To assess the safety and efficacy of exenatide in overweight or obese patients treated with olanzapine.

Adults with stable major mood or psychotic disorders were randomized to double-blind exenatide or placebo for 16 weeks. Weight and body mass index (BMI) were monitored throughout the study. A secondary objective was to evaluate the tolerability of exenatide and its effects on mood and psychotic symptoms.

A significant difference in weight change was detected between the treatment groups. Participants in the exenatide group experienced on average a minor weight loss, while participants in the placebo group on average experienced weight gain (-0.5 kg [-0.6 %] vs. +2.6 kg [+2.8 %], both p < .01). The most common side effects in the exenatide group were gastrointestinal symptoms and headaches. There were no clinically meaningful differences between the groups in changes to mood or psychotic symptoms.

Exenatide is effective and well-tolerated for attenuating olanzapine-associated weight gain.

Exenatide for the Treatment of Weight Gain Associated with Olanzapine in Obese Adults. NCT00845507.

Resveratrol (RSV) is a natural ingredient used in the treatment of diabetes mellitus. However, the antidiabetic mechanism of RSV is not clear. In the present study the antidiabetic mechanism of RSV was investigated using mice with high-fat diet (HFD)-induced insulin resistance (IR). C57BL/6J mice were divided into the following three groups: Control (CON), HFD, and HFD + RSV (RSV, 100 mg/kg body weight/day). Mice were administered RSV for 6 weeks; then biochemical and histological parameters, as well as gene and protein expression were detected. Compared with the CON group, the circulating levels of blood glucose, insulin, triglycerides, total cholesterol and high-density lipoprotein cholesterol, and area under the glucose curve were increased (P<0.05), the quantitative insulin sensitivity check index was decreased (P<0.05), and lipid accumulation in skeletal muscle was increased in the HFD group. RSV treatment was able to reverse this process and promote the IRS-1/PI3K/AKT/GLUT4 signaling pathway. Moreover, DNA damage-inducible transcript 4 (DDIT4) expression was upregulated, while the expression levels of mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase were downregulated in the HFD + RSV group compared with the HFD group (P<0.05). Cell experiments inhibiting DDIT4 or activating mTOR also confirmed the role of these pathways. In summary, RSV ameliorated IR and glucose as well as lipid metabolism, and promoted the IRS-1/PI3K/AKT/GLUT4 signaling pathway through the DDIT4/mTOR signaling pathway in mice with HFD-induced IR.

The effects of an eight-month marathon school training program on blood pressure (BP) and underlying hemodynamics were examined in 45 participants and 43 controls. Hemodynamics were recorded using whole-body impedance cardiography, radial tonometric pulse wave analysis, and third-finger BP measurements during passive head-up tilt. The mean ages were 40.9 and 42.2 years, and body mass indexes (BMI) 25.1 and 25.8 kg/m2, respectively. Marathon training decreased mean weight (-1.6 kg), fat percentage (-2.7%), and BMI (-0.5 kg/m2) and increased maximal oxygen uptake (+3.2 ml/kg/min) and insulin sensitivity (+0.013 units) (p < 0.03 for all). During head-up tilt, systolic BP and cardiac output decreased, while diastolic BP, heart rate, and systemic vascular resistance (SVR) increased, but training did not affect these posture-induced changes. Initial aortic and third finger systolic/diastolic BP were numerically but not significantly lower in the marathon vs. control group (by 3.4/2.3 and 5.5/4.5 mmHg, respectively, p > 0.075). Final BP values were significantly lower in the marathon group (by 7.2/4.5 and 10.9/10.2 mmHg, respectively, p < 0.01). Marathon training reduced SVR by 167 dyn×s/cm5×m2(p = 0.041), and extracellular water volume by 0.34 L (p = 0.045). To conclude, aerobic exercise training appears to lower BP, a significant cardiovascular risk factor, by reducing SVR and decreasing extracellular water volume.

Obesity, insulin resistance (IR), and diabetes are common in heart failure with preserved ejection fraction (HFpEF) and are associated with worsening heart failure, but their independent contributions remain unknown.

In this study, we sought to determine the contribution of diabetes vs obesity to left heart abnormalities in HFpEF METHODS: Indices of adiposity (body mass index [BMI], bioimpedance fat mass, waist circumference) and IR (homeostasis-model assessment [HOMA]) were measured among PVDOMICS study participants with HFpEF. Rest and exercise pulmonary capillary wedge pressure (PCWP) responses were compared, stratified by obesity (BMI ≥30 kg/m2), IR status (HOMA-IR ≥2.6), and diabetes diagnosis. Findings were also tested in an independent HFpEF cohort.

Of 276 patients with HFpEF, 246 (89%) had increased waist/height ratio, and 166 (60%) had BMI ≥30 kg/m2, with 114 (69%) of the latter having IR and 75 (45%) having diabetes. Of 110 (40%) with HFpEF and BMI <30 kg/m2, 44 (40%) had IR and 27 (25%) had diabetes (both P < 0.0001 vs obesity phenotype). The presence of IR was not associated with worse left heart remodeling or PCWP. In contrast, obesity (regardless of IR status) was associated with greater biventricular enlargement, worse exercise performance, poorer quality of life, and higher rest and exercise PCWP (P < 0.01 for all). Obesity was associated with higher rest and dynamic PCWP responses (+4.4 mm Hg; 95% CI: +2.5 to +6.4 mm Hg; P < 0.0001), even after adjustment for HOMA-IR (+4.7 mm Hg; 95% CI: +2.7 to +6.7 mm Hg; P < 0.0001). Greater fat mass, BMI, and waist circumference were associated with higher PCWP at rest and exercise (P < 0.0009 for all), but HOMA-IR was not (+0.01 mm Hg; 95% CI: -0.13 to +0.16 mm Hg; P = 0.84). Findings were similar evaluating diabetes in place of IR, and were replicated in the independent HFpEF cohort (n = 254), where BMI remained independently associated with higher rest and exercise PCWP (+0.19 mm Hg [95% CI: +0.11 to +0.27 mm Hg] per kg/m2; P < 0.0001), but diabetes was not.

Excess adiposity is present in most patients with HFpEF, even among those not considered obese according to BMI, calling for further study of cardiometabolic therapies among patients with HFpEF and excess adiposity with BMI <30 kg/m2. Although excess body fat is associated with IR and diabetes, cardiac remodeling, hemodynamics, and functional impairment are independently correlated with body fat, but not IR. These findings suggest that diabetes is primarily a marker of greater adiposity in HFpEF, with less direct impact on heart failure severity. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).

Insulin sensitivity (IS) is a key determinant of metabolic health and may share genetic factors with obesity-related traits. Previous large-scale genetic studies have identified variants associated with IS as well as obesity related traits like body mass index (BMI) and waist-to-hip ratio (WHR). Notably, many of these associations are shared across traits, indicating a potential genetic overlap. However, the genetic intersection between IS and obesity-related traits remains underexplored. To explore this gap, we investigated associations between six IS indices, including fasting and post-glucose load measures, and genetic variants linked to BMI and WHR to determine their influence on IS and related cardiometabolic traits. To achieve this, we calculated six IS indices using fasting and oral glucose tolerance test (OGTT) data from 5,007 non-diabetic individuals, grouping them into fasting, OGTT0,120, and OGTT0,30,120 categories. A total of 678 BMI-associated and 265 WHR-associated genetic variants were analysed using linear regression, adjusting for age and sex, with sex-specific analyses for WHR. Analyses were conducted with and without BMI adjustments and corrected for multiple testing (padj). Additionally, we explored the relationship between IS-linked variants and their associations with type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Among the 678 BMI-associated variants, 100 showed nominal associations (p < 0.05) with at least one IS index; and 20 remained significant after multiple testing correction (padj < 0.05) when not adjusting for BMI. After adjusting for BMI, 70 variants retained nominal associations, and six remained significant (padj < 0.05). In sex-specific analyses of the 265 WHR-associated variants, 12 variants were associated in females when adjusted for BMI, whereas no significant associations were observed in males. Furthermore, BMI- and WHR-associated variants linked to decreased IS, such as those in FTO and VPS13C loci, were also associated with increased T2D and stroke risk, whereas IS-increasing variants, including those in VPS13C and PPARG, were linked to lower T2D and stroke risk, with some, like THADA, showing opposing effects on CAD. This study offers insights into genetic variants that influence both IS and obesity-related traits, revealing BMI- and WHR-associated variants with both positive and negative effects on IS and their potential impact on cardiometabolic health.

Background: Type 2 Diabetes Mellitus (T2DM) is associated with insulin resistance, hyperglycemia, and hyperlipidemia. Anthocyanins, which are natural antioxidants, have been reported to manage T2DM-related complications. However, the potential of anthocyanin-rich black wheat as a functional food for managing diabetes remains unexplored. Aim: This study aimed to investigate the effects of anthocyanin-rich black wheat on glucose metabolism, insulin sensitivity, lipid profile, oxidative stress, inflammation, and organ protection in high fat diet-streptozotocin (HFD-STZ) induced T2DM rats. Methods: T2DM was induced in rats using HFD-STZ. The rats were fed with either white wheat or anthocyanin-rich black wheat chapatti. Glucose metabolism, insulin sensitivity, lipid profile, antioxidant enzymes, inflammatory markers, and glucose transporters were assessed. Histopathological analysis of the liver, kidneys, and spleen was performed. Results: Compared to white wheat chapatti, black wheat chapatti exhibited higher α-amylase and α-glucosidase inhibitory activities. Black wheat chapatti consumption significantly reduced blood glucose and HbA1c levels, and improved insulin sensitivity, oral glucose tolerance, and insulin tolerance. Antioxidant enzyme (superoxide dismutase and catalase) activities were enhanced. Atherogenic dyslipidemia was attenuated, with improved high-density lipoprotein cholesterol levels. Inflammatory markers (TNF-α, IL-1β, leptin, resistin and cortisol) were reduced, while adiponectin (Acrp-30) levels increased. Black wheat chapatti activated adiponectin-AMPK and PI3K-AKT pathways, upregulating glucose transporters (GLUT-2 and GLUT-4). Histopathology revealed protective effects on the liver, kidneys, and spleen. Conclusions: Anthocyanin-rich black wheat chapatti ameliorates insulin resistance and associated complications in HFD-STZ-induced T2DM rats. It modulates key signaling pathways and glucose transporters, demonstrating its potential as a functional food for managing T2DM and its complications.

Suboptimal preweaning nutrition of dairy calves has been causally associated with impaired adult metabolic health and lactation performance. However, the biological mechanisms linking early life nutrient supply and future performance remain insufficiently understood. Thus, the objective of this study was to characterize growth, reproductive performance, glucose metabolism, and the metabolic profile of growing heifers fed a restricted (RES) or an elevated (ELE) milk supply preweaning. Heifer calves (n = 86) born from a single herd of ∼120 dairy cows were blocked in pairs by the dam's parity and birth date. Within block, calves were fed an identical colostrum supply and randomly assigned to a milk replacer (MR) allowance level treatment of either 5.41 Mcal of ME in 8 L of MR/d (ELE) or 2.71 Mcal of ME in 4 L of MR/d (RES). The MR (150 g/L), containing 24% crude protein, 18% crude fat, and 45% lactose, was fed from d 2 after birth until calves were stepped down by 50% at d 49 and fully weaned at d 56. All calves were kept in individual hutches until wk 10 and had ad libitum access to fresh pelleted calf starter, chopped wheat straw, and water. Starting from wk 8, heifers from both treatments were fed and managed in the same way, and preweaning treatments were blind to caretakers. Blood samples for metabolomics analysis were collected at 330 d of age, and an insulin-modified intravenous glucose tolerance test was conducted at 370 ± 12 d of age. Heifers fed the ELE diet exhibited higher average daily gain in the preweaning period, leading to higher body weight at 70 d of age (+ 9 kg). At 330 d of age, growth advantages were no longer significant, and preweaning nutrition had no effect on age at first service, first service conception rates, age at conception, or number of services per conception. The metabolomic serum data sampled at 330 d of age revealed that carnitine, glycerolipid, and purine metabolism were predicted to be significantly affected by preweaning nutrient supply, reflecting long-term metabolic programming. At 370 d of age, during the first 20 min following the glucose infusion, blood insulin levels were greater (10.3 ng/mL vs. 7.7 ng/mL), the area under the curve for insulin tended to be greater, and insulin sensitivity was lower in RES heifers. Increasing the amount of MR fed to calves preweaning had a sustained impact on metabolic processes, but long-term differences could not be detected in growth or reproductive performance, potentially due to the low number of animals.

Patients with chronic kidney disease (CKD) experience high mortality rates from cardiovascular disease (CVD). Insulin resistance (IR) is a frequent complication of CKD and is associated with poorer cardiovascular outcomes. This study investigates the prevalence and associations of IR in hemodialysis (HD) patients.

A descriptive-analytic cross-sectional study was conducted on 103 HD patients. We used the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI) to measure IR. We examined potential associations between IR and the following factors: age, gender, etiology of kidney failure, BMI, waist circumference, blood lipids, hemoglobin concentration, uric acid, and duration of HD.

The prevalence of IR, as measured by HOMA-IR, was 61.2%, and by QUICKI, it was 48.5%. Age, gender, etiology of kidney failure and increased waist circumference did not significantly influence IR. A significant associations were observed between IR and higher BMI, anemia, dyslipidemia, and longer duration of HD therapy. Interestingly, the HOMA-IR and QUICKI indices correlated for most factors except total cholesterol, LDL-C, and uric acid.

This study found a high prevalence of IR in HD patients, with 61.2% identified by HOMA-IR and 48.5% by QUICKI. We confirmed significant associations between IR and BMI, anemia, dyslipidemia, and duration of HD therapy in this population.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder that requires effective dietary strategies for management. In this randomized, double-blind, placebo-controlled clinical trial, the effects of low-fat yogurt enriched with konjac glucomannan (KGM) and inulin on glycemic control, lipid profiles, anthropometric indices, and oxidative stress were investigated in patients with T2DM. Eighty participants were randomly assigned to consume either 150 g of yogurt enriched with 1.5 g of KGM and 1.5 g of inulin (n=40) or plain low-fat yogurt (n=40) daily for 8 weeks. The primary outcomes were fasting blood glucose and fasting insulin levels, insulin sensitivity indices [homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)], and glycated hemoglobin. Secondary outcomes included lipid profile [total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (TG)], anthropometric indices (weight, body mass index, fat mass, skeletal muscle, and waist circumference), and oxidative stress markers. Compared to control group, the intervention significantly improved fasting insulin levels (-1.85 µIU/mL, P=0.042), HOMA-IR (-0.89, P=0.029), and QUICKI (0.11, P=0.032). Lipid profile analysis revealed reductions in TC (-18.51 mg/dL, P=0.049) and TG levels (-15.0 mg/dL, P=0.041). These findings suggest that daily consumption of yogurt fortified with KGM and inulin significantly enhances insulin sensitivity and lipid profiles in patients with T2DM over an 8-week period. This dietary intervention shows promise as a complementary strategy for T2DM management. Further studies are needed to assess the long-term outcomes, optimize doses, and elucidate the underlying mechanisms of this intervention.

New concepts have emerged regarding how interrelationships of hyperandrogenism and hyperinsulinemia from systemic insulin resistance contribute to the origins of polycystic ovary syndrome (PCOS). Although these androgen-insulin interrelationships are associated with several reproductive and metabolic variables, their specific cause and effect relationships remain unclear. This review examines specific causal relationships between hyperandrogenism and hyperinsulinemia from systemic insulin resistance to understand how these complex interactions contribute to the phenotypic expression of PCOS.

Clinical interventions for the treatments of hyperandrogenism and hyperinsulinemia from systemic insulin resistance as well as in-vitro studies of androgen and insulin actions on critical target tissues are examined to understand why androgen-insulin interrelationships are central to the origins of PCOS.

Bidirectional interrelationships between hyperandrogenism and hyperinsulinemia from systemic insulin resistance in normal-weight PCOS women may have originally evolved as an ancient metabolic adaptation to simultaneously favor fat storage and energy utilization for survival and reproduction during famine. These androgen-insulin interactions in PCOS now predispose to metabolic diseases and pregnancy complications in today's obesogenic environment and, therefore, require improved preventive healthcare to optimize the long-term health of PCOS women and their children.

BackgroundThe triglyceride-glucose (TyG) index is considered a robust surrogate for insulin resistance (IR). The relationship between the trajectory patterns of the TyG index and subsequent brain structure changes is still unclear.ObjectiveThis study investigates the relationship between 10-year trajectories of TyG-related indices and brain structural integrity in a 10-year follow-up.MethodsThis prospective study included 898 participants (mean age 55.6 years, 34.4% males) from the community-based Shunyi Study. IR was assessed using the TyG index, TyG-body mass index (BMI) index, TyG-waist circumference index, and TyG-waist-to-height ratio (WHtR) index. The group-based trajectory model was employed to identify the 10-year trajectories. Structural brain measurements included structural changes of the whiter matter (white matter hyperintensities (WMHs), fractional anisotropy, and mean diffusivity) and gray matter (brain parenchymal fraction (BPF), cortical thickness, and hippocampal volume). General linear models were utilized to examine the association between the trajectory patterns of TyG-related indices and brain structure.ResultsThree distinct trajectories of TyG-related indices were identified from 2013 to 2023. The high-level trajectory groups of TyG-related indices exhibited a greater volume of WMHs and were more susceptible to disruptions in white matter microstructural integrity. This association was most significant for the TyG-BMI and TyG-WHtR trajectory groups. No significant correlations were found for BPF and cortical thickness among the different TyG-related indices trajectories.ConclusionsThe findings suggest that long-term IR primarily damages brain white matter rather than causing structural changes in gray matter.

Ketogenic conditions have gained attention due to their favorable metabolic prognoses. We aimed to investigate the association between blood levels of beta-hydroxybutyrate (βHB), the most abundant form of ketone body, and type 2 diabetes (T2D) incidence in patients with impaired fasting glucose (IFG).

We randomly selected 500 patients with IFG from the prospective Korean Cancer Prevention Study II biobank. Blood levels of βHB were measured from the stored samples, and the diagnostic data from the Korean National Health Insurance Service were used to determine the probability of T2D-free survival. A multivariable Cox regression analysis was performed to assess the association between blood βHB levels and the incidence of new-onset T2D.

A total of 453 patients with IFG were included, and 105 (23%) developed T2D during a mean follow-up period of 10.9 years. Higher blood βHB levels in patients with IFG were associated with improved T2D-free survival, although it was not statistically significant (log-rank test, p = 0.058). In multivariable Cox regression models, βHB levels showed a tendency toward a lower risk of T2D, but it was not statistically significant (HR 0.70; 95% CI 0.47-1.04; p = 0.07).

In patients with IFG, the blood βHB level showed a tendency to be associated with the risk of new-onset T2D; however, this tendency was not statistically significant.

Objective: Various insulin resistance (IR) indices have been developed to assess cardiovascular (CVS) risk. We compared the association between ten IR indices and cardiac, renal, and vascular end-organ measures in a predominantly young (age 45.0 ± 18.3 years) South African Black population. Methods: We assessed the relationships between ten IR indices (homeostatic model assessment for IR [HOMA-IR], quantitative insulin sensitivity check index [QUICKI], metabolic score for IR [METS-IR], triglyceride-glucose index [TyG], TyG-body mass index [TyG-BMI], TyG-waist circumference [TyG-WC], TyG-waist-to-height ratio [TyG-WHtR], triglyceride to high-density cholesterol concentration [TyG-HDL], lipid accumulation product [LAP], visceral adiposity index [VAI]) and end-organ measures in 779 community participants of African ancestry. Results: HOMA-IR and QUICKI were the only IR indices consistently associated with end-organ measures (left ventricular [LV] mass index, p ≤ 0.005; LV relative wall thickness, p < 0.0001; early-to-late mitral velocity, p ≤ 0.01; E/e', p ≤ 0.002; e', p < 0.0001; pulse wave velocity, p = 0.036 (HOMA-IR only); glomerular filtration rate [GFR], p < 0.0001), independent of confounders. Furthermore, HOMA-IR was consistently higher, and QUICKI lower, in those with compared to those without end-organ damage (LV hypertrophy [p ≤ 0.03], concentric LV [p < 0.03], and reduced GFR [p ≤ 0.008]), independent of confounders. Importantly, the associations between HOMA-IR or QUICKI and end-organ measures were independent of additional CVS risk factors, including adiposity measures, and were replicated in the participants without diabetes mellitus (n = 669) and in the participants without high blood pressure (n = 505). Conclusions: In a predominantly young community of African ancestry, of ten recommended IR indices, only HOMA-IR and QUICKI were consistently associated with end-organ damage independent of CVS risk factors.

The aim of the study was to determine the correlation between insulin resistance (IR) indexes in children with overweight or obesity.

A total of 276 children with overweight or obesity and 100 normal-weight children were enrolled in the study. IR indexes such as homeostasis model assessment insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI), fasting glucose/insulin ratio (FGIR), Triglyceride glucose index (TyG), and lipid-derived ratios were determined.

The mean ages were 13.0 ± 2.6, 13.1 ± 2.7 and 12.72 ± 2.23 (range:6 - 18 years) for children with overweight, obesity and normal-weight, respectively. A statistically significant positive correlation was found between HOMA-IR and TyG index, and a negative correlation between QUICKI, FGIR and TyG index (r = 0.193, P < 0.001; r = - 0.456, P < 0.001 and r = - 0.392, P < 0.001, respevtively). TyG index, triglyceride (TG)/high-density lipoprotein (HDL), total cholesterol (TC)/HDL, and low-density lipoprotein (LDL)/HDL were higher in children with IR than those without IR (P < 0.05). In receiver operating characteristic curves analysis, cut-off points were found to be ≤ 0.31 for QUICKI (94.31% sensitivity and 97.58% specificity), ≤ 6.3 for FGIR (89.1% sensitivity and 93.94% specificity), and > 4.62 for TyG (49.29% sensitivity and 84.85% specificity).

HOMA-IR, FGIR, and QUICKI constitute stronger predictors of IR than TyG index in children with overweight and obesity.

Maternal diabetes mellitus is linked to neurobiological and cognitive impairments, increasing the risk of brain and cerebellar defects in diabetic pregnant rats and their offspring. Momordica charantia (bitter melon) possesses antidiabetic properties due to its bioactive compounds, including phenolics, alkaloids, proteins, steroids, inorganic compounds, and lipids. Forty pregnant rats were randomly assigned to four groups: control; M charantia (BM); diabetic (DM); and diabetic treated with M charantia (BM+DM). Diabetic maternal rats showed significantly elevated serum glucose, insulin, leptin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels, with a concomitant decrease in insulin sensitivity check index (QUICKI), glucose transporter 4 (GLUT4), adenosine monophosphate-activated protein kinase (AMPK), acetylcholine (ACh), and dopamine. Oxidative stress markers in cerebellar tissue indicated increased malondialdehyde (MDA) and decreased glutathione (GSH) levels. Cerebellar tissue analysis revealed significantly reduced superoxide dismutase (SOD), catalase (CAT), B-cell lymphoma 2 (Bcl-2), and nerve growth factor (NGF), while Bcl-2-associated X protein (BAX) and glial fibrillary acidic protein (GFAP) were elevated. Histological and ultrastructural analysis of the diabetic maternal cerebellum showed moderate vacuolation of the neuropil in all cerebellar cortical layers, along with Purkinje cell degeneration and necrosis, including Nissl substance loss. Offspring of diabetic mothers exhibited multifocal Purkinje cell loss, empty baskets, and cerebellar cortical dysplasia with abnormal tissue development and organization. In conclusion, M. charantia supports central nervous system health in diabetic pregnant rats and their offspring by enhancing antioxidant markers, regulating GFAP and NGF, and mitigating apoptosis, ultimately improving cerebellar pathology and neural development.

The identification of mothers at risk for gestational diabetes mellitus (GDM) at start of pregnancy may be beneficial to improve perinatal outcomes. This study aims evaluating the predictive performance of fasting and dynamic indices of glucose metabolism at first trimester and their association with later GDM development. A cohort of 198 women received detailed metabolic assessment at median gestational age (13 weeks) including 75-g oral glucose tolerance test (OGTT) with assessment of glucose, insulin and C-peptide, and biochemical markers (including triglycerides) to calculate different indices of insulin sensitivity either at fasting and in the OGTT dynamic conditions. Moreover, parameters of β-cell function were assessed. A second OGTT was performed between 24 and 28 gestational weeks (GW) to identify women with GDM. We found that 28 women developed GDM, and, in univariable analysis, this was fairly predicted by several first trimester indices, both at fasting and in dynamic conditions. However, fasting indices containing maternal triglycerides showed better accuracy as compared to traditional indices (even the dynamic ones). In multivariable analysis, the best predictive model of GDM development included fasting and OGTT glucose values, HbA1c, and an insulin sensitivity marker that includes triglycerides (e.g. the improved triglyceride-glucose index, TyGIS). β-Cell function was not included in such predictive model, but at 24-28 GW it showed remarkable impairment in women with GDM. In conclusion, both fasting and dynamic parameters of glucose homeostasis at early pregnancy showed fair predictive accuracy for later GDM, with TyGIS showing excellent performance. β-Cell dysfunction role needs being further elucidated.

This study examined the effects of hyperthermic therapy (HT) on mice fed normal chow or a high-fat diet (HFD) for 18 or 22 weeks, undergoing four or eight weekly HT sessions.

Mice were housed within their thermoneutral zone (TNZ) to simulate a physiological response. HFD-induced obesity-related changes, including weight gain, visceral fat accumulation, muscle loss (indicative of obesity sarcopenia), glucose intolerance, and hepatic triglyceride buildup.

HT upregulated HSP70 expression in muscles, mitigated weight gain, normalised QUICK index, and reduced plasma HSP70 concentrations. It also lowered the H-index of HSP70 balance, indicating improved immunoinflammatory status, and decreased activated caspase-1 and proliferative senescence in adipose tissue, both linked to insulin resistance.

The findings suggest that even animals on a "control" diet but with insufficient physical activity and within their TNZ may experience impaired glycaemic homeostasis.

Dietary guidance recommends consuming low- or non-fat dairy foods for metabolic health, yet observational research indicates full-fat yogurt intake may not detrimentally affect type 2 diabetes risk. Randomized-controlled trials are needed to further explore this relationship. Our aim was to evaluate the effect of substituting full-fat (3.25%) yogurt for non-fat yogurt on type 2 diabetes risk in individuals with prediabetes. We hypothesized beneficial effects on measures of glucose homeostasis, insulin sensitivity, and metabolic hormone response following short-term consumption of 3 full-fat yogurt servings daily. Thirteen individuals completed the 8-week randomized, double-masked crossover controlled-feeding trial comprised 2, 3-week experimental diet periods in which participants consumed 3 daily servings of full-fat or non-fat yogurt; a 1-week control preceded each diet period. Following each diet period, changes in whole-body glucose handling and metabolic hormone concentrations were measured using mixed meal and oral glucose tolerance tests. Our primary outcome measure was the blood glucose concentration at the 120-minute time point during the oral glucose tolerance test. Though differences in the primary outcome measure were not observed, the full-fat yogurt diet resulted in lower concentrations of blood fructosamine, a marker of average blood glucose concentrations over 2 to 3 weeks. Further, fasting glucagon-like peptide-1 and post-prandial glucose-dependent insulinotropic polypeptide concentrations were greater following the full-fat yogurt diet. Our preliminary results indicate that short-term consumption of full-fat relative to non-fat yogurt beneficially affected aspects of glucose homeostasis and metabolic hormone regulation in individuals with prediabetes, warranting further randomized-controlled research. This trial is registered at clinicaltrials.gov (NCT03577119).

The triglyceride-glucose (TyG) index, a recognized marker for insulin resistance, holds potential implications for skeletal health. However, its relationship with fragility fractures remains uncertain. We aimed to elucidate the association between the TyG index and fragility fractures in the general US population.

Cross-sectional data of 25,082 participants were obtained from the National Health and Nutrition Examination Survey. The association between the TyG index and fragility fractures was investigated using univariate and weighted multivariate logistic regression as well as restricted cubic spline (RCS) regression models. The least absolute shrinkage and selection operator regression with ten-fold cross-validation was employed to identify key variables, leading to the development of a nomogram model. Calibration and receiver operating characteristic curves were utilized to evaluate the model's validity.

The overall prevalence of fragility fractures among participants was 1.10%. After adjusting for confounders, the TyG index exhibited a robust association with the risk of fragility fractures (odds ratio, 1.94; 95% confidence interval, 1.31-2.88; P < 0.001). RCS regression demonstrated a positive linear relationship between the TyG index and fragility fractures. The predictive nomogram, incorporating the TyG index and other clinical factors, demonstrated favorable predictive performance (consistency index = 0.901).

Elevated TyG index levels were significantly correlated with the risk of fragility fractures in the general US population. These findings suggest that the TyG index may serve as a predictive marker for fragility fractures, underscoring the importance of early intervention and improved fracture risk assessment tools in clinical practice.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease often associated with metabolic disorders such as diabetes mellitus. Recent research suggests a link between systemic inflammation and insulin-glucose dysregulation in HS. This study investigates the relationship between insulin-glucose homeostasis, diabetes mellitus and the haptoglobin concentration in HS patients. Methods: We assessed 95 HS patients and 49 controls using validated fasting-based function tests, including the Structural Parameter Inference Approach (SPINA), Homeostasis Model Assessment (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI). Results: The HS patients had a significantly higher fasting insulin concentration (97.2 vs. 69.0 pmol/L, p = 0.035), increased insulin resistance (HOMA-IR: 3.47 vs. 2.57, p = 0.016) and impaired insulin sensitivity (SPINA-GR: 1.34 vs. 1.76 mol/s, p = 0.017). In diabetes, the insulin sensitivity was more strongly reduced (SPINA-GR: 0.61 vs. 1.41 mol/s, p = 0.0057) and the insulin resistance increased (HOMA-IR: 7.3 vs. 3.2, p = 0.017). Higher haptoglobin concentrations were accompanied by worse glycaemic control, demonstrating a significantly elevated fasting glucose (5.77 vs. 5.11 mmol/L, p = 0.043) concentration and HbA1c (5.7% vs. 5.4%, p = 0.0081) fraction. Conclusions: Our findings suggest that chronic inflammation in HS contributes to metabolic dysregulation, worsening insulin resistance and glycaemic control, particularly in those with elevated haptoglobin or diabetes.

Metabolic syndrome (MetS) is a cluster of several disorders where many challenges hinder effective treatment. The downregulation of SIRT1 or inhibition of its activity is implicated in its pathophysiology. We hypothesized that the combined SIRT1 direct activator E1231 and the SIRT1 stabilizer nicotinamide mononucleotide (NMN) could offer a novel approach to mitigate the pathophysiological features of MetS. Our results revealed that E1231 alone or combined with NMN increased SIRT1 level and activity. This SIRT1 activation was accompanied by upregulation in the IRS-1 and activation of AKT. In parallel, the Nrf2 level and activity were increased while the NFκB activity and subsequent inflammatory cytokines were decreased. Additionally, SIRT1 activation was associated with improved insulin resistance, blood pressure, lipid profile, fasting blood glucose, glucose tolerance, and kidney and liver functions. Moreover, improved liver histology, decreased hepatic fibrosis markers, and increased survival rates were observed. These protective functions were counteracted when EX527, a SIRT1 inhibitor, was dually administered with E1231. Furthermore, correlation analysis revealed that SIRT1 was negatively correlated with NFκB, insulin resistance, and oxidative stress, while positive correlations were observed between SIRT1, p-AKT, and Nrf2 activity. Random Forest regression algorithm and partial dependence plots highlighted the significant roles of SIRT1, IRS-1, p-AKT, and NFκB in predicting MetS severity. These analyses underscore the strong interconnections between these signals. This reinforces the central role of SIRT1 in coordinating a multifaceted protective response against MetS. To conclude, SIRT1 alleviates MetS by modulating AKT/Nrf2/NFκB signaling and their interactions. Further research is necessary to validate these findings.

Industrialization adversely affects the gut microbiome and predisposes individuals to chronic non-communicable diseases. We tested a microbiome restoration strategy comprising a diet that recapitulated key characteristics of non-industrialized dietary patterns (restore diet) and a bacterium rarely found in industrialized microbiomes (Limosilactobacillus reuteri) in a randomized controlled feeding trial in healthy Canadian adults. The restore diet, despite reducing gut microbiome diversity, enhanced the persistence of L. reuteri strain from rural Papua New Guinea (PB-W1) and redressed several microbiome features altered by industrialization. The diet also beneficially altered microbiota-derived plasma metabolites implicated in the etiology of chronic non-communicable diseases. Considerable cardiometabolic benefits were observed independently of L. reuteri administration, several of which could be accurately predicted by baseline and diet-responsive microbiome features. The findings suggest that a dietary intervention targeted toward restoring the gut microbiome can improve host-microbiome interactions that likely underpin chronic pathologies, which can guide dietary recommendations and the development of therapeutic and nutritional strategies.

Increased blood pressure upon standing is considered a cardiovascular risk factor. We investigated the reproducibility of changes in aortic blood pressure, heart rate, stroke volume, cardiac output, and systemic vascular resistance during three passive head-up tilts (HUT) in 223 participants without cardiovascular medications (mean age 46 yr, BMI 28 kg/m2, 54% male). The median time gap between the first and the second HUT was 9 wk and the second and the third HUT was 4 wk. We utilized whole body impedance cardiography and radial artery tonometry as methods. The participants were divided into quartiles of the changes in each hemodynamic variable during the first HUT, and the reproducibility of these changes was tested during successive HUTs. During the first HUT, significant differences were present in all between-quartile comparisons (n = 6) of all variables. The differences persisted as follows: reduction of stroke volume in six out of six (6/6) between-quartile comparisons (P < 0.001), decrease in cardiac output (P < 0.001) and increase in heart rate in 5/6 comparisons (P < 0.001), change in systemic vascular resistance in 3/6 comparisons (P < 0.001), change in aortic systolic blood pressure in 1/6 comparisons (P = 0.043), and change in aortic diastolic blood pressure in none (P = 0.266). To conclude, the reproducibility of upright posture-induced changes is high for stroke volume, cardiac output, and heart rate, moderate for systemic vascular resistance, and modest for aortic blood pressure. Although an increase in blood pressure during upright posture may be a cardiovascular risk factor, this effect may be attributed to other underlying hemodynamic variables that exhibit more reproducible posture-related changes.NEW & NOTEWORTHY We examined the reproducibility of hemodynamic responses to three passive head-up tilts. The associated changes in stroke volume, cardiac output, and heart rate were highly reproducible. Systemic vascular resistance showed moderate reproducibility, whereas blood pressure changes during upright posture were modestly reproducible. If an exaggerated blood pressure response to upright posture is a cardiovascular risk factor, it is likely attributed to other hemodynamic variables that exhibit more reproducible posture-related changes.

Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720's protective role improved liver function and histology and prolonged rats' survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.

Kisspeptin has a major role in reproductive regulation. Furthermore, it is also involved in metabolic and cardiovascular regulation as well as is a potent vasoconstrictor. This study aimed to: 1) determine correlations between serum kisspeptin levels with obesity/metabolic parameters; 2) compare parameters between non-hypertensive ([non-HT] N.=15) and hypertensive ([HT] N.=15) female subjects; and 3) determine correlations between leptin, systolic blood pressure (SBP) or diastolic blood pressure (DBP) with obesity and metabolic factors.

Clinical parameters and fasting blood and adipose tissue samples were collected from women undergoing open abdominal surgery.

Serum kisspeptin was not correlated with obesity parameters but was positively correlated with only SBP (P<0.05). Serum kisspeptin, SBP, DBP, body weight, waist circumference, hip circumference, plasma glucose, plasma insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and height of visceral adipocytes (VA) were higher but the Quantitative Insulin Sensitivity Check Index (QUICKI) was lower in hypertensive compared to non-hypertensive female subjects (P<0.05). Leptin was positively correlated with obesity and metabolic paramters including area, width, and perimeter of subcutaneous adipocytes, and area, width, height, and perimeter of VA (P<0.05) but was negatively correlated the QUICKI (P<0.001). SBP had positive correlations with insulin, glucose, HOMA-IR, and kisspeptin, but had a negative correlation with QUICKI (P<0.05). DBP had positive correlations with body weight, BMI, waist circumference, hip circumference, insulin, glucose, HOMA-IR, and width of VA (P<0.05), but had a negative correlation with the QUICKI (P<0.05).

Kisspeptin, obesity especially visceral adiposity, and insulin resistance might contribute to increased blood pressure. Further studies are required to reveal the underlying mechanism of kisspeptin on metabolic and cardiovascular regulation.

Obesity and metabolic syndrome are significant contributors to infertility in women and are closely associated with insulin resistance (IR). The metabolic score for insulin resistance (METS-IR) is a new, non-insulin-based fasting index used to measure IR. However, the potential of METS-IR as a predictive indicator of female infertility risk has not been established. This study aimed to explore the association between METS-IR and the risk of female infertility.

This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2018. We conducted multivariate logistic regression, restricted cubic spline (RCS), and threshold effect analyses to investigate the relationship between METS-IR and female infertility.

According to the self-reported data, 188 (12.20%) participants were classified as infertile. A significantly higher proportion of participants with elevated METS-IR were found to have infertility. Multivariable logistic regression analysis revealed that METS-IR was significantly associated with increased risk of female infertility, irrespective of the independent variable analysis by continuous variables or tertiles in the fully adjusted model (Model 3, continuous variable: OR = 1.02, 95% confidence interval (CI):1.01-1.04, p = 0.005; tertile 3 vs. tertile 1: OR = 2.00, 95% CI = 1.21-3.28, p = 0.0128, p for trend =0.0126). RCS analysis indicated a linear correlation between METS-IR and the risk of infertility (p = 0.121), and threshold effect analysis further supported this linear association (p = 0.136). Moreover, above the inflection point of 32.94, the risk of infertility significantly increased with increasing METS-IR level (p < 0.0001).

Our results suggest that high levels of the METS-IR index are positively associated with infertility among reproductive-aged females in the United States.

Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Sixty Holstein cows were enrolled at -76 days from calving (DFC) and classified based on the daily SCC during the previous week from an automated milking system. The separation thresholds for low (L, n = 46) and high (H, n = 14) classifications were 100 K/mL for primiparous and 200 K/mL for multiparous cows. Cows were then assigned to two homogeneous groups to receive diets supplemented with 19 g/d of a Saccharomyces cerevisiae fermentation product (TRT; NutriTek, Diamond V, Cedar Rapids, IA, USA) or without supplementation (CTR) until 60 DFC. Cows were dried off at -56 DFC and monitored for disease incidence, milk yield and composition, plasma metabolic profile, and whole blood count from -76 to 60 DFC. Data were analyzed utilizing ANOVA and mixed models for repeated measures. During the dry period, TRT cows had greater plasma thiol and albumin compared to CTR. TRT-L cows had greater plasma protein and globulin than CTR-L. TRT-H cows had heightened hematocrit; reduced plasma globulin and haptoglobin; and higher albumin, albumin to globulin ratio, and thiol than CTR-H. TRT-H cows had greater concentrations of leukocytes and lymphocytes and lower plasma protein and ceruloplasmin at -54 DFC; lower reactive oxygen species to ferric ion-reducing antioxidant power ratios at -44 DFC; and greater concentrations of lymphocytes and plasma gamma glutamyl transferase at -7 DFC than CTR-H. After calving, TRT cows had a lower incidence of mastitis and higher butterfat, as well as greater plasma haptoglobin and aspartate amino transferase (AST) and reduced Mg compared to CTR. TRT cows had lower SCC between 1 and 7 DFC and a greater ECM between 41 and 60 DFC compared to CTR. TRT-H cows had lower SCC between 1 and 7 DFC and greater hemoglobin and plasma AST than CTR-H. Ameliorated immune system functions due to Saccharomyces cerevisiae fermentation product administration lowered the SCC in TRT-H cows and prevented the onset of new intramammary infections across both L and H SCC groups, supporting the improved productive performance of dairy cows.

Docosahexaenoic acid (DHA) is a long-chain omega-3 polyunsaturated fatty acid. We investigated the dual health ability of DHA to modulate gut microbiota in children with obesity and to exert anti-inflammatory activity on human intestinal Caco-2 cells.

In a pilot study involving 18 obese children (8-14 years), participants received a daily DHA supplement (500 mg/day) and dietary intervention from baseline (T0) to 4 months (T1), followed by dietary intervention alone from 4 months (T1) to 8 months (T2). Fecal samples, anthropometry, biochemicals and dietary assessment were collected at each timepoint. At preclinical level, we evaluated DHA's antioxidant and anti-inflammatory effects on Caco-2 cells stimulated with Hydrogen peroxide (H2O2) and Lipopolysaccharides (LPS), by measuring also Inducible nitric oxide synthase (iNOS) levels and cytokines, respectively.

Ten children were included in final analysis. No major changes were observed for anthropometric and biochemical parameters, and participants showed a low dietary compliance at T1 and T2. DHA supplementation restored the Firmicutes/Bacteroidetes ratio that was conserved also after the DHA discontinuation at T2. DHA supplementation drove a depletion in Ruminococcaceae and Dialisteraceae, and enrichment in Bacteroidaceae, Oscillospiraceae, and Akkermansiaceae. At genus level, Allisonella was the most decreased by DHA supplementation. In Caco-2 cells, DHA decreased H2O2-induced reactive oxygen species (ROS) and nitric oxide (NO) production via iNOS pathway modulation. Additionally, DHA modulated proinflammatory (IL-1β, IL-6, IFN-γ, TNF-α) and anti-inflammatory (IL-10) cytokine production in LPS-stimulated Caco-2 cells.

An improvement in gut dysbiosis of children with obesity seems to be triggered by DHA and to continue after discontinuation. The ability to modulate gut microbiota, matches also with an anti-inflammatory effect of DHA on Caco-2 cells.

Leukocyte cell-derived chemotaxin 2 (LECT2) is an obesity-associated hepatokine that causes skeletal muscle insulin resistance. Since LECT2 is up-regulated by the inactivation of the energy sensor AMPK in the liver, we hypothesized that LECT2 has potential as a biomarker for metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we investigated whether circulating LECT2 levels are associated with insulin sensitivity, liver enzymes, and MASLD.

This cross-sectional study included 138 Japanese individuals. Plasma LECT2 levels were measured using fasting blood samples. B-mode ultrasonography was used to assess hepatic steatosis.

The mean age and body mass index (BMI) of participants were 63.5 ± 10.2 years and 23.0 ± 3.1 kg/m2, respectively. Higher LECT2 levels positively correlated with homeostatic model assessment for insulin resistance (HOMA-IR) values and negatively correlated with the quantitative insulin sensitivity check index (QUICKI) among all participants (HOMA-IR; non-standardized β (B) = 6.38, P < 0.01: QUICKI; B = -161, P < 0.01). These correlations were stronger in the low BMI group (HOMA-IR; B = 13.85, P < 0.01: QUICKI; B = -180, P < 0.01). LECT2 levels also positively correlated with gamma-glutamyl transferase levels (B = 0.01, P = 0.01) and alanine aminotransferase levels (B = 0.33, P = 0.02). Higher LECT2 levels correlated with the prevalence of MASLD (odds ratio = 1.14, P = 0.02).

The present results suggest the potential of plasma LECT2 levels as a biomarker for insulin resistance in individuals who are not overweight and the prevalence of MASLD in the general population.

The increase in age-related comorbidities, such as cardiometabolic diseases, has become a global health priority. There is a growing need to find new parameters capable of improving the detection of cardiometabolic risk factors, and circulating endocannabinoids (eCBs) are a promising tool in this context. Here, we aimed to investigate the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors in middle-aged adults. Seventy-two individuals (54% women; 53.6 ± 5.1 years old) were included in this study. Plasma levels of eCBs and analogues were determined using liquid chromatography-tandem mass spectrometry. Body composition was measured by dual-energy X-ray absorptiometry. Cardiometabolic risk factors (i.e., glucose and lipid profile, blood pressure, liver and renal parameters, and gonadal hormones) were also assessed. The plasma levels of 1- and 2-arachidonylglycerol (1-AG&2-AG) were positively correlated with adiposity (all r ≥ 0.23, P < 0.05). Interestingly, the plasma levels of 1-AG&2-AG, arachidonoylethanolamide, and palmitoyl-ethanolamide were positively correlated with the homeostatic model assessment index - Insulin Resistance (HOMA-IR) (all r ≥ 0.32, P < 0.01). Our results also showed that high levels of 1-AG&2-AG, arachidonoylethanolamide, linoleoyl ethanolamide, and palmitoleoyl ethanolamide were correlated with poorer liver (all r ≥ 0.27, P < 0.05), kidney (all r ≥ 0.24, P < 0.05), and gonadal function parameters (testosterone: all r > 0.26, P < 0.05, SHBG: 1-AG&2-AG r=-0.33, P < 0.01). The plasma levels of some eCBs and analogues are correlated with a worse cardiometabolic profile in middle-aged adults.

Chronic inflammatory diseases, e.g., obesity, cardiovascular disease and type-2 diabetes, progressively suppress the anti-inflammatory heat shock response (HSR) by impairing the synthesis of key components, perpetuating inflammation. Monitoring HSR progression offers predictive value for countering chronic inflammation. This study quantified HSR in high-fat diet (HFD) and normal chow (NC) mice by measuring 70 kDa heat shock protein (HSP70) expression after heat treatment of whole blood samples. To align with human translational relevance, animals were housed within their thermoneutral zone (TNZ). Whole blood was heat-challenged weekly at 42 °C for 1-2 hours over 22 weeks, and ΔHSP70 was calculated as the difference between HSP70 expressions at 42 °C and 37 °C. Results correlated with fasting glycaemia, oral glucose tolerance test, intraperitoneal insulin tolerance test and 2-hour post-glucose load glycaemia. ΔHSP70 levels >0.2250 indicated normal fasting glycaemia, while levels <0.2125 signalled insulin resistance and type-2 diabetes onset. A logistic model (five-parameter logistic) showed progressive HSR decline, with HFD mice exhibiting earlier ΔHSP70 reduction (t1/2 = 3.14 weeks) compared with NC mice (t1/2 = 8.24 weeks), highlighting compromised anti-inflammatory capacity in both groups of mice maintained at TNZ. Remarkably, even NC mice surpassed insulin resistance thresholds by week 22, relevant as control diets confronted interventions. Observed HSR decline mirrors tissue-level suppression in obese and type-2 diabetic individuals, underscoring HSR failure as a hallmark of obesity-driven inflammation. This study introduces a practical whole-blood assay to evaluate HSR suppression, allowing assessment of glycaemic status during obesity onset before any clinical manifestation.

An insulin resistant state is characteristic of patients with type 2 diabetes, polycystic ovary syndrome, and metabolic syndrome. Identification of insulin resistance (IR) is most readily achievable using formulae combining plasma insulin and glucose results. In this study, we have used data from the European Biological Variation Study (EuBIVAS) to examine the biological variability (BV) of IR using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and the Quantitative Insulin sensitivity Check Index (QUICKI).

Ninety EuBIVAS non-diabetic subjects (52F, 38M) from five countries had fasting HOMA-IR and QUICKI calculated from plasma glucose and insulin samples collected concurrently on 10 weekly occasions. The within-subject (CVI) and between-subject (CVG) BV estimates with 95 % CIs were obtained by CV-ANOVA after analysis of trends, variance homogeneity and outlier removal.

The CVI of HOMA-IR was 26.7 % (95 % CI 25.5-28.3), driven largely by variability in plasma insulin and the CVI for QUICKI was 4.1 % (95 % CI 3.9-4.3), reflecting this formula's logarithmic transformation of glucose and insulin values. No differences in values or BV components were observed between subgroups of men or women below and above 50 years.

The EuBIVAS, by utilising a rigorous experimental protocol, has produced robust BV estimates for two of the most commonly used markers of insulin resistance in non-diabetic subjects. This has shown that HOMA-IR, in particular, is highly variable in the same individual which limits the value of single measurements.

Simultaneous pancreas-kidney (SPK) transplantation is an effective treatment option for type 1 diabetes mellitus and concurrent end-stage kidney disease. However, the diabetogenic effects of immunosuppression can counteract the beneficial effects of sustained normoglycemia. Long-term metabolic trends that reflect cardiovascular risk are reported poorly in the literature.

A total of 500 patients with type 1 diabetes mellitus receiving SPK transplants at a single center with at least 2-y follow-up were evaluated retrospectively. Metabolic parameters and allograft function were followed longitudinally, including patient and allograft survival, body mass index (BMI), lipid profile, quantitative insulin sensitivity check index, estimated glomerular filtration rate, and urinary albumin-creatinine ratio up to 10 y posttransplant.

Patient survival at 1, 5, and 10 y was 97%, 92%, and 87%, and overall death-censored graft survival was 87%, 84%, and 80%, respectively. Survival remained unchanged when stratified by BMI. Compared with pretransplant measurements, BMI significantly increased at 1, 3, and 5 y posttransplant. Total cholesterol, triglycerides, and low-density lipoprotein cholesterol decreased at 10 y posttransplant, with significantly increased high-density lipoprotein cholesterol at 5 y posttransplant. Insulin sensitivity improved significantly at 10 y posttransplant but did not normalize. Urinary albumin-creatinine ratio decreased by 3 y posttransplant but increased significantly between 3 and 10 y posttransplant, although the estimated glomerular filtration rate was unchanged during this time.

SPK transplantation is associated with excellent patient and graft survival. Significant long-term weight gain occurs despite improving lipid profiles and insulin sensitivity posttransplant. These data potentially reflect an overall cardiovascular burden that should be addressed in this population.

Prolonged heat exposure is suggested to improve glucose metabolism and fat oxidation, but no studies have addressed whether brief heat stimuli represent a viable, time-efficient, alternative approach. Consequently, we examined the ability of brief stimuli evoked by 45 °C water to improve glucose tolerance, insulin sensitivity, and fat oxidation in young, non-obese, males and females. Twenty-four participants completed fourteen 5-min sessions involving whole body passive heating in 45 °C water. Changes in resting catecholamines, cytokines, substrate oxidation, resting energy expenditure, glucose tolerance, and insulin release in response to an oral glucose tolerance test, were assessed before and 24-h after intervention, and 1 month after the end of the intervention. The results showed that repeated short-duration heat intervention had no significant effects on epinephrine, norepinephrine, interleukin-6, and tumor necrosis factor alpha production in both sexes. Glucose area under the curve (AUC) was not affected. However, females had a lower insulin AUC and improved insulin sensitivity as indicated by a decrease in homeostatic model assessment for insulin resistance, and an increase in the quantitative insulin sensitivity check index and the Matsuda insulin sensitivity index values one month after the end of the heat intervention. No effect was observed in resting energy expenditure, but carbohydrate oxidation per kilogram increased in females, and this substrate oxidation change was maintained after one month. In conclusion, fourteen sessions of brief 5-min whole-body immersion in 45 °C water produced an improvement in insulin sensitivity and increased reliance on carbohydrate oxidation in females.

There is evidence that 1-h plasma glucose (PG) concentration during the 75-g oral glucose tolerance test (OGTT) is superior to 2-h PG level in predicting diabetes. We investigated the characteristics of insulin sensitivity and β-cell function behind this observation. After age, sex, and BMI matching, 496 study participants selected from 3,965 individuals without diabetes who were at high risk of type 2 diabetes in a tertiary medical center were categorized into four groups in a 1:1:1:1 ratio based on OGTT results: 1) 1-h PG level <8.6 mmol/L and 2-h PG level <7.8 mmol/L (normal glucose tolerance [NGT]/1h-normal); 2) 1-h PG level ≥8.6 mmol/L and 2-h level <7.8 mmol/L (NGT/1h-high); 3) 1-h PG level <8.6 mmol/L and 2-h level ≥7.8 mmol/L (impaired glucose tolerance [IGT]/1h-normal); and 4) 1 h PG level ≥8.6 mmol/L and 2-h level ≥7.8 mmol/L. Compared with participants with IGT/1h-normal, those with NGT/1h-high had a similar extent of insulin resistance but lower early-phase insulin secretion. Additionally, participants with NGT/1h-high had a lower disposition index at both 0-30 min and 0-120 min than those with IGT/1h-normal. The fitted regression line relating PG to log-transformed disposition index (0-30 min and 0-120 min) was significantly steeper for 1-h than 2-h PG. In conclusion, 1-h PG seemed to be more sensitive to the deterioration in β-cell function than was 2-h PG. The use of 1-h PG may identify individuals at high risk of type 2 diabetes at an earlier stage.