The effects of gut microbiome manipulation on glycemic indices in patients with non-alcoholic fatty liver disease: a comprehensive umbrella review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant risk factor for non-alcoholic fatty liver disease (NAFLD). Increased fasting blood sugar (FBS), fasting insulin (FI), and insulin resistance (HOMA-IR) are observed in patients with NAFLD. Gut microbial modulation using prebiotics, probiotics, and synbiotics has shown promise in NAFLD treatment. This meta-umbrella study aimed to investigate the effects of gut microbial modulation on glycemic indices in patients with NAFLD and discuss potential mechanisms of action. METHODS: A systematic search was conducted in PubMed, Web of Science, Scopus, and Cochrane Library until March 2023 for meta-analyses evaluating the effects of probiotics, prebiotics, and synbiotics on patients with NAFLD. Random-effect models, sensitivity analysis, and subgroup analysis were employed. RESULTS: Gut microbial therapy significantly decreased HOMA-IR (ES: -0.41; 95%CI: -0.52, -0.31; P < 0.001) and FI (ES: -0.59; 95%CI: -0.77, -0.41; P < 0.001). However, no significant effect was observed on FBS (ES: -0.17; 95%CI: -0.36, 0.02; P = 0.082). Subgroup analysis revealed prebiotics had the most potent effect on HOMA-IR, followed by probiotics and synbiotics. For FI, synbiotics had the most substantial effect, followed by prebiotics and probiotics. CONCLUSION: Probiotics, prebiotics, and synbiotics administration significantly reduced FI and HOMA-IR, but no significant effect was observed on FBS.

Lactobacillus casei-fermented Amomum xanthioides ameliorates metabolic dysfunction in high-fat diet-induced obese mice.

Amomum xanthioides (AX) has been used as an edible herbal medicine to treat digestive system disorders in Asia. Additionally, Lactobacillus casei is a well-known probiotic commonly used in fermentation processes as a starter. The current study aimed to investigate the potential of Lactobacillus casei-fermented Amomum xanthioides (LAX) in alleviating metabolic disorders induced by high-fat diet (HFD) in a mouse model. LAX significantly reduced the body and fat weight, outperforming AX, yet without suppressing appetite. LAX also markedly ameliorated excessive lipid accumulation and reduced inflammatory cytokine (IL-6) levels in serum superior to AX in association with UCP1 activation and adiponectin elevation. Furthermore, LAX noticeably improved the levels of fasting blood glucose, serum insulin, and HOMA-IR through positive regulation of glucose transporters (GLUT2, GLUT4), and insulin receptor gene expression. In conclusion, the fermentation of AX demonstrates a pronounced mitigation of overnutrition-induced metabolic dysfunction, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and obesity, compared to non-fermented AX. Consequently, we proposed that the fermentation of AX holds promise as a potential candidate for effectively ameliorating metabolic disorders.

Maternal Neudesin Levels in Pregnant Women with Gestational Diabetes Mellitus.

BACKGROUND: Our aim was to investigate the changes in neudesin levels in pregnant women with GDM and the relationship between neudesin and metabolic parameters. METHODS: Forty pregnant women diagnosed with GDM and forty age- and gestational week-matched control subjects were included in the study. Demographic data were obtained from records. Maternal lipid profiles, glucose levels, fasting insulin, HbA1C, and HOMA-IR results were compared between the groups. Correlation tests were performed to evaluate the relationship between neudesin and clinical and laboratory diagnostic parameters. p < 0.05 were interpreted as statistically significant. RESULTS: The human serum neudesin levels were significantly lower in the GDM group compared with the controls. The correlation tests showed statistically negative and weak correlations between the neudesin levels and the maternal age, 50 g OGCT, 100 g OGTT 3 hours, and HbA1C. The optimum neudesin cutoff value for a diagnosis of GDM disease is 6.94 ng/dL, with a sensitivity of 65.9% and a specificity of 63.2%. CONCLUSIONS: This study has shown that lower neudesin levels may occur as a reflection of changes in glucose metabolism during intrauterine life.

Effects of acute and chronic stair-climbing exercise on metabolic health: A systematic review.

Stair climbing exercise (SE) provides a feasible approach to elevate physical activity, but the effects on metabolic health are unclear. We systematically reviewed the currently available evidence on the effects of SE on fasting and postprandial glycaemia and lipidaemia. Studies were included if they investigated the effects of acute or chronic (at least 2 weeks) SE on fasting and/or postprandial glycaemic (insulin and glucose) and lipidaemic (triacylglycerols and non-esterified fatty acids) responses in healthy, prediabetic or type 2 diabetic adult populations. PubMed, Web of Science and Scopus were searched for eligible studies until July 2022. A total of 25 studies (14 acute and 11 chronic) were eligible for review. Acute bout(s) of SE can reduce postprandial glycaemia in individuals with prediabetes and type 2 diabetes (8 of 9 studies), but not in normoglycemic individuals. The effects of acute SE on postprandial lipidaemic responses and SE training on both fasting and postprandial glycaemia/lipidaemia were unclear. Acute SE may reduce postprandial glucose concentrations in people with impaired glycaemic control, but high-quality studies are needed. More studies are needed to determine the effect of chronic SE training on postprandial glucose and lipid responses, and the acute effects of SE on lipid responses.

An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin.

The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere® Insulin dose (22U or 20U). In the 30-120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin. Moreover, the supra-basal area-under-the-curve of endogenous insulin in the test with inhaled insulin was significantly lower than that in the test without (2.1 ± 1.7 × 104 pmol·min/L vs 4.2 ± 1.8 × 104 pmol·min/L, p < 0.01). The percentage of exogenous insulin reaching the plasma, relative to the inhaled dose, was 42 ± 21%. The proposed in-silico approach separates exogenous and endogenous insulin contributions to total plasma insulin, provides individual bioavailability estimates, and can be used to assess the effect of inhaled insulin on endogenous insulin secretion during a meal.

Surrogate indices of insulin resistance using the Matsuda index as reference in adult men-a computational approach.

Background: Overweight and obesity, high blood pressure, hyperglycemia, hyperlipidemia, and insulin resistance (IR) are strongly associated with non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular disease, stroke, and cancer. Different surrogate indices of IR are derived and validated with the euglycemic-hyperinsulinemic clamp (EHC) test. Thus, using a computational approach to predict IR with Matsuda index as reference, this study aimed to determine the optimal cutoff value and diagnosis accuracy for surrogate indices in non-diabetic young adult men. Methods: A cross-sectional descriptive study was carried out with 93 young men (ages 18-31). Serum levels of glucose and insulin were analyzed in the fasting state and during an oral glucose tolerance test (OGTT). Additionally, clinical, biochemical, hormonal, and anthropometric characteristics and body composition (DEXA) were determined. The computational approach to evaluate the IR diagnostic accuracy and cutoff value using difference parameters was examined, as well as other statistical tools to make the output robust. Results: The highest sensitivity and specificity at the optimal cutoff value, respectively, were established for the Homeostasis model assessment of insulin resistance index (HOMA-IR) (0.91; 0.98; 3.40), the Quantitative insulin sensitivity check index (QUICKI) (0.98; 0.96; 0.33), the triglyceride-glucose (TyG)-waist circumference index (TyG-WC) (1.00; 1.00; 427.77), the TyG-body mass index (TyG-BMI) (1.00; 1.00; 132.44), TyG-waist-to-height ratio (TyG-WHtR) (0.98; 1.00; 2.48), waist-to-height ratio (WHtR) (1.00; 1.00; 0.53), waist circumference (WC) (1.00; 1.00; 92.63), body mass index (BMI) (1.00; 1.00; 28.69), total body fat percentage (TFM) (%) (1.00; 1.00; 31.07), android fat (AF) (%) (1.00; 0.98; 40.33), lipid accumulation product (LAP) (0.84; 1.00; 45.49), leptin (0.91; 1.00; 16.08), leptin/adiponectin ratio (LAR) (0.84; 1.00; 1.17), and fasting insulin (0.91; 0.98; 16.01). Conclusions: The computational approach was used to determine the diagnosis accuracy and the optimal cutoff value for IR to be used in preventive healthcare.

Insulin sensitivity estimates and their longitudinal association with coronary artery disease in type 1 diabetes. Does it matter?

BACKGROUND: Insulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes. METHODS: The baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status. RESULTS: In 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status. CONCLUSIONS: In type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.

Assessing the Postprandial Glycemic Response to Japonica Rice (Oryza sativa L. cv. Koshihikari) with a Small Amount of Lysolecithin and Canola Oil in Japanese Adult Men: a Double-blind, Placebo-controlled, Crossover Study.

A double-blind, placebo-controlled, crossover trial was performed to analyze the effects of a small amount of lysolecithin and canola oil on blood glucose levels after consuming japonica rice. Overall, 17 Japanese adult men were assigned to consume 150 g of normally cooked japonica rice (placebo group) and 150 g of japonica rice cooked with 18 mg of lysolecithin and 1.8 g of canola oil (treatment group); these lipids were added as emulsified formulation (EMF) for stability and uniformity. Subsequently, blood samples were collected before and 30, 45, 60, 90, and 120 min after consuming test foods. There was no significant difference in blood glucose, insulin, and triglyceride levels between the groups. However, a stratified analysis of 11 subjects with body mass index (BMI) ≥ 22 revealed that blood glucose levels were significantly lower after 30 min in the treatment group than in the placebo group (p = 0.041). Through in vitro digestibility test, the rice sample of the treatment group was observed to release significantly less glucose within 20 min than that in the placebo group rice. These results suggest that the combination of a small amount of lysolecithin and canola oil modulated the increase in postprandial blood glucose levels induced by the intake of cooked japonica rice in adult men with BMI ≥ 22. This clinical trial was registered with the University Hospital Medical Information Network (UMIN) Center, (UMIN000045744; registered on 15/10/2021).

Activation and inhibition of the sweet taste receptor TAS1R2-TAS1R3 differentially affect glucose tolerance in humans.

The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R2 = 0.41, p<0.05), as well as increases in plasma insulin (R2 = 0.38, p<0.05) when sucralose was added to the OGTT (15 minute AUC). Sensitivity to lactisole sweetness inhibition was correlated with decreased plasma glucose (R2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.

Metabolic responses, PPAR-γ and TNF-α gene expression in type2 diabetic rats subsequent vanadyl sulfate treatment.

Vanadyl sulfate (VS), is a component of some food supplements and experimental drugs. This study was carried out to present a novel method for induction of Type 2 diabetes in rats, then for the first time in literature, for evaluating the effect of VS on metabolic parameters and gene expression, simultaneously. 40 male wistar rats were distributed between the four groups, equally. High fat diet and fructose were used for diabetes induction. Diabetic rats treated by two different dose of VS for 12 weeks. Metabolic profiles were evaluated by commercial available kits and gene expression were assayed by real time-PCR. Compared to controls, in non-treated diabetic rats, weight, glucose, triglyceride, total cholesterol, insulin and insulin resistance were increased significantly (p-value <0.05) that indicated induction of type 2 diabetes. Further, the results showed that VS significantly reduced weight, insulin secretion, Tumor Necrosis Factor-alpha (TNF-α) genes expression, lipid profiles except HDL that we couldn't find any significant change and increased Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) gene expression in VS-treated diabetic animals in comparison with the non-treated diabetics. Our study demonstrated that vanadyl supplementation in diabetic rats had advantageous effects on metabolic profiles and related gene expression.

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Effects of Wheat Biscuits Enriched with Plant Proteins Incorporated into an Energy-Restricted Dietary Plan on Postprandial Metabolic Responses of Women with Overweight/Obesity.

This study investigates the effect of daily consumption of wheat biscuits enriched with plant proteins in postprandial metabolic responses of women with overweight/obesity who follow an energy-restricted diet. Thirty apparently healthy women participated in a 12-week randomized controlled trial and were assigned either to a control (CB) or an intervention (PB) group. Participants consumed daily either a conventional (CB) or an isocaloric wheat biscuit enriched with plant proteins (PB) containing high amounts of amino acids with appetite-regulating properties, i.e., BCAAs and L-arg. At baseline and the end of the intervention, a mixed meal tolerance test was performed. The responses of glucose, insulin, ghrelin, GLP-1, and glicentin were evaluated over 180 min. After 12 weeks, both groups experienced significant decreases in body weight, fat mass, and waist circumference. In the PB group, a trend towards higher weight loss was observed, accompanied by lower carbohydrate, fat, and energy intakes (p < 0.05 compared to baseline and CB group), while decreases in fasting insulin and the HOMA-IR index were also observed (p < 0.05 compared to baseline). In both groups, similar postprandial glucose, ghrelin, and GLP-1 responses were detected, while iAUC for insulin was lower (p < 0.05). Interestingly, the iAUC of glicentin was greater in the PB group (p < 0.05 compared to baseline). Subjective appetite ratings were beneficially affected in both groups (p < 0.05). Consumption of wheat biscuits enriched in plant proteins contributed to greater weight loss, lower energy intake, and insulin resistance and had a positive impact on postprandial glicentin response, a peptide that can potentially predict long-term weight loss and decreased food intake.

Evaluating the therapeutic potential of moxibustion on polycystic ovary syndrome: a rat model study on gut microbiota and metabolite interaction.

Polycystic ovary syndrome (PCOS) is a common systemic disorder related to endocrine disorders, affecting the fertility of women of childbearing age. It is associated with glucose and lipid metabolism disorders, altered gut microbiota, and insulin resistance. Modern treatments like pioglitazone, metformin, and spironolactone target specific symptoms of PCOS, while in Chinese medicine, moxibustion is a common treatment. This study explores moxibustion's impact on PCOS by establishing a dehydroepiandrosterone (DHEA)-induced PCOS rat model. Thirty-six specific pathogen-free female Sprague-Dawley rats were divided into four groups: a normal control group (CTRL), a PCOS model group (PCOS), a moxibustion treatment group (MBT), and a metformin treatment group (MET). The MBT rats received moxibustion, and the MET rats underwent metformin gavage for two weeks. We evaluated ovarian tissue changes, serum testosterone, fasting blood glucose (FBG), and fasting insulin levels. Additionally, we calculated the insulin sensitivity index (ISI) and the homeostasis model assessment of insulin resistance index (HOMA-IR). We used 16S rDNA sequencing for assessing the gut microbiota, 1H NMR spectroscopy for evaluating metabolic changes, and Spearman correlation analysis for investigating the associations between metabolites and gut microbiota composition. The results indicate that moxibustion therapy significantly ameliorated ovarian dysfunction and insulin resistance in DHEA-induced PCOS rats. We observed marked differences in the composition of gut microbiota and the spectrum of fecal metabolic products between CTRL and PCOS rats. Intriguingly, following moxibustion intervention, these differences were largely diminished, demonstrating the regulatory effect of moxibustion on gut microbiota. Specifically, moxibustion altered the gut microbiota by increasing the abundance of UCG-005 and Turicibacter, as well as decreasing the abundance of Desulfovibrio. Concurrently, we also noted that moxibustion promoted an increase in levels of short-chain fatty acids (including acetate, propionate, and butyrate) associated with the gut microbiota of PCOS rats, further emphasizing its positive impact on gut microbes. Additionally, moxibustion also exhibited effects in lowering FBG, testosterone, and fasting insulin levels, which are key biochemical indicators associated with PCOS and insulin resistance. Therefore, these findings suggest that moxibustion could alleviate DHEA-induced PCOS by regulating metabolic levels, restoring balance in gut microbiota, and modulating interactions between gut microbiota and host metabolites.

Role of ghrelin hormone in the development of alcohol-associated liver disease.

Fatty liver is the earliest response of the liver to excessive alcohol consumption. Previously we identified that chronic alcohol administration increases levels of stomach-derived hormone, ghrelin, which by reducing circulating insulin levels, ultimately contributes to the development of alcohol-associated liver disease (ALD). In addition, ghrelin directly promotes fat accumulation in hepatocytes by enhancing de novo lipogenesis. Other than promoting ALD, ghrelin is known to increase alcohol craving and intake. In this study, we used a ghrelin receptor (GHSR) knockout (KO) rat model to characterize the specific contribution of ghrelin in the development of ALD with emphasis on energy homeostasis. Male Wistar wild type (WT) and GHSR-KO rats were pair-fed the Lieber-DeCarli control or ethanol diet for 6 weeks. At the end of the feeding period, glucose tolerance test was conducted, and tissue samples were collected. We observed reduced alcohol intake by GHSR-KOs compared to a previous study where WT rats were fed ethanol diet ad libitum. Further, when the WTs were pair-fed to GHSR-KOs, the KO rats exhibited resistance to develop ALD through improving insulin secretion/sensitivity to reduce adipose lipolysis and hepatic fatty acid uptake/synthesis and increase fatty acid oxidation. Furthermore, proteomic data revealed that ethanol-fed KO exhibit less alcohol-induced mitochondrial dysfunction and oxidative stress than WT rats. Proteomic data also confirmed that the ethanol-fed KOs are insulin sensitive and are resistant to hepatic steatosis development compared to WT rats. Together, these data confirm that inhibiting ghrelin action prevent alcohol-induced liver and adipose dysfunction independent of reducing alcohol intake.

Insulin-like peptide 3 (INSL3) as an indicator of leydig cell insufficiency (LCI) in Middle-aged and older men with hypogonadism: reference range and threshold.

Insulin-like peptide 3 (INSL3) is a circulating biomarker for Leydig cell functional capacity in men, also indicating Leydig Cell Insufficiency (LCI) and potential primary hypogonadism. Using results from large cohort studies we explore sources of biological and technical variance, and establish a reference range for adult men. It is constitutively secreted with little within-individual variation and reflects testicular capacity to produce testosterone. The main INSL3 assays available indicate good concordance with low technical variance; there is no effect of ethnicity. INSL3 declines with age from 35 years at about 15% per decade. Like low calculated free testosterone, and to a lesser extent low total testosterone, reduced INSL3 is significantly associated with increasing age-related morbidity, including lower overall sexual function, reflecting LCI. Consequently, low INSL3 (≤0.4 ng/ml; ca. <2 SD from the population mean) might serve as an additional biochemical marker in the assessment of functional hypogonadism (late-onset hypogonadism, LOH) where testosterone is in the borderline low range. Excluding individuals with low LCI (INSL3 ≤ 0.4 ng/ml) leads to an age-independent (> 35 years) reference range (serum) for INSL3 in the eugonadal population of 0.4 - 2.3 ng/ml, with low INSL3 prospectively identifying individuals at risk of increased future morbidity.

Glucagon kinetics assessed by mathematical modelling during oral glucose administration in people spanning from normal glucose tolerance to type 2 diabetes.

Background/Objectives: Glucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels ("alpha-cell insulin sensitivity"), during oral glucose administration. Subjects/Methods: We studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously. Results: The alpha-cell insulin sensitivity parameter (named SGLUCA; "GLUCA": "glucagon") was remarkably variable among participants (CV=221%). SGLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N=28, and impaired glucose regulation/type 2 diabetes, IGR_T2D, N=22), we found that SGLUCA was lower in the latter (1.50 ± 0.50·10-2 vs. 0.26 ± 0.14·10-2 ng·L-1 GLUCA/pmol·L-1 INS, in NGT and IGR_T2D, respectively, p=0.009; "INS": "insulin"). Conclusions: The alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents.

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects.

BACKGROUND: Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects. METHODS: We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26). RESULTS: Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P < 0.0001) was significant suggesting a sex-specific association. CONCLUSIONS: Our data suggest that deterioration of glucose homeostasis in women is associated with a greater impairment in myocardial glucose metabolism as compared with men. The sex-specific myocardial insulin resistance could be an important factor responsible for the greater effect of T2DM on the excess risk of cardiovascular disease in women than in men.

Maternal Vitamin D Deficiency Impairs the Development of ß Cells in Offspring Rats in a Sex-Dependent Manner.

Recent studies have shown that maternal vitamin D deficiency (VDD) causes long-term metabolic changes in offspring. However, little is known about the impact of maternal VDD on offspring endocrine pancreas development and insulin secretion in the adult life of male and female animals. Female rats (Wistar Hannover) were fed either control (1000 IU Vitamin D3/kg), VDD (0 IU Vitamin D3/kg), or a Ca2+-enriched VDD diet (0 IU Vitamin D3/kg + Ca2+ and P/kg) for 6 weeks and during gestation and lactation. At weaning, VDD status was confirmed based on low serum calcidiol levels in dams and pups. Next, male and female offspring were randomly separated and fed a standard diet for up to 90 days. At this age, serum calcidiol levels were restored to normal levels in all groups, but serum insulin levels were decreased in VDD males without affecting glucagon levels, glycemia, or glucose tolerance. Islets isolated from VDD males showed lower insulin secretion in response to different glucose concentrations, but this effect was not observed in VDD females. Furthermore, VDD males, but not females, showed a smaller total pancreatic islet area and lower ß cell mass, an effect that was accompanied by reduced gene expression of Ins1, Ins2, Pdx1, and SLC2A2. The decrease in Pdx1 expression was not related to the methylation profile of the promoter region of this gene. Most of these effects were observed in the male VDD+Ca2+ group, indicating that the effects were not due to alterations in Ca2+ metabolism. These data show that maternal VDD selectively impairs the morphology and function of ß cells in adult male offspring rats and that female offspring are fully protected from these deleterious effects.

Hypoglycemic Effects of Gynura divaricata (L.) DC Polysaccharide and Action Mechanisms via Modulation of Gut Microbiota in Diabetic Mice.

Aiming to provide a basis for the application of Gynura divaricata (L.) DC polysaccharide (GDP) in functional foods, the hypoglycemic effects of GDP, and action mechanisms, were investigated. Results showed that GDP effectively inhibited α-glucosidase and remarkably increased the glucose absorption, glycogen content, and pyruvate kinase and hexokinase activities of insulin-resistant HepG2 cells, indicating its potent in vitro hypoglycemic effect. In streptozotocin-induced type 2 diabetes mice, GDP significantly improved various glycolipid metabolism-related indices in serum and liver, e.g., fasting blood glucose, oral glucose tolerance, glycosylated serum protein content, serum insulin level, antioxidant enzyme activities, TG, TC, LDL-C, and HDL-C levels, and hepatic glycogen content, and recovered the structure of gut microbiota to the normal level. It was also found that GDP significantly affected the expression of related genes in the PI3K/Akt, AMPK, and GS/GSK-3ß signaling pathways. Therefore, GDP regulates blood glucose possibly by directly inhibiting α-glucosidase, exerting antioxidant activity, and regulating intestinal microbiota.

Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis.

Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key ß-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in ß-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.