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BACKGROUND: 2-Fucosyllactose (2-FL) is an oligosaccharide contained in human milk and possesses prebiotic and anti-inflammatory effects, which may alleviate skeletal muscle atrophy under caloric restriction. This study evaluated the impacts of 12 weeks of 2-FL supplementation in conjunction with exercise (10,000 steps/day, 5 days/week) and energy-reduced (-300 kcals/day) dietary interventions on changes in body composition and health-related biomarkers. METHODS: A total of 41 overweight and sedentary female and male participants (38.0 ± 13 years, 90.1 ± 15 kg, 31.6 ± 6.6 kg/m2, 36.9 ± 7% fat) took part in a randomized, double-blind, and placebo-controlled study. The participants underwent baseline assessments and were then assigned to ingest 3 g/day of a placebo (PLA) or Momstamin 2-F while initiating the exercise and weight-loss program. Follow-up tests were performed after 6 and 12 weeks. Data were analyzed using general linear model statistics with repeated measures and mean changes from baseline values with 95% confidence intervals (CIs). RESULTS: No group × time × sex interaction effects were observed, so group × time effects are reported. Participants in both groups saw comparable reductions in weight. However, those with 2-FL demonstrated a significantly greater reduction in the percentage of body fat and less loss of the fat-free mass. Additionally, there was evidence that 2-FL supplementation promoted more favorable changes in resting fat oxidation, peak aerobic capacity, IL-4, and platelet aggregation, with some minimal effects on the fermentation of short-chain fatty acids and monosaccharides in fecal samples. Moreover, participants perceptions regarding some aspects of the functional capacity and ratings of the quality of life were improved, and the supplementation protocol was well tolerated, although a small, but significant, decrease in BMC was observed. CONCLUSIONS: The results support contentions that dietary supplementation of 2-FL (3 g/d) can promote fat loss and improve exercise- and diet-related markers of health and fitness in overweight sedentary individuals initiating an exercise and weight-loss program. Further research is needed to explore the potential health benefits of 2-FL supplementation in both healthy and elderly individuals (Registered clinical trial #NCT06547801).

This study investigated the effects of 14 days low energy availability (LEA) versus optimal energy availability (OEA) in endurance‐trained females on substrate utilization, insulin sensitivity, and skeletal muscle mitochondrial oxidative capacity; and the impact of metabolic changes on exercise performance. Twelve endurance‐trained females (V̇O2max 55.2 ± 5.1 mL × min−1 × kg−1) completed two 14‐day randomized, blinded, cross‐over, controlled dietary interventions: (1) OEA (51.9 ± 2.0 kcal × kg fat‐free mass (FFM)−1 × day−1) and (2) LEA (22.3 ± 1.5 kcal × kg FFM−1 × day−1), followed by 3 days OEA. Participants maintained their exercise training volume during both interventions (approx. 8 h × week−1 at 79% heart rate max). Skeletal muscle mitochondrial respiratory capacity, glycogen, and maximal activity of CS, HAD, and PFK were unaltered with LEA. 20‐min time trial endurance performance was impaired by 7.8% (Δ −16.8 W, 95% CI: −23.3 to −10.4, p <.001) which persisted following 3 days refueling post‐LEA (p <.001). Fat utilization was increased post‐LEA as evidenced by: (1) 99.4% (p <.001) increase in resting plasma free fatty acids (FFA); (2) 270% (p =.007) larger reduction in FFA in response to acute exercise; and (3) 28.2% (p =.015) increase in resting fat oxidation which persisted during submaximal exercise (p <.001). These responses were reversed with 3 days refueling. Daily glucose control (via CGM), HOMA‐IR, HOMA‐β, were unaffected by LEA. Skeletal muscle O2 utilization and carbohydrate availability were not limiting factors for aerobic exercise capacity and performance; therefore, whether LEA per se affects aspects of training quality/recovery requires investigation. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) is the most hazardous public health challenge requiring engineering study to prevent disease complications. In this paper, a Sorensen-based diabetic model is presented in which the insulin-glucose process of a Type 1 patient is maintained by considering other factors such as physical characteristics and changes in mental aspects of the diabetic patient. The purpose of the research is to include a non-linear model of a patient with diabetes who is affected by stress, meals, exercise, and Insulin Sensitivity (IS), and a suitable RECCo controller is designed as a notable recent innovation that implements the concept of ANYA fuzzy rule-based system, which is an online adaptive type of controller that is used in this research work with an uncertainty case of the condition, where the blood glucose must be regulated. To ensure the performance of the proposed controller, a simple insulin pump is designed in a practical case, and a hardware experiment is conducted. The result of the hardware is analyzed and shows the success of the implementation of the controller in blood glucose regulation, thereby preventing complications such as hypoglycemia and hyperglycemia. The comparison analysis of RECCo was performed with other types of controllers, such as MPC and MRAC. The accuracy of the model was validated using the N-BEATS algorithm with a data-set collected from the simulated model, which is around 98%. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major global cause of disability and mortality. TBI results in a spectrum of primary and secondary injuries that impact neural function and overall survival. Insulin, beyond its well‐known role in regulating blood glucose levels, plays critical roles in the central nervous system (CNS). These roles include the modulation of synaptic plasticity, neurotransmitter levels, neurogenesis, and neuroprotection. Central insulin resistance, a reduced sensitivity to insulin in the brain, has been observed in TBI patients. This insulin resistance impairs insulin function in the brain and increases the risk of neurodegenerative processes. This review will delve into the central role of insulin resistance in the pathological changes observed after TBI and explore the potential benefits of insulin therapy as a treatment approach for TBI. [ABSTRACT FROM AUTHOR]

Background: During the transition period, excessive negative energy balance (NEB) lead to metabolic disorders and reduced milk yield. Rumen microbes are responsible for resolving plant material and producing volatile fatty acids (VFA), which are the primary energy source for cows. In this study, we aimed to investigate the effect of citrus peel extract (CPE) supplementation on rumen microbiota composition, energy metabolism and milk performance of peripartum dairy cows. Methods: Dairy cows were fed either a basal diet (CON group) or the same basal diet supplemented with CPE via intragastric administration (4 g/d, CPE group) for 6 weeks (3 weeks before and 3 weeks after calving; n = 15 per group). Samples of serum, milk, rumen fluid, adipose tissue, and liver were collected to assess the effects of CPE on rumen microbiota composition, rumen fermentation parameters, milk performance, and energy metabolic status of dairy cows. Results: CPE supplementation led to an increase in milk yield, milk protein and lactose contents, and serum glucose levels, while reduced serum concentrations of non-esterified fatty acid, β-hydroxybutyric acid, insulin, aspartate aminotransferase, alanine aminotransferase, and haptoglobin during the first month of lactation. CPE supplementation also increased the content of ruminal VFA. Compared to the CON group, the abundance of Prevotellaceae, Methanobacteriaceae, Bacteroidales_RF16_group, and Selenomonadaceae was found increased, while the abundance of Oscillospiraceae, F082, Ruminococcaceae, Christensenellaceae, Muribaculaceae UCG-011, Saccharimonadaceae, Hungateiclostridiaceae, and Spirochaetaceae in the CPE group was found decreased. In adipose tissue, CPE supplementation decreased lipolysis, and inflammatory response, while increased insulin sensitivity. In the liver, CPE supplementation decreased lipid accumulation, increased insulin sensitivity, and upregulated expression of genes involved in gluconeogenesis. Conclusions: Our findings suggest that CPE supplementation during the peripartum period altered rumen microbiota composition and increased ruminal VFA contents, which further improved NEB and lactation performance, alleviated lipolysis and inflammatory response in adipose tissue, reduced lipid accumulation and promoted gluconeogenesis in liver. Thus, CPE might contribute to improve energy metabolism and consequently lactation performance of dairy cows during the transition period. [ABSTRACT FROM AUTHOR]

Background: Previous studies have been limited by their inability to differentiate between the effects of insulin sensitivity and β-cell function on the risk of kidney function decline, cardiovascular disease (CVD), and all-cause mortality. To address this knowledge gap, we aimed to investigate whether the physiological subtypes based on homeostasis model assessment-2 (HOMA2) indices of β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) could be used to identify individuals with subsequently high or low of clinical outcome risk. Methods: This retrospective cohort study included 7,317 participants with a follow-up of up to 5 years. Based on HOMA2 indices, participants were categorized into four physiologic subtypes: the normal phenotype (high insulin sensitivity and high β-cell function), the insulinopenic phenotype (high insulin sensitivity and low β-cell function), the hyperinsulinaemic phenotype (low insulin sensitivity and high β-cell function), and the classical phenotype (low insulin sensitivity and low β-cell function). The outcomes included kidney function decline, CVD events (fatal and nonfatal), and all-cause mortality. Cox regression models were used to calculate hazard ratios (HRs) for outcomes, and spline models were used to examine the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. Results: A total of 1,488 (20.3%) were classified as normal, 2,179 (29.8%) as insulinopenic, 2,173 (29.7%) as hyperinsulinemic, and 1,477 (20.2%) as classical subtypes. Compared with other physiological subtypes, the classical subtype presented the highest risk of kidney function decline (classical vs. normal HR 11.50, 95% CI 4.31–30.67). The hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality (hyperinsulinemic vs. normal: fatal CVD, HR 6.56, 95% CI 3.09–13.92; all-cause mortality, HR 4.56, 95% CI 2.97–7.00). Spline analyses indicated the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. Conclusions: The classical subtype had the strongest correlation with the risk of kidney function decline, and the hyperinsulinemic subtype had the highest risk of CVD and all-cause mortality, which should be considered for interventions with precision medicine. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Type 2 diabetes (T2D) patients with a clinical phenotype characterized by a high degree of insulin resistance are at increased risk of chronic kidney disease (CKD). We previously demonstrated that the endothelin receptor antagonist (ERA) atrasentan reduced insulin resistance in T2D. In this study, we compared the effect of atrasentan on insulin resistance across different phenotypic clusters of patients with T2D.We performed a post hoc analysis of the SONAR trial, a randomized, placebo‐controlled trial of the ERA atrasentan in patients with T2D and CKD. Patients were stratified into four previously identified phenotypic clusters: severe insulin‐deficient diabetes (SIDD), severe insulin‐resistant diabetes (SIRD), mild obesity‐related diabetes (MOD) and mild age‐related diabetes (MARD). Changes in insulin resistance, assessed by HOMA‐IR, were compared between the phenotypic clusters using a mixed effects model.In total, 931 patients were included in the analysis. In the overall population, atrasentan compared to placebo reduced HOMA‐IR by 12.9% [95%CI 3.5,21.4]. This effect of atrasentan was more pronounced in clusters characterized by insulin resistance or deficiency: (SIRD cluster 26.2% [95% CI 3.8,43.3] and SIDD cluster 18.5% [95%CI −3.8,35.9]), although the latter did not reach statistical significance. The effect of atrasentan compared to placebo was less pronounced in the other two clusters (MARD 12.2% [95% CI −1.7,24.12] and MOD −5.3% [95% CI −28.9,13.9]).Atrasentan significantly improved insulin sensitivity in patients with T2D and CKD, especially in those characterized by high insulin resistance (SIRD cluster). Further studies are warranted to investigate the long‐term clinical outcomes of atrasentan treatment in these distinct phenotypic clusters. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusion Maternal hyperglycemia is linked to adverse neonatal outcomes. However, current evidence was insufficient for mechanistic pathways. We aim to use two‐sample Mendelian randomization (MR) to obtain a comprehensive understanding of the causal association and mediation pathways.Genetic variants of fasting glucose (FG), insulin sensitivity index (ISI), glycated haemoglobin (HbA1c), gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) were used as instruments (N = 50 404–898 130). The associations with offspring birthweight, gestational duration, spontaneous preterm and post‐term birth were assessed by the inverse‐variance weighted method, using summary statistics of European genome‐wide association studies (N = 131 279–210 248). Sensitivity analyses, including multivariable MR removing pleiotropic effect from maternal body mass index (BMI), assessed the robustness. Mediation via placental weight and maternal hypertension were assessed via a two‐step MR design.FG (0.46 SD per mmol/L, 95% confidence interval [95% CI]: 0.32, 0.61) and GDM liability (0.18 SD per log odds, 95% CI: 0.08, 0.18) were positively associated with birthweight, with consistent findings for HbA1c, T2D liability and ISI. These associations were mediated by placental weight (proportion mediated: 32.8% to 77.7%). Higher HbA1c, GDM and T2D liability were associated with preterm birth (odds ratios for GDM: 1.07, 95% CI: 1.01, 1.14) and shorter gestational duration, whilst the association for T2D attenuated after adjusted for maternal BMI and gestational hypertension.Maternal hyperglycemia is associated with higher birthweight (possibly indicating macrosomia), mediated via increased placental growth. GDM and T2D liability are related to preterm birth, whilst the association for T2D liability is driven by maternal adiposity. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a complex heterogenous disorder manifesting with various reproductive, endocrine, and metabolic derangements such as insulin resistance and hyperglycemia. The arginine vasopressin peptide (AVP), also called or antidiuretic hormone (ADH), modulates metabolic functions such as glucose hemostasis, insulin sensitivity, and lipid metabolism via binding to two central and peripheral receptors (AVPR1A and AVPR1B). In the present study, we aimed to detect whether the AVPR1A and AVPR1B genes confer risk for PCOS. Methods: In peninsular Italian families, we tested 7 variants in the AVPR1B gene and 2 variants in the AVPR1A gene via Pseudomarker for linkage and linkage joint to association (i.e.., linkage disequilibrium) with PCOS. Results: We identified two risk variants in each gene, significantly associated with the risk of PCOS. Conclusion: To the best of our knowledge, this is the first study to report risk variants in AVPR1A and AVPR1B genes in association with PCOS. However, replication in other ethnic groups as well as functional studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1 /Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1 ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/ Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1 ΔEC mice. Mechanistically, Glut1- dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis. [Display omitted] • EC-specific loss of Glut1 impairs insulin sensitivity in skeletal muscle • Angiocrine OPN controls resident macrophage phenotype and function • Resident macrophage accumulation and activation impair muscle insulin sensitivity • Endothelial glucose metabolic control of OPN is serine dependent Zhang et al. found that endothelial GLUT1 regulates muscle insulin sensitivity independently of transendothelial glucose transport. Lowering endothelial GLUT1 through genetic deletion or upon a short-term high-fat diet rewires endothelial glucose metabolism, thereby increasing angiocrine OPN secretion. This promotes resident macrophage accumulation and activation, which leads to muscle insulin resistance. [ABSTRACT FROM AUTHOR]

Introduction Passive heat treatment has been suggested to improve glycemic control in individuals with type 2 diabetes mellitus (T2DM). Previous studies have focused predominantly on hot water immersion and traditional sauna bathing, as opposed to the more novel method of infrared-based sauna bathing. Here, the impact of a single infrared sauna session on post-prandial glycemic control was assessed in older individuals with T2DM. Methods In this randomized controlled crossover trial, 12 participants with T2DM (male/female: 10/2, age: 69±7 y, BMI: 27.5±2.9 kg/m2) rested in an infrared sauna twice: once in a heated (60°C) and once in a thermoneutral (21°C) condition for 40 min, immediately followed by a 2-h oral glucose tolerance test (OGTT). Venous blood samples were obtained to assess plasma glucose and insulin concentrations and to determine the whole-body composite insulin sensitivity index. Results Body core and leg skin temperature were higher following the heated condition compared to the thermoneutral condition (38.0±0.3 vs. 36.6±0.2°C and 39.4±0.8 vs. 31.3±0.8°C, respectively; P<0.001 for both). The incremental area under the curve (iAUC) of plasma glucose concentrations during the OGTT was higher after the heated condition compared to the thermoneutral condition (17.7±3.1 vs. 14.8±2.8 mmol/L/120 min; P<0.001). No differences were observed in plasma insulin concentrations (heated: 380±194 vs. thermoneutral: 376±210 pmol/L/120 min; P=0.93) or whole-body composite insulin sensitivity indexes (4.5±2.8 vs. 4.5±2.1; P=0.67). Conclusions A single infrared sauna session does not improve postprandial blood glucose handling in individuals with T2DM. Future studies should assess the effect of more prolonged application of infrared sauna bathing on daily glycemic control. [ABSTRACT FROM AUTHOR]

Brain‐derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high‐fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia‐inducible factor 1α (Hif1α) and platelet‐derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti‐inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin‐mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin‐mediated glucose uptake.Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic–euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]).Insulin‐mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor‐β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin‐mediated Tyr phosphorylation of IRβ and downstream insulin‐signalling proteins in LOW.Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin‐mediated glucose uptake commonly found in adults with obesity. [ABSTRACT FROM AUTHOR]

Insulin is preferred as the first-line agent for glucose management of gestational diabetes mellitus and type 2 diabetes in pregnancy when nutritional and lifestyle modifications are unable to achieve pregnancy-specific glucose targets. Individual heterogeneity in defects of insulin secretion or sensitivity in liver and muscle, unique genetic influences on pregnancy glycemic regulation, and variable cultural and lifestyle behaviors that affect meal, activity, sleep, and occupational schedules necessitate a personalized approach to insulin regimens. Newer insulin preparations have been developed to mimic the physiologic release of endogenous insulin, maintaining appropriate basal levels to cover hepatic gluconeogenesis and simulate the rapid, meal-related, bolus rise of insulin. Such physiologic basal-bolus dosing of insulin can be administered safely, achieving tighter glycemic control while reducing episodes of hypoglycemia. Insulin initiation and titration require understanding the pharmacodynamics of different insulin preparations in addition to a patient's glycemic profiles, effect of variable nutritional intake and mealtimes, physical activity, stress, timing of sleep cycles, and cultural habits. Educating and empowering patients to learn how their glucose responds to insulin, portion and content of meals, and physical activity can increase personal engagement in therapy, flexibility in eating patterns, and improved glycemic control. This Clinical Expert Series article is focused on optimizing insulin management (initiation, dosing, and titration) of gestational and type 2 diabetes in pregnancy. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIIT-CR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerves, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMPK. We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerves. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression. Article Highlights: Diet and exercise are recommended for treating peripheral neuropathy in prediabetes. To identify the optimal regimen and the underlying neuroprotective mechanisms, we compared the effects of caloric restriction (CR), high-intensity interval training (HIIT), and their combination (HIIT-CR), on metabolic and neuropathy outcomes following high-fat diet feeding. While all interventions improved neuropathy, CR and HIIT-CR, but not HIIT alone, improved metabolic profiles and promoted insulin sensitivity in peripheral nerves of high-fat diet–fed mice. In vitro, palmitate-treated Schwann cells developed insulin resistance, which was reversed by AMPK activation. CR, alone or combined with HIIT, ameliorates neuropathy by restoring nerve insulin sensitivity. [ABSTRACT FROM AUTHOR]

The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β-cells. However, its pathophysiological significance in maintaining islet β-cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β-cell–specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that although TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin to proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β-cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues. Article Highlights: Translocon-associated protein-δ (TRAPδ) plays a pivotal role in insulin biosynthesis and potentially contributes to β-cell survival in type 2 diabetes mellitus. Nevertheless, its specific function in preserving islet β-cell function in vivo has yet to be fully explored and elucidated. Specific knockout of TRAPδ in pancreatic β-cells leads to a decrease in proinsulin and insulin content within the islets, subsequently resulting in a slight reduction of serum insulin levels. Remarkably, despite this insulin decrease, euglycemia is preserved. The moderate decrease in circulating insulin levels may potentially enhance insulin sensitivity in target tissues. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. Following medical diagnosis of MASH, individuals were randomized to treatment (n = 16) or control (n = 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO 2 peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. Treatment induced significant (p < 0.05) reductions in body weight, fat mass, and liver injury, while VO 2 peak (p < 0.05) and non-esterified fatty acid suppression (p = 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p < 0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO 2 peak and resolution of liver disease. Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. NCT03151798. [Display omitted] • Diet and exercise improved liver histology in metabolic-dysfunction associated steatohepatitis. • Standard of care improved metabolic health with minimal effects on histology. • Peripheral, not hepatic, insulin sensitivity was related to histologic resolution. • Improved substrate use at the muscle may relieve the liver of excess nutrients. [ABSTRACT FROM AUTHOR]

Aim: To identify the characteristics and pregnancy outcomes across different subgroups of gestational diabetes mellitus (GDM) categorized by insulin resistance index and body mass index (BMI) in early pregnancy. Methods: This retrospective study included 1804 women who underwent a 75 g-OGTT during 22–28 weeks of gestation, categorized into normal glucose tolerance (NGT) (1487) and GDM (317 [17.57%] of the total cohort). Metabolic parameters were assessed, and equation of homeostatic model assessment (HOMA) were utilized to compute indices of insulin resistance (HOMA-IR), β-cell secretory (HOMA-B), and insulin sensitivity (HOMA-%S) in early and mid-pregnancy. The cut-off value of HOMA-IR (1.61) in early pregnancy was determined via ROC curve analysis. This value, combined with pre-pregnancy BMI, further categorized NGT and GDM into six subgroups respectively, based on HOMA-IR levels (≥ 1.61 or < 1.61) and BMI categories (< 18.5 kg/m2, 18.5–25 kg/m2, or ≥ 25 kg/m2). Results: In comparison to women with NGT, those with GDM were notably older, had higher pre-BMI, fasting plasma glucose (FPG), insulin, and lipid levels in early pregnancy. They also exhibited more pronounced insulin resistance in both early and mid-pregnancy, leading to poorer outcomes. Following an oral glucose load, the peaks of glucose and insulin were out of sync in GDM and its subgroups, accompanied by further increases in HOMA-IR, HOMA-B, and a decrease in HOMA-%S, except for the GDM subgroup with HOMA-IR < 1.61/BMI < 18.5 kg/m2. Conversely, glucose and insulin secretion in NGT and its subgroups peaked synchronously at 60 min. GDM women with HOMA-IR ≥ 1.61/18.5 kg/m2 ≤ BMI < 25 kg/m2 had higher rates of neonatal jaundice (34.5% vs 13.9%, p < 0.0001), LGA (28.9% vs 13.2%, p = 0.001), macrosomia (9.8% vs 3.7%, p = 0.025) compared to peers, while in GDM women with HOMA-IR ≥ 1.61/BMI ≥ 25 kg/m2, the rates of LGA and macrosomia were 26.6% and 8.4%, respectively. The GDM subgroup with HOMA-IR < 1.61/BMI < 18.5 kg/m2 exhibited the highest rates of premature rupture of membrane (46.7%) and postpartum hemorrhage (20%), predominantly with vaginal delivery and a 1 min Apgar score of 4.5% in GDM women with HOMA-IR < 1.61/18.5 kg/m2 ≤ BMI < 25 kg/m2. Conclusion: GDM and its subgroups displayed severe insulin resistance and poorer insulin sensitivity, leading to an increased risk of adverse pregnancy outcomes. GDM women with higher IR and normal or over weight were more likely to experience LGA and macrosomia, while those with lower IR and underweight were prone to premature rupture of membrane and postpartum hemorrhage during vaginal delivery. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the moderating role of cardiorespiratory fitness (CRF) between the relationship of cardiometabolic risk factors and adiponectin in adolescents. This is a cross-sectional study conducted with 255 adolescents of both sexes, aged 11 to 17 years. Anthropometric and biochemical parameters such as body mass, height, fat mass (FM), fat-free mass, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin, adiponectin, systolic blood pressure, diastolic blood pressure, and peak oxygen consumption (VO2peak) were measured. Body mass index z-score (BMI-z), tri-ponderal mass index (TMI), homeostasis model assessment insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and age peak height velocity were calculated. The moderation analyses were tested using linear regression models. Interaction was observed with low CRF, indicating that those who achieved more than 2.27 (BMI-z), 2.18 (TMI), 2.10 (FM), 2.57 (insulin), 2.65 (HOMA-IR), and 2.81 (QUICKI) in L·min−1 on the CRF test may experience reduced risks in cardiometabolic risk factors. Conclusion: The deleterious effects attributed to excess adiposity and unfavorable changes related to insulin resistance and sensitivity may be attenuated by CRF. What is Known: • Adiponectin, a protein derived from adipose tissue, may play a role as a potential marker of protection and predictor of cardiometabolic disorders and its relationship with cardiorespiratory fitness is controversial. What is New: • The deleterious effects attributed to overweight and unfavorable changes related to insulin resistance and sensitivity may be attenuated by high cardiorespiratory fitness in adolescents. [ABSTRACT FROM AUTHOR]

Aim: Diminished hepatic insulin clearance (HIC) is observed in obese adults and is presumed to be mediated by fatty liver. However, few reports have examined HIC in Chinese children with metabolic (dysfunction)‐associated fatty liver disease (MAFLD). This study aimed to investigate the correlation between HIC, insulin sensitivity and β‐cell function in obese Chinese children with MAFLD. Methods: In total, 204 obese children (74 MAFLD) aged 4–17 years were enrolled into this study. HIC, insulin sensitivity and β‐cell function were calculated using the oral glucose tolerance test (1.75 g/kg body weight). Correlation analyses between the HIC and clinical variables were performed using Pearson's product–moment correlation coefficients. HIC and glucose homeostasis were assessed in a high‐fat diet mouse model, and liver samples were collected for molecular analysis. Results: Obese children with MAFLD exhibited significantly lower HIC (AUCC‐peptide/insulin ratio, p = 0.0019), higher insulin resistance (homeostatic model assessment of insulin resistance, p = 0.002), and increased compensatory β‐cell function (homeostatic model assessment‐β, p = 0.046) than obese children without liver involvement. Notably, HIC was negatively correlated with insulin sensitivity (r = −0.5035, p < 0.0001) and β‐cell function (r = −0.4576, p < 0.0001). However, pancreatic β‐cell dysfunction (p = 0.046) was accompanied by future reduced HIC (p = 0.034) in children with MAFLD in prediabetes. In a high‐fat diet mouse model, MAFLD mice showed a 50% reduction in insulin‐degrading enzyme expression, consistent with the observed decrease in HIC. Conclusions: A lower HIC may offload pancreatic β‐cells at an early stage. However, obese children with MAFLD are at risk of developing diabetes, and preventive efforts should be prioritized. [ABSTRACT FROM AUTHOR]

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of a small‐molecule nicotinamide N‐methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet‐induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. Materials and Methods: DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age‐ and strain‐matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. Results: 5A1MQ treatment dose‐dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ‐treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. Conclusions: This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity. [ABSTRACT FROM AUTHOR]

Aim: To examine the hypothesis that there would be ethnic differences in the relationship between ectopic fat and tissue‐specific insulin resistance (IR) across a spectrum of glucose tolerance in Black African (BA) and White European (WE) men. Materials and Methods: Fifty‐three WE men (23/10/20 normal glucose tolerance [NGT]/impaired glucose tolerance [IGT]/type 2 diabetes [T2D]) and 48 BA men (20/10/18, respectively) underwent a two‐step hyperinsulinaemic‐euglycaemic clamp with infusion of D‐[6,6‐2H2]‐glucose and [2H5]‐glycerol to assess hepatic, peripheral and adipose tissue IR. Magnetic resonance imaging was used to measure subcutaneous adipose tissue, visceral adipose tissue (VAT) and intrahepatic lipid (IHL). Associations between ectopic fat and IR were assessed using linear regression models. Results: There were no differences in tissue‐specific IR between ethnic groups at any stage of glucose tolerance. VAT level was consistently lower in the BA population; NGT (p = 0.013), IGT (p = 0.006) and T2D (p = 0.015). IHL was also lower in the BA compared with the WE men (p = 0.013). VAT and IHL levels were significantly associated with hepatic IR in the BA population (p = 0.001) and with peripheral IR in the WE population (p = 0.027). Conclusions: The present study suggests that BA and WE men exhibit the same degree of IR across a glucose tolerance continuum, but with lower VAT and IHL levels in the BA population, suggesting that IR may be driven by a mechanism other than increased ectopic fat accumulation in BA men. [ABSTRACT FROM AUTHOR]

Background and Purpose: Metal‐based therapeutic agents are limited by the required concentration of metal‐based agents. Hereby, we determined if combination with 17β‐oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach: The metal‐based agent (vanadyl acetylacetonate [VAC])– 17β‐oestradiol (E2) combination is administered using the membrane‐permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X‐ray photoelectron spectroscopy. In db/db type 2 diabetic mice, the anti‐diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA‐IR] and homeostasis model assessment of β‐cell function [HOMA‐β]), histochemical assays and western blot. Key Results: In diabetic mice, GQD–E2–VAC complex had comprehensive anti‐diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β‐cell loss. Co‐regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β‐oestradiol contributed to the enhanced anti‐diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications: A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi‐modal therapies towards type 2 diabetes treatment. [ABSTRACT FROM AUTHOR]

Background/Objectives: Understanding the metabolic responses to different macronutrients is crucial for assessing their impacts on health. This study aims to investigate the postprandial metabolomic profiles of healthy individuals following the consumption of glucose, protein, and lipids. Methods: Twenty-three healthy, normal-weight adults participated in the study, randomly assigned to consume 300 kcal from glucose, protein, or lipids after an overnight fast. Blood samples were collected at baseline and at 1, 2, and 3 h post-ingestion. An untargeted metabolomic approach using mass spectrometry was employed to analyze plasma metabolites. Results: In total, 21, 59, and 156 dysregulated metabolites were identified after glucose, protein, and lipid intake, respectively. Notably, 3'-O-methylguanosine levels decreased significantly after glucose consumption while remaining stable during lipid intake before increasing at 2 h. Common metabolites shared between glucose and lipid groups included 3'-O-methylguanosine, 3-oxotetradecanoic acid, poly-g-D-glutamate, and triglyceride (TG) (15:0/18:4/18:1). Conclusions: The findings highlight distinct metabolic responses to macronutrient intake, emphasizing the role of specific metabolites in regulating postprandial metabolism. These insights contribute to understanding how dietary components influence metabolic health and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Epidemiological studies demonstrate that maternal obesity and maternal allergy are major risk factors for asthma in offspring. However, the impact of maternal allergy and obesity on offspring lung insulin signaling and allergen responsiveness is not known. To evaluate this, allergic and nonallergic female mice were fed a high-fat diet or low-fat diet from 7 wk before pregnancy until weaning. Neonatal pups were allergen-sensitized and allergen-challenged and then were assessed for obesity, insulin signaling, and allergic inflammation. Compared with pups of nonobese nonallergic mothers, allergen-challenged pups of obese nonallergic mothers, nonobese allergic mothers, and obese allergic mothers had bronchoalveolar lavage (BAL) eosinophilia, with the pups of obese allergic mothers having the highest BAL eosinophilia. These pups also had lower insulin-induced lung AKT phosphorylation, indicating a decrease in lung parenchymal insulin sensitivity. In cross-fostering experiments, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of BAL eosinophilia. Maternal obesity or allergy increased offspring serum allergen-specific IgE and interleukin-5 that was highest when the mother was both obese and allergic. Also, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of interleukin-5. In summary, offspring born to obese allergic mothers have decreased lung insulin sensitivity and increased lung allergic inflammation. Interestingly, our data also demonstrate that there is both a pregnancy and postpregnancy aspect of maternal allergy and obesity that enhances allergen responsiveness in offspring. [ABSTRACT FROM AUTHOR]

In rodents, loss of growth hormone (GH) or its receptor is associated with extended lifespan. We aimed to determine the signaling process resulting in this longevity using GH receptor (GHR)-mutant mice with key signaling pathways deleted and correlate this with cancer incidence and expression of genes associated with longevity. GHR uses both canonical janus kinase (JAK)2-signal transducer and activator of transcription (STAT) signaling as well as signaling via the LYN-ERK1/2 pathway. We used C57BL/6 mice with loss of key receptor tyrosines and truncation resulting in 1) loss of most STAT5 response to GH; 2) total inability to generate STAT5 to GH; 3) loss of Box1 to prevent activation of JAK2 but not LYN kinase; or 4) total knockout of the receptor. For each mutant we analyzed lifespan, histopathology to determine likely cause of death, and hepatic gene and protein expression. The extended lifespan is evident in the Box1-mutant males (retains Lyn activation), which have a median lifespan of 1016 days compared to 890 days for the Ghr −/− males. In the females, GhrBox1 −/− mice have a median lifespan of 970 days compared to 911 days for the knockout females. Sexually dimorphic GHR-STAT5 is repressive for longevity, since its removal results in a median lifespan of 1003 days in females compared to 734 days for wild-type females. Numerous transcripts related to insulin sensitivity, oxidative stress response, and mitochondrial function are regulated by GHR-STAT5; however, LYN-responsive genes involve DNA repair, cell cycle control, and anti-inflammatory response. There appears to be a yin-yang relationship between JAK2 and LYN that determines lifespan. [ABSTRACT FROM AUTHOR]

Context Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. Objective We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. Methods We computed 21 IS indices, classified as fasting, OGTT0,120, and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in 2 cohorts. We used data from a family cohort (n = 313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n = 5343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. Results Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 variant was associated only with fasting indices and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1 , GCK , C2CD4A/B , and FTO loci were associated only with OGTT0,120 indices. Conclusion Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT-based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices. [ABSTRACT FROM AUTHOR]

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD. [ABSTRACT FROM AUTHOR]

Objective: The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population. Participants: Ninety-eight young, healthy, underweight women participated in this study. Design: To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively. Results: Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR. Conclusions: Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels. [ABSTRACT FROM AUTHOR]

Psoriasis is linked to insulin resistance (IR). Nevertheless, the applicability of the METS-IR index, a new IR evaluation tool, for evaluating changes in insulin sensitivity in psoriasis populations is currently unknown. This study aimed to investigate the relationship between the METS-IR index and psoriasis in a US adult population. This cross-sectional study utilized data from adults aged 20 to 80 years from the U.S. National Health and Nutrition Examination Survey (NHANES) spanning 2003–2006 and 2009–2014. The associations between the METS-IR index and psoriasis were examined using multivariate logistic regression and smoothed curve fitting. Subgroup analyses and interaction tests were conducted to verify the stability of the association within the population. This study included 5,966 participants, of whom 182 had psoriasis. In the fully adjusted model, the METS-IR index was positively associated with psoriasis, showing a 1.7% increase in psoriasis prevalence for each one-unit increase in the METS-IR index (Model 2: OR 1.017, 95% CI 1.006–1.028). Participants in the highest quartile group were 91.9% more likely to develop psoriasis compared to those in the lowest quartile group (OR = 1.919, 95% CI 1.180–3.118). Smooth curve fitting revealed a nonlinear association between the METS-IR index and psoriasis, with an inflection point of 41.675. This positive association was more pronounced in females, non-obese individuals, those with light alcohol consumption, comorbid coronary heart disease and hyperlipidemia, non-hypertensive and non-diabetic individuals. The results of the study suggest that higher METS-IR scores are associated with an increased likelihood of psoriasis among U.S. adults. The METS-IR index is specifically recommended as a clinical indicator for the management and treatment of psoriasis in women, non-obese individuals, light alcohol consumers, individuals with comorbid coronary artery disease andhyperlipidemia, non-hypertensive and non-diabetic individuals. However, Considering the many known and unknown covariates that may be associated with psoriasis and influence theresults of the study, we remain cautious about the results obtained and look forward to the addition of subsequent studies. [ABSTRACT FROM AUTHOR]

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer's disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. Methods: In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. Results: We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Conclusions: Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor. [ABSTRACT FROM AUTHOR]

Background: The dietary glycemic index (GI) and load (GL) reflect carbohydrate quality and quantity, potentially impacting fertility through modulation of insulin sensitivity and generation of oxidative stress. While fertility is influenced by both women and men, reproductive research often emphasizes maternal factors. We first examined periconception dietary intake in both women and male partners, and subsequent associations of dietary GI and GL with fecundability and subfertility. Methods: Among 830 women and 651 male partners, participating in a population-based prospective cohort study from preconception onwards, we assessed periconception dietary intake and calculated GI and GL, using a food frequency questionnaire (FFQ) at median 12.4 weeks gestation (95% range 10.9, 18.4). Information on time to pregnancy was obtained through questionnaires, with subfertility defined as a time to pregnancy ≥ 12 months or use of assisted reproductive technology. Results: In the periconception period, mean energy intake in women was 1870 kcal (SD: 500; 46% carbohydrates, 16% protein, 33% fat; dietary GI 56.2 (SD: 3.5) and GL 141.4 (SD: 67.4)). Mean energy intake in men was 2350 kcal (SD: 591; 43% carbohydrates, 16% protein, 33% fat; dietary GI 56.8 (SD: 3.2) and GL 156.7 (SD: 75.4)). Median time to pregnancy was 4.8 months (IQR: 1.2, 16.4), with 30.6% of 830 women experiencing subfertility. Dietary GI and GL were not associated with fertility outcomes in women. In men, higher dietary GI and GL across the full range were associated with decreased fecundability, after adjusting for socio-demographic and lifestyle factors, as well as dietary GI or GL of female partners [FR: 0.91, 95% CI 0.83, 0.99; FR: 0.90, 95% CI 0.81, 0.99, per SDS increase in dietary GI and GL, respectively]. When assessing the combined influence of dietary GI clinical categories in women and men, both partners adhering to a low GI diet tended to be associated with increased fecundability, but not with subfertility risk. Conclusions: Suboptimal periconception carbohydrate intake may be negatively associated with male fertility, but not with fertility outcomes in women. Further studies are needed to assess whether a lower GI and GL diet is a feasible lifestyle intervention to improve couples fertility. [ABSTRACT FROM AUTHOR]

Background: Obesity and type 2 diabetes (T2D) are associated with alterations in testosterone concentrations. While evidence indicates that aerobic training can influence testosterone in healthy populations or females with hyperandrogenism, its impact in individuals with obesity or T2D remains unclear. Thus, the aim of this study was to investigate whether aerobic training can influence circulating testosterone concentrations in individuals with obesity or T2D. Methods: EBSCOhost (CINAHL, MEDLINE, SPORTDiscus), PubMed and Embase were searched for articles published until August 2023. Eligible articles included individuals with obesity or T2D that underwent an aerobic exercise intervention with testosterone concentrations measured at baseline and post intervention. Two reviewers independently screened the seven articles included in this meta-analysis and conducted data extraction and risk of bias assessments. Results: A total of 103 participants (62 men / 41 women) from three randomised controlled trials and four non-randomised controlled trials were included. Effect sizes were computed with random effects models. Aerobic exercise moderately increased testosterone concentrations in men (g = 0.565, 95% CI = 0.307 to 0.822, p < 0.001), but had no significant effect in women (g = -0.523, 95% CI = -1.541, 0.496, p = 0.314). Aerobic exercise had no significant effect on sex hormone-binding globulin or markers of insulin sensitivity (p > 0.05). Conclusions: Aerobic training may be used to increase testosterone concentrations in men with obesity or T2D, but potentially has no influence in women. Given the low number of studies, further studies investigating the effect of exercise on circulating sex hormones in men and women with obesity or T2D are needed. Key Points: • Aerobic exercise training can significantly increase testosterone concentrations in men who are obese or have type 2 diabetes. • Aerobic exercise training does not appear to significantly influence testosterone concentrations in women who are obese or have type 2 diabetes. • Aerobic exercise training could be utilised to improve testosterone concentrations in men who are obese or have type 2 diabetes. [ABSTRACT FROM AUTHOR]

4-cresol (4-methylphenol, p-cresol) is a xenobiotic substance negatively correlated with type 2 diabetes and associated with health improvement in preclinical models of diabetes. We aimed at refining our understanding of the physiological role of this metabolite and identifying potential signalling mechanisms. Functional studies revealed that 4-cresol does not deteriorate insulin sensitivity in human primary adipocytes and exhibits an additive effect to that of insulin on insulin sensitivity in mouse C2C12 myoblasts. Experiments in mouse isolated islets showed that 4-cresol potentiates glucose induced insulin secretion. We demonstrated the absence of off target effects of 4-cresol on a panel of 44 pharmacological compounds. Screening large panels of 241 G protein-coupled receptors (GPCRs) and 468 kinases identified binding of 4-cresol only to TNK1, EIF2AK4 (GCN2) and RPS6KA3 (RSK2), a kinase strongly expressed in human and rat pancreatic islets. Islet expression of RPS6KA3 is reduced in spontaneously diabetic rats chronically treated with 4-cresol and Rps6ka3 deficient mice exhibit reduction in both body weight and fasting glycemia, modest improvement in glycemic control and enhanced insulin release in vivo. Similar to low doses of 4-cresol, incubation of isolated rat islets with low concentrations of the RPS6KA3 inhibitor BIX 02565 stimulates both glucose induced insulin secretion and β-cell proliferation. These results provide further information on the role of low 4-cresol doses in the regulation of insulin secretion. [ABSTRACT FROM AUTHOR]

Backgroud: Pregnancy is a state of increased metabolic demand, and poor maternal nutrition can exacerbate these changes, potentially increasing the risk of cardiometabolic disorders.This study is significant as it investigates the effect of high energy nutritional supplements on cardio metabolic risk markers in underweight primigravidas. Methodology: A single blinded randomized controlled trial was conducted from April 2018- August 2019 among the Pakistani tertiary care facilities of Khyber Pakhtunkhwa. A total of thirty six participants were randomized into two groups receiving either high energy nutritional supplement 'MAAMTA' or Placebo. They were instructed to take Placebo/Supplement alongside to their regular prenatal care and food from their first antenatal visit till a week postnatally. Anthropometric measurements and blood samples for biochemical parameters insulinlevels, fasting blood glucose & lipid profile were taken at baseline visit, between 16 and 20 weeks gestation and a post natal visit. Results: The two-way repeated measures ANOVA showed that there was a highly significant time effect on participant's Insulin level (F (1.8, 53.6) = 10.64, P < 0 0.000, ηp2 = 0.269). A highly significant time effect on participant's insulin resistance (F (2, 68) = 8.116,P < 0 0.001, ηp2 = 0.193) was also observed. There was a highly significant time effect on participant's LDL level as well (F (2, 68) = 11.82, P < 0 0.000, ηp2 = 0.258). Conclusion: Supplementation with high energy nutritional supplements may improve insulin levels and insulin sensitivity in underweight primigravidas. Trial registration: https://www.ClinicalTrials.govClinicalTrials.gov Identifier: ISRCTN 10088578. Registered on 27 March 2018. https://www.isrctn.com/ISRCTN10088578. [ABSTRACT FROM AUTHOR]

Recent research has highlighted the essential role of the microbiome in maintaining skeletal muscle physiology. The microbiota influences muscle health by regulating lipid metabolism, protein synthesis, and insulin sensitivity. However, metabolic disturbances such as obesity can lead to dysbiosis, impairing muscle function. Time‐restricted feeding (TRF) has been shown to mitigate obesity‐related muscle dysfunction, but its effects on restoring healthy microbiomes remain poorly understood. This study utilizes 16S microbiome analysis and bacterial supplementation to investigate the bacterial communities influenced by TRF that may benefit skeletal muscle physiology. In wild‐type and obese Drosophila models (axenic models devoid of natural microbial communities), the absence of microbiota influence muscle performance and metabolism differently. Specifically, axenic wild‐type Drosophila exhibited reduced muscle performance, higher glucose levels, insulin resistance, ectopic lipid accumulation, and decreased ATP levels. Interestingly, in obese Drosophila (induced by a high‐fat diet or predisposed obesity mutant Sk2), the absence of microbiota improved muscle performance, lowered glucose levels, reduced insulin resistance, and increased ATP levels. TRF was found to modulate microbiota composition, notably increasing Acetobacter pasteurianus (AP) and decreasing Staphylococcus aureus (SA) in both obesity models. Supplementation with AP improved muscle performance and reduced glucose and insulin resistance, while SA supplementation had the opposite effect. This study provides novel insights into the complex interactions between TRF, microbiota, and skeletal muscle physiology in different Drosophila models. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes. Caloric restriction (CR) can extend the organism life- and health-span. Here, the authors show that mild caloric restriction enhances insulin sensititivy to promote beta cell health and longevity, through an optimization of energy metabolism and homeostasis pathways. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionsCapsiate (cap) is a metabolite that affects a number of biological processes, and diabetic retinopathy (DR) is now known to be the primary cause of end-stage eye illness.In order to examine the effects of the cap intervention on body weight, nutritional intake, changes in body weight composition, glucose metabolism levels, retinopathy, and oxidative stress levels, we proposed using a mouse model of diabetic retinopathy caused by STZ.Our findings demonstrated that, in addition to increasing lean body mass and lowering fat body mass content, cap intervention significantly improved body weight and dietary consumption in STZ mice. Additionally, our results on glucose metabolism revealed that cap had a significant impact on insulin resistance and the stabilization of OGTT levels. In conclusion, we examined the levels of oxidative stress and retinopathy. We discovered that the cap intervention greatly reduced the levels of MDA and significantly improved the levels of VEGF and retinopathy. In contrast, the STZ group’s levels of SOD, CAT, and GSH were significantly higher.According to our research, the Cap intervention improved the damage caused by diabetic retinopathy by reversing the levels of oxidative stress and the disrupted state of glucose metabolism, which in turn decreased the levels of VEGF. [ABSTRACT FROM AUTHOR]

Enteroendocrine cells (EECs) are gut epithelial cells that respond to intestinal contents by secreting hormones, including the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory protein (GIP), which regulate multiple physiological processes. Hormone release is controlled through metabolite-sensing proteins. Low expression, interspecies differences, and the existence of multiple EEC subtypes have posed challenges to the study of these sensors. We describe differentiation of stomach EECs to complement existing intestinal organoid protocols. CD200 emerged as a pan-EEC surface marker, allowing deep transcriptomic profiling from primary human tissue along the stomach-intestinal tract. We generated loss-of-function mutations in 22 receptors and subjected organoids to ligand-induced secretion experiments. We delineate the role of individual human EEC sensors in the secretion of hormones, including GLP-1. These represent potential pharmacological targets to influence appetite, bowel movement, insulin sensitivity, and mucosal immunity. [ABSTRACT FROM AUTHOR]

Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short‐term exercise would raise neuronal insulin signaling and pro‐BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty‐one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m2) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work‐matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak for 3 min each) sessions over 2‐wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole‐body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time‐points of the OGTT, and levels of insulin signaling proteins (i.e., p‐IRS‐1, total−/p‐Akt, pERK1/2, pJNK1/2, and pp38) and pro‐BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60‐0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (−0.4 ± 0.9 kg, p = 0.04) and whole‐body glucose tAUC120min (p = 0.02). Training lowered 0‐min pro‐BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT‐stimulated tAkt (−51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro‐BNDF among adults with prediabetes, thereby potentially lowering ADRD risk. [ABSTRACT FROM AUTHOR]

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. Methods: In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. Results: After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. Conclusions: The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis. [ABSTRACT FROM AUTHOR]

Goto‐Kakizaki (GK) rats develop a well‐defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T‐regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata‐3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti‐inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH) represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS. Methods: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups. Results: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005). Conclusion: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Roux‐en‐Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post‐bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB‐operated patients with PBH compared to non‐operated healthy controls (HC).We enrolled RYGB‐operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6′‐2H2]‐glucose (d‐glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post‐d‐glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco‐regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models.In RYGB subjects, the hepatic d‐glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d‐glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between‐group differences in peripheral insulin sensitivity.Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose–insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The glycemic response to critical COVID‐19 remains uncertain. We aimed to assess the association between COVID‐19, insulin requirements, glycemic control, and mortality in intensive care unit (ICU) patients.We conducted a retrospective observational study of 350 COVID‐19 patients and 1067 non‐COVID‐19 patients admitted to the ICU. Insulin requirement was defined as the total units of exogenous insulin required to cover one gram of administered carbohydrates (insulin‐to‐carbohydrate ratio, ICR). We used multivariable generalized linear mixed‐model (GLMM) analysis to assess the association of the interaction between COVID‐19 and ICU‐day with daily ICR, adjusted for fixed and time‐dependent covariates. Glycemic control was assessed after stratification on diabetes and COVID‐19. We used multivariable logistic regression analysis to assess the association between ICR and 90‐day mortality.The mean (95% CI) of the mean daily ICR among patients without diabetes was 0.09 (0.08–0.11) U/g and 0.15 (0.11–0.18) U/g in the non‐COVID‐19 group and COVID‐19 group (p = .01), respectively. In diabetes patients, the corresponding ICRs were 0.52 (0.43–0.62) U/g and 0.59 (0.50–0.68) U/g (p = .32). In multivariable GLMM analysis, the interaction between COVID‐19 and ICU‐day was independently associated with ICR (risk estimate 1.22, 95% CI 1.15–1.31, p < .001). COVID‐19 was associated with higher hypoglycemia prevalence irrespective of diabetes status, higher average glucose levels, more pronounced glucose variability, and a lower proportion of glucose values within target range among patients without diabetes. On multivariable logistic regression analysis, the adjusted odds ratio for 90‐day mortality was 1.77 (95% CI 0.94–3.34, p = .076) per one unit increase in mean ICR.In our cohort of ICU patients, COVID‐19 was associated with higher daily insulin requirements per gram of administered carbohydrates, and worse glycemic control. We found no robust association between ICR and increased odds of death at 90 days. [ABSTRACT FROM AUTHOR]

To validate the therapeutic efficacy of metformin on diabetic bladder dysfunction (DBD) and further elucidate whether the TXNIP-NLRP3-GSDMD axis serves as a target for metformin in ameliorating DBD. C57BL/6J mice were induced with diet-induced obesity by being fed a high-fat diet (HFD) for 16 weeks. After establishing the model, the mice were treated with metformin for 4 weeks, and their glucose metabolism-related parameters were assessed. Urine spot assays and urodynamic measurements were conducted to reflect the bladder function and urinary behavior in mice, while histological examination was performed to observe morphological changes. Western blot analysis was employed to measure the expression levels of pyroptotic factors such as TXNIP, NLRP3, GSDMD, and tight junction proteins. Metformin treatment significantly improved glucose tolerance and insulin sensitivity in mice. Moreover, it showed promise in decreasing urinary spot occurrence, reducing urination frequency, alleviating non-voiding contractions, and stabilizing peak urinary pressure. Following metformin therapy, mice displayed restored epithelial fold structure, increased thickness of the muscular layer, substantial decrease in muscle fiber content, notably reduced levels of TXNIP and GSDMD proteins in the metformin-treated group compared to the DBD group, and restored expression of tight junction proteins Zo-1, Claudin-1, and Occludin. Metformin ameliorates urothelial cells damage in DBD mice by inhibiting TXNIP generation and reducing NLRP3 and GSDMD production. [ABSTRACT FROM AUTHOR]