceride levels, were also observed in some studies.&#x0D; Conclusions: The reviewed studies provide strong evidence supporting the effectiveness of IF regimens in improving metabolic factors, including weight, insulin sensitivity and lipid profiles in individuals with abnormal glucose metabolism. IF offers a promising dietary strategy potentially providing additional benefits beyond conventional dietary interventions. However, further research is needed to elucidate the long-term effects, optimal fasting protocols and potential mechanisms underlying the benefits of intermittent fasting in these conditions.

Anthropometric Indices With Insulin Resistance in Obese Patients: A Literature Review.

The hormone insulin is responsible for regulating the metabolism of proteins, carbs, and lipids by promoting the absorption of molecules such as glucose from the bloodstream into fat, the liver, and skeletal muscle cells. Insulin resistance (IR) is considered to be a physiological response to obesity that inhibits fat from accumulating and supports weight stabilization. People with IR gain less weight than those with insulin sensitivity, and therefore IR individuals have a three-fold increased likelihood of losing more weight when compared with insulin-sensitive individuals. A person's health is jeopardized by obesity, which is defined as excessive or unusual storage of fat in adipose tissue. Early identification using different anthropometric measuring parameters and proper and suitable therapy is essential as the incidence of obesity cases is increasing as a result of sedentary lifestyles, bad eating habits, a lack of physical exercise, and alack of knowledge among young adults. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, following which based on inclusion and exclusion criteria, eight articles were considered for the review. The analysis showed that all the parameters are easily accessible and hence can be used in daily practices. Due to being readily available, body mass index (BMI) and waist circumference (WC) constituted the most often employed anthropometric measures in everyday practices. In addition, variances in the values of the variables were seen due to differences in gender.

The effect of weight loss on whole-body and tissue-specific insulin sensitivity and hepatic lipid content and composition: SWEET substudy.

This study (1) investigated the effect of weight loss on whole-body and tissue-specific insulin sensitivity and on intrahepatic lipid (IHL) content and composition and (2) investigated the association between weight-loss-induced changes in insulin sensitivity and IHL content in individuals with overweight or obesity. In this secondary analysis of the European SWEET project, 50 adults (age 18-65 years) with overweight or obesity (BMI ≥ 25 kg/m2 ) followed a low-energy diet (LED) for 2 months. At baseline and after the LED, body composition (dual-energy x-ray absorptiometry), IHL content and composition (proton magnetic resonance spectroscopy), whole-body insulin sensitivity (Matsuda index), muscle insulin sensitivity index (MISI), and hepatic insulin resistance index (HIRI) were determined (7-point oral glucose tolerance test). The LED reduced body weight (p < 0.001). This was accompanied by increased Matsuda index and reduced HIRI (both p < 0.001) but no change in MISI (p = 0.260). Weight loss decreased IHL content (mean [SEM], 3.9% [0.7%] vs. 1.6% [0.5%], p < 0.001) and the hepatic saturated fatty acid fraction (41.0% [1.5%] vs. 36.6% [1.9%], p = 0.039). The reduced IHL content was associated with an improvement in HIRI (r = 0.402, p = 0.025). Weight loss decreased IHL content and the hepatic saturated fatty acid fraction. The decrease in IHL content was associated with weight-loss-induced improvement in hepatic insulin sensitivity in individuals with overweight or obesity.

The Metabolic Switch of Physical Activity in Non-Obese Insulin Resistant Individuals.

Healthy non-obese insulin resistant (IR) individuals are at higher risk of metabolic syndrome. The metabolic signature of the increased risk was previously determined. Physical activity can lower the risk of insulin resistance, but the underlying metabolic pathways remain to be determined. In this study, the common and unique metabolic signatures of insulin sensitive (IS) and IR individuals in active and sedentary individuals were determined. Data from 305 young, aged 20-30, non-obese participants from Qatar biobank, were analyzed. The homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires were utilized to classify participants into four groups: Active Insulin Sensitive (ISA, n = 30), Active Insulin Resistant (IRA, n = 20), Sedentary Insulin Sensitive (ISS, n = 21) and Sedentary Insulin Resistant (SIR, n = 23). Differences in the levels of 1000 metabolites between insulin sensitive and insulin resistant individuals in both active and sedentary groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. The study indicated significant differences in fatty acids between individuals with insulin sensitivity and insulin resistance who engaged in physical activity, including monohydroxy, dicarboxylate, medium and long chain, mono and polyunsaturated fatty acids. On the other hand, the sedentary group showed changes in carbohydrates, specifically glucose and pyruvate. Both groups exhibited alterations in 1-carboxyethylphenylalanine. The study revealed different metabolic signature in insulin resistant individuals depending on their physical activity status. Specifically, the active group showed changes in lipid metabolism, while the sedentary group showed alterations in glucose metabolism. These metabolic discrepancies demonstrate the beneficial impact of moderate physical activity on high risk insulin resistant healthy non-obese individuals by flipping their metabolic pathways from glucose based to fat based, ultimately leading to improved health outcomes. The results of this study carry significant implications for the prevention and treatment of metabolic syndrome in non-obese individuals.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Dietary Methionine Restriction Alleviates Hyperglycemia in Pigs with Intrauterine Growth Restriction by Enhancing Hepatic Protein Kinase B Signaling and Glycogen Synthesis

BackgroundIndividuals with intrauterine growth restriction (IUGR) are prone to developing type 2 diabetes mellitus (T2DM). Dietary methionine restriction (MR) improves insulin sensitivity and glucose homeostasis in individuals with normal birth weight (NBW). ObjectiveThis study investigated the effects of MR on plasma glucose concentration and hepatic and muscle glucose metabolism in pigs with IUGR. MethodsThirty female NBW and 60 same-sex spontaneous IUGR piglets (Landrace × Yorkshire) were selected. After weaning (day 21), the piglets were fed diets with adequate methionine (NBW-CON and IUGR-CON) or 30% less methionine (IUGR-MR) (n = 6). At day 180, 1 pig with a body weight near the mean of each replication was selected for biochemical analysis. ResultsThe IUGR-CON group showed 41.6%, 68.6%, and 67.1% higher plasma glucose concentration, hepatic phosphoenolpyruvate carboxykinase activity, and glucose-6-phosphatase activity, respectively, than the NBW-CON group (P < 0.05). Muscle glycogen content and glycogen synthase activity were 36.9% and 38.8% lower, respectively, in the IUGR-CON than the NBW-CON group (P < 0.05), respectively, and there was decreased hepatic and muscle protein kinase B phosphorylation in the IUGR-CON group (P < 0.05). Compared with the IUGR-CON pigs, the IUGR-MR pigs had 28.7% lower plasma glucose concentrations (P < 0.05), which were similar to those of the NBW-CON pigs (P ≥ 0.05). The hepatic glycogen content and glycogen synthase activity of the IUGR-MR pigs were 62.9% and 50.8% higher than those of the IUGR-CON pigs (P < 0.05) and 53.5% and 84.3% higher than the NBW-CON pigs (P < 0.05), respectively. The IUGR-MR pigs’ hepatic and muscle protein kinase B phosphorylation was higher than that of the IUGR-CON pigs (P < 0.05) and similar to that of the NBW-CON pigs (P ≥ 0.05). ConclusionsMR attenuates hyperglycemia in IUGR pigs by enhancing hepatic protein kinase B signaling and glycogen synthesis, implying a potential nutritional strategy to prevent type 2 diabetes mellitus in IUGR offspring.

Impact of physical exercise on metabolic dysfunction-associated fatty liver disease (MAFLD)

Obesity is a chronic multifactorial disease characterized by excess adiposity. Adipose tissue hypertrophy favors lipid deposition in ectopic tissues, such as the liver, which favors the development of the metabolic dysfunction-associated fatty liver disease (MAFLD), characterized by excessive accumulation of lipids in the cytoplasm of hepatocytes (fatty liver). Triglyceride overload in hepatocytes observed in obesity is associated with inflammation and insulin resistance status. Non-pharmacological strategies, such as the practice of physical exercise, seem to be an effective in reducing inflammatory markers and improving insulin sensitivity in obese individuals with MAFLD attenuating hepatocellular steatosis. Thus, this review aims to demonstrate the factors involved in the development of hepatic steatosis, as well as investigate the impact of physical exercise on insulin sensitivity and inflammatory markers in the condition of obesity-associated MAFLD.

Machine learning-derived gut microbiome signature predicts fatty liver disease in the presence of insulin resistance

A simple predictive biomarker for fatty liver disease is required for individuals with insulin resistance. Here, we developed a supervised machine learning-based classifier for fatty liver disease using fecal 16S rDNA sequencing data. Based on the Kangbuk Samsung Hospital cohort (n = 777), we generated a random forest classifier to predict fatty liver diseases in individuals with or without insulin resistance (n = 166 and n = 611, respectively). The model performance was evaluated based on metrics, including accuracy, area under receiver operating curve (AUROC), kappa, and F1-score. The developed classifier for fatty liver diseases performed better in individuals with insulin resistance (AUROC = 0.77). We further optimized the classifiers using genetic algorithm. The improved classifier for insulin resistance, consisting of ten microbial genera, presented an advanced classification (AUROC = 0.93), whereas the improved classifier for insulin-sensitive individuals failed to distinguish participants with fatty liver diseases from the healthy. The classifier for individuals with insulin resistance was comparable or superior to previous methods predicting fatty liver diseases (accuracy = 0.83, kappa = 0.50, F1-score = 0.89), such as the fatty liver index. We identified the ten genera as a core set from the human gut microbiome, which could be a diagnostic biomarker of fatty liver diseases for insulin resistant individuals. Collectively, these findings indicate that the machine learning classifier for fatty liver diseases in the presence of insulin resistance is comparable or superior to commonly used methods.

The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes

Aim/hypothesisThe risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear.MethodsBeta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial–Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes.ResultsAmong the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (−13.7 [21.2] vs −11.9 [21.5] pmol min−1 m−2 [mmol/l]−1, median [IQR], p=0.52) or insulin sensitivity (−22 [37] vs −14 [40] ml min−1 m−2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years.Conclusions/interpretationOur data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.Graphical abstract

Effects of Time-Restricted Feeding and Ramadan Fasting on Body Weight, Body Composition, Glucose Responses, and Insulin Resistance: A Systematic Review of Randomized Controlled Trials.

Time-restricted feeding (TRF) and Ramadan fasting (RF) have been recently associated with several health outcomes. However, it is not yet clear if they are superior to existing treatments in terms of glucose metabolism, insulin action, and weight loss. This review aims to summarize the current data on the effects of these regimes on body weight, body composition, and glycemia. An electronic search was conducted in PUBMED and SCOPUS databases up to August 2022. Twenty-four records met the inclusion criteria and underwent a risk-of-bias assessment. The main outcomes were: (a) TRF may result in moderate weight loss in individuals with overweight/obesity; when TRF is combined with caloric restriction, weight loss is >5% of the initial body weight, (b) 14 h of fasting may be as effective as 16 h in terms of weight loss, and (c) TRF may lead to improved insulin sensitivity and glycemic responses/variability throughout the day in individuals with overweight/obesity. Concerning RF, only two studies were available and thus, conclusions were not drawn. TRF may be an effective nutritional approach for weight loss, and the amelioration of glycemic control and insulin sensitivity in individuals with overweight/obesity. However, more long-term, well-designed studies are needed.

PSUN312 Interaction Between Insulin Sensitivity Status and Cex in control of Gene Expression in Human iPS Cell-Derived Myoblasts

Abstract Insulin resistance is a major risk factor in the development of type 2 diabetes, metabolic syndrome, polycystic ovarian disease, and many other disorders. About 25% of people within the general non-diabetic population are insulin resistant, and this has been shown to increase the risk for type 2 diabetes and cardiovascular disease. The aim of this study was to uncover the nature of the cell autonomous differences in gene expression that contribute to differences in insulin sensitivity and disease risk using induced pluripotent stem cell (iPSC) derived from humans at both ends of the insulin sensitivity spectrum, i.e., top 20% of insulin resistance vs. top 20% of insulin sensitive. We find that iPSCs differentiated into myoblasts (iMyos) from non-diabetic individuals in the highest quintile of insulin resistance (I-Res) show impaired insulin signaling, defective insulin-stimulated glucose uptake, and decreased glycogen synthase activity compared to iMyos from the insulin sensitive individuals (I-Sen), indicating these cells mirror in vitro the alterations seen in vivo. Transcriptomic analysis of these iMyos revealed a major effect of insulin resistance on gene expression, but an even larger, and unexpected, effect of sex of the donor on gene expression ex vivo. Thus, in cells from male donors, there were 184 significantly up-regulated and 167 significantly down-regulated genes in iMyos from I-Res vs I-Sen donors. The I-Res up-regulated genes were mostly related to the extracellular matrix organization and integrin signaling pathways, while the down-regulated genes belonged to immuno-regulatory pathways (p&amp;lt;0.05). Interestingly, in cells from females, distinct genes expression differences marked insulin resistance. Thus, iMyos from females showed up-regulation of 69 genes in the I-Res subgroup linked to cellular senescence and response to stress (p&amp;lt;0.05). In addition, and more strikingly, we also observed over 1500 sex-specific changes in gene expression that were independent of the insulin sensitivity status, with 766 genes significantly higher in cells from male donors and 786 genes higher in cells from female donors (FDR&amp;lt;0.2). Chromosomal positional analysis of the most sex-biased genes (FC&amp;gt;1.5) showed that only 7% of the differentially expressed genes were encoded by the X- or Y-chromosomes, while the remainder were spread across the autosomes. Furthermore, a comparison of the RNA sequencing data from these cell lines at the iPS cell and iMyos stage showed that X chromosome inactivation during the myoblast differentiation process was normal and that the sex-specific changes were not due to differences in X chromosome dosage in males and females but represent either persistent epigenetic changes and/or crosstalk between X and Y encoded genes and autosomal genes. Thus, insulin sensitivity status and patient sex interact to produce changes in gene expression that can contribute to how insulin resistance and other diseases are manifest differently in men and women. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The effect of regular consumption of four low- or no-calorie sweeteners on glycemic response in healthy women: A randomized controlled trial

ObjectivesThe aim of this study was to determine the effects of regular exposure to certain low- or no-calorie sweeteners (LNCS) on glucose tolerance and glucagon-like peptide 1 (GLP-1) release in healthy individuals. MethodsIt was designed as a randomized, single-blinded, controlled study. Healthy and normoglycemic adults who did not have regular consumption of LNCS were recruited. Participants underwent a 75-g oral glucose tolerance test (OGTT) at baseline and were randomly assigned to consume 330 mL water sweetened with saccharine, sucralose, or aspartame + acesulfame-K (Asp+Ace-K), or plain water for the control group, daily for 4 wk. Fasting plasma glucose, insulin, GLP-1, and glycated hemoglobin A1c (HbA1c) levels and 1-h, 2-h, and 3-h plasma glucose and insulin levels during OGTT were obtained at baseline. The change in insulin sensitivity was assessed by both the Homeostatic Model Assessment Insulin Resistance (HOMA-IR) Index and the Matsuda Index. Anthropometric measurements and dietary intakes were determined at baseline. Baseline measurements were repeated at week 4. ResultsOf the participants enrolled in the study, 42 (age, 21.24 ± 2.26 y; body mass index, 20.65 ± 2.88 kg/m2) completed the 4-wk intervention period. There were no differences for glucose, insulin, GLP-1, or HbA1c levels or HOMA-IR scores at baseline or at week 4 when compared with the control group. The area under the curve of mean glucose and insulin values during OGTT were also found to be similar between groups at baseline and week 4. There were also no effects of LNCS intake on body weight, body composition, and waist circumference. ConclusionsThese results suggest that regular consumption of LNCS-sweetened water similar to doses consumed in daily life over 4 wk had no significant effect on glycemic response, insulin sensitivity, GLP-1 release, and body weight in healthy individuals. This trial was registered at www.clinicaltrials.gov as NCT04904133.

Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties.

Neurological diseases such as stroke and multiple sclerosis are associated with high morbidity and mortality, long-term disability, and social and economic burden. Therefore, they represent a major challenge for medical treatment. Numerous evidences support the beneficial effects of polyphenols from olive trees, which can alleviate or even prevent demyelination, neurodegeneration, cerebrovascular diseases, and stroke. Polyphenols from olive oils, especially extra virgin olive oil, olive leaves, olive leaf extract, and from other olive tree derivatives, alleviate inflammation and oxidative stress, two major factors in demyelination. In addition, they reduce the risk of stroke due to their multiple anti-stroke effects, such as anti-atherosclerotic, antihypertensive, antioxidant, anti-inflammatory, hypocholesterolemic, hypoglycemic, and anti-thrombotic effects. In addition, olive polyphenols have beneficial effects on the plasma lipid profiles and insulin sensitivity in obese individuals. This review provides an updated version of the beneficial properties and mechanisms of action of olive polyphenols against demyelination in the prevention/mitigation of multiple sclerosis, the most common non-traumatic neurological cause of impairment in younger adults, and against cerebral insult with increasing incidence, that has already reached epidemic proportions.

IPSCs derived from insulin resistant offspring of type 2 diabetic patients show increased oxidative stress and lactate secretion

BackgroundThe genetic factors associated with insulin resistance (IR) are not well understood. Clinical studies on first-degree relatives of type 2 diabetic (T2D) patients, which have the highest genetic predisposition to T2D, have given insights into the role of IR in T2D pathogenesis. Induced pluripotent stem cells (iPSCs) are excellent tools for disease modeling as they can retain the genetic imprint of the disease. Therefore, in this study, we aimed to investigate the genetic perturbations associated with insulin resistance (IR) in the offspring of T2D parents using patient-specific iPSCs.MethodsWe generated iPSCs from IR individuals (IR-iPSCs) that were offspring of T2D parents as well as from insulin-sensitive (IS-iPSCs) individuals. We then performed transcriptomics to identify key dysregulated gene networks in the IR-iPSCs in comparison to IS-iPSCs and functionally validated them.ResultsTranscriptomics on IR-iPSCs revealed dysregulated gene networks and biological processes indicating that they carry the genetic defects associated with IR that may lead to T2D. The IR-iPSCs had increased lactate secretion and a higher phosphorylation of AKT upon stimulation with insulin. IR-iPSCs have increased cellular oxidative stress indicated by a high production of reactive oxygen species and higher susceptibility to H2O2 -induced apoptosis.ConclusionsIR-iPSCs generated from offspring of diabetic patients confirm that oxidative stress and increased lactate secretion, associated with IR, are inherited in this population, and may place them at a high risk of T2D. Overall, our IR-iPSC model can be employed for T2D modeling and drug screening studies that target genetic perturbations associated with IR in individuals with a high risk for T2D.