Search Results (26)

Background/Objectives: Chronic ethanol (EtOH) consumption is a major cause of metabolic dysfunction and multi-organ injury, particularly in the liver and pancreas. Because oxidative stress and endoplasmic reticulum (ER) stress are central mechanisms in both organs, this study evaluated the protective efficacy of 4-hexylresorcinol (4HR) against EtOH-induced hepato-pancreatic injury. Methods: Male C57BL/6J mice (6 weeks old) were assigned to four groups (n = 10/group): control, EtOH, EtOH + 4HR (5 mg/kg), and EtOH + 4HR (10 mg/kg). After a 1-week adaptation period, mice were fed a liquid EtOH diet for 5 weeks. Glucose tolerance, fasting glucose, serum insulin, and insulinogenic index were assessed. Liver and pancreas were analyzed by histology, immunohistochemistry, Western blotting, periodic acid-Schiff staining, Oil Red O staining, and malondialdehyde assay. Results: Chronic EtOH exposure impaired glucose homeostasis, reduced the insulinogenic index, increased hepatic inflammation and ALT levels, depleted hepatic glycogen, elevated pancreatic lipid peroxidation, and upregulated GADD153 (CHOP) expression in both the liver and pancreas. 4HR administration, particularly at 10 mg/kg, attenuated several of these alterations. 4HR treatment was associated with reduced hepatic inflammatory changes and ALT elevation, decreased pancreatic malondialdehyde levels, and suppressed GADD153 expression in both organs. Although PAS staining in the 4HR-treated group showed a qualitative tendency toward increased hepatic glycogen deposition, quantitative analysis did not demonstrate significant recovery relative to the EtOH group. Conclusions: 4HR showed protective effects against several aspects of chronic EtOH-induced hepatic and pancreatic injury, including hepatic inflammation, pancreatic lipid peroxidation, and ER stress-related GADD153 expression. However, quantitative PAS analysis did not support significant restoration of EtOH-induced hepatic glycogen depletion by 4HR. These findings suggest that 4HR may serve as a potential multi-organ protective agent against alcohol-induced inflammatory, oxidative stress-, and ER stress-related injury, although its effect on hepatic glycogen metabolism remains limited under the present experimental conditions. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is characterized by progressive β-cell dysfunction and insulin resistance. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may enhance β-cell function. Semaglutide, a long-acting GLP-1 RA, improves glycemic control and weight, but its direct effects on β-cell function remain uncertain. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420251034071). PubMed, Embase, and Scopus were searched through April 2025 for randomized controlled trials evaluating semaglutide’s effects on β-cell function in adults with T2DM. Primary outcomes included HOMA-B, HOMA-IR, and the proinsulin/insulin ratio; secondary outcomes included insulin secretion rate, insulinogenic index, and C-peptide. Two reviewers independently performed data extraction and risk-of-bias assessment using the Cochrane RoB 1 tool. Random-effects models were used for pooling. Certainty of evidence was evaluated using GRADE. Results: Sixteen trials (n = 6591) met inclusion criteria, with nine included in the meta-analysis. Semaglutide improved β-cell function (HOMA-B log ratio of means 1.50, 95% confidence interval [CI]: 1.25–1.80) and reduced insulin resistance (HOMA-IR ratio 0.82, 95% CI: 0.73–0.94) compared with placebo or active comparators. The pooled treatment ratio for proinsulin/insulin was 0.70 (95% CI: 0.63–0.79). However, risk of bias was generally high due to open-label designs, and certainty of evidence for all primary outcomes was rated very low. Conclusions: Semaglutide appears to improve β-cell function and insulin sensitivity in adults with T2DM, but conclusions remain uncertain given the very low certainty of evidence and substantial heterogeneity. High-quality trials with standardized β-cell outcomes are needed to confirm these findings. Full article

Background: Roux-en-Y gastric bypass (RYGB) surgery results in weight reduction and decreased energy intake and can ameliorate type 2 diabetes. These beneficial effects are usually attributed to changes in hunger and satiety and relatively rapid improvements in glycemic control, but these effects may depend on dietary adherence. The aim of this study is to investigate the relatively early effects of RYGB surgery on weight reduction (by focusing on eating patterns) and glycemic control in rats subjected to a healthy maintenance diet or an unhealthy Western-style diet. Methods: Rats were fed a high-fat diet with added sucrose (HF/S) or a low-fat (LF) diet. Body weight, high-resolution tracking of meal-related parameters, and glucose regulation after overnight fasting and during a mixed meal tolerance test (MMTT; 2 mL sweet/condensed milk) were measured before and after RYGB (RYGB+) or sham surgery (RYGB−). Results: HF/S feeding led to an increased body weight just before RYGB surgery, but it also caused enhanced weight loss following RYGB, which led to similar body weights in the HF/S and LF diet groups twenty-four days post-operatively. RYGB surgery and diet dependently and independently influenced meal-related parameter outcomes, where both RYGB+ and HF/S feeding resulted in shorter meal duration (p < 0.01), higher ingestion rates (p < 0.001), and increased satiety ratio (p < 0.05), especially in the HF/S diet group subjected to RYGB. While RYGB surgery generally improved baseline glycemic parameters including HOMA-IR (p < 0.01), it often interacted with diet to affect MMTT-induced hyperglycemia (p < 0.05), beta-cell sensitivity (p < 0.01), and the insulinogenic index (p < 0.01), with the LF rats overall maintaining better glycemic control than the HF/S-fed rats. Conclusions: This study shows the importance of controlling diet after RYGB surgery, as diet type significantly influences ingestive behavior, post-prandial glucose regulation, beta-cell sensitivity, and glucose tolerance after RYGB. Full article

Background/Objectives: Glucose tolerance progressively declines with age. However, the effects of aging on insulin secretion and insulin sensitivity in Japanese subjects are unclear. Methods: We conducted an oral glucose tolerance test (OGTT) in residents aged between 22 and 85 years in Koshi City, Kumamoto Prefecture, Japan, to clarify the characteristics of insulin secretion and insulin sensitivity in older adults. Participants were recruited using a flyer, and the OGTT was performed after an overnight fast (12–16 h) between 8:00 and 10:30 am. Results: HOMA-IR and the Matsuda index are indices of insulin action. No correlation of age with HOMA-IR or the Matsuda index was found, whereas HOMA-β, the insulinogenic index, and the disposition index, all indices of insulin secretion, were negatively correlated with age in all participants and in individuals with normal glucose tolerance. Multiple regression analysis showed that age was an explanatory factor for insulin secretion. Conclusions: Impaired insulin secretion may contribute to age-related glucose intolerance in Japanese individuals. Full article

Background/Objectives: Chronic low-grade inflammation is associated with insulin resistance and poor glycemic control, leading to the development of type 2 diabetes mellitus (T2DM). The present study investigated the effect of regular mango intake on inflammation and insulin sensitivity in participants with overweight or obesity and chronic low-grade inflammation. Methods: A human clinical study was performed using a randomized, controlled, two-arm, parallel design with a 2 h oral glucose tolerance test (OGTT) administered before and after 4 weeks (4 W) of mango or control product intake (1 cup/twice a day). Fasting and time course blood sampling for 2 h post-OGTT were analyzed for effects on plasma metabolic and inflammation endpoints using analysis of covariance and repeated-measure approaches (SAS 9.4). Results: Forty-eight adults (37.6 ± 2.8 years, 30.5 ± 4.1 BMI kg/m²) completed the study. Markers of inflammation (IL-6, TNFα, hs-CRP) were not different at the end of 4 W (p > 0.05). The intervention did not significantly influence fasting glucose concentrations; however, insulin was significantly lowered with the mango compared to the control intervention (8.2 ± 1.2 vs. 15.3 ± 1.2 µIU/mL respectively, p = 0.05). Furthermore, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), along with the disposition index (DI), was significantly improved in the mango compared to the control interventions (HOMA-IR, 2.28 ± 1.19 vs. 4.67 ± 1.21, p = 0.03; DI, 2.76 ± 1.02 vs. 5.37 ± 1.03, p = 0.04). Mean insulin concentrations were also significantly lower at W4 compared to W0 after the OGTT in the mango vs. control intervention (intervention × week effect, p = 0.04). Relative expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), a gene regulating endogenous antioxidant defense, was non-significantly increased twofold in the mango intervention (W4 vs. W0). Conclusions: Collectively, the data suggest that mango intake increased insulin sensitivity in individuals with chronic low-grade inflammation, possibly through activating Nrf-2 genes and increasing cellular antioxidant status. The data warrant further research on consuming mango fruit as part of a dietary pattern to address insulin resistance and the mechanisms underpinning the actions of mango intake. Full article

Background/Objectives: Recently, it was reported that glucose variability (GV) calculated using the 75 g oral glucose tolerance test (OGTT) is associated with adverse perinatal outcomes. However, its role in gestational diabetes mellitus (GDM) remains unclear. We investigated the association between GV and insulin parameters in Japanese women diagnosed with GDM after 24 weeks of gestation (late GDM). Methods: A total of 280 mothers with late GDM cared for at Keio University Hospital were included in this study. Using 75 g OGTT, the initial increase and subsequent decrease were calculated as the GV. Results: The initial increase was significantly positively associated with 1 h plasma glucose level (PG) and 2 h PG with 75 g OGTT (p < 0.001), but fasting PG, insulinogenic index (IGI), and homeostasis model assessment—insulin resistance were negatively associated with the initial increase (all p < 0.001). The subsequent decrease was significantly positively correlated with 1 h PG (p < 0.001) but negatively correlated with 2 h PG (p < 0.001), IGI (p = 0.009), and the whole-body insulin sensitivity index derived from the OGTT (p = 0.02). Insulin Secretion-Sensitivity Index-2 was not associated with an initial increase or subsequent decrease. Conclusions: Since the initial increase might reflect insulin secretion and the subsequent decrease might reflect insulin sensitivity in Japanese women with late GDM, GV could alter several insulin parameters. Further studies are required to investigate the usefulness of GV in the management of GDM. Full article

Background/Objectives: Some individuals with obesity may exhibit fewer metabolic disturbances and face a lower long-term risk of complications; however, the existence of this so-called “metabolically healthy obesity” (MHO) compared to “metabolically unhealthy obesity” (MUO) remains controversial. We hypothesized that children with MHO might have a more favorable profile than children with MUO. Markers of glucose metabolism and insulin sensitivity were compared between children and adolescents diagnosed with MHO and MUO. Methods: This study recruited prospectively 104 children and adolescents (aged 6–16 years, 47 boys) with obesity. All participants underwent an oral glucose tolerance test (OGTT), and a comparative analysis was performed on HOMA-IR, QUICKI, insulin sensitivity index (ISI), insulinogenic index (IGI), disposition index (DI), and oral disposition index (oDI). Glucose metabolism indices were compared in these subgroups according to pubertal status. Results: Forty-seven children (45.2%) were diagnosed with MHO. The whole-body ISI differed significantly between the MHO and MUO groups (4.02 vs. 2.7, p < 0.01). The IGI was statistically lower in the MHO group compared to MUO (1.26 vs. 1.54, p < 0.01), while neither the DI nor the oDI differed significantly. A higher ISI (4.5 vs. 3.9, p < 0.01) was observed in prepubertal MHO individuals compared to MHO adolescents. Conclusions: Children classified as MHO according to the more recent criteria exhibit a more favorable metabolic profile than those with MUO. However, a completely healthy profile was not demonstrated in the MHO group, as many crucial metabolic profile parameters were comparable to those observed in the MUO group. The findings of this study indicate that all children with obesity, irrespective of whether they are categorized as having MUO or MHO, necessitate close monitoring. Full article

Introduction: Limited studies have explored the impact of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on glucose tolerance and insulin secretion in patients with CF, yielding varied results. This study aims to assess alterations in glucose metabolism and insulin secretion over 24 and 52 weeks following CFTR modulator initiation in a cohort of pediatric and adult patients with CF. Materials and Methods: A prospective longitudinal study conducting oral glucose tolerance test (OGTT) with C-peptide and insulin levels. The insulin secretion rate at 60 min (ISR60) and the insulinogenic index (IGI) were calculated during the first 60 and 30 min of the OGTT, respectively. Glucose metabolism status was categorized as normal (NGT), indeterminate (INDET), impaired glucose tolerance (IGT), or cystic fibrosis-related diabetes (CFRD). Additionally, continuous glucose monitoring (CGM) was performed for 14 days at each visit. We employed a repeated-measures general linear model to assess changes in insulin secretion and CGM metrics, with glucose tolerance status as the between-subjects factor and visit (baseline, 24 and 52 weeks) as the within-subjects factor. Results: The study comprised 25 patients (11 adults and 14 pediatrics). At baseline, 2 patients (8%) had NGT, 8 (32%) had INDET, 10 (40%) had IGT, and 5 (20%) had CFRD. Overall, there were no significant changes in insulin and C-peptide area under the curve (AUC), IGI and DI after 52 weeks. However, we observed an increase in ISR60 among NGT patients (mean change: 1.766; 95% CI: 1.414; 2.118, p < 0.001). Consistently, average glucose exhibited a significant decrease in NGT patients between 24 and 52 weeks (mean change: −5.645; 95% CI: −4.233; −10.866, p = 0.028). Conclusions: Treatment with CFTR modulators potentially enhances insulin secretion in patients with CF NGT. Early initiation of treatment, as evaluated through long-term prospective trials, is essential to further investigate whether decreased glucose control is preventable or reversible. Full article

Postprandial hyperglycemia was shown to be an independent risk factor for microvascular and macrovascular complications in type 2 diabetes mellitus (T2D). We aimed to investigate the glucose, insulin, and subjective appetite at 0, 15, 30, 45, 60, 90, 120, 150, and 180 min of three treatments: diabetes-specific formula (DSF), noodle soup, and glutinous rice. This was a randomized, crossover study with a one-week interval between treatments. Sixty-four T2D adults with oral glucose-lowering medication and HbA1c between 7% and <10% were randomized. The glucose positive area under the curve from 0 to 180 min (pAUC) was significantly lower with DSF than with glutinous rice (LSM ± SE: DSF 354 ± 32 vs. glutinous rice 451 ± 32 mmol.min/L, p = 0.033). The insulin pAUC was significantly lower with DSF (median [IQR]: 2733 [1542, 4204]) compared to glutinous rice (3359 [2193, 4744] µIU.min/mL), p = 0.042). The insulinogenic index at 30 min was significantly higher in DSF (median [IQR], 8.1 [4.2, 19.7]) compared to glutinous rice (5.4 [2.7, 11.7], p < 0.001). No significant differences were found in subjective appetite between the three treatments (all, p ≥ 0.827). There were also no significant differences in hunger, fullness, desire to eat, and prospective consumption ratings between DSF and the other two breakfasts (all p ≥ 0.181). Noodle soup led to the shortest time for hunger to return to baseline (165 min), 21 min earlier than DSF (186 min) and 32 min earlier than glutinous rice (197 min). DSF significantly reduced postprandial glucose and insulin responses compared with glutinous rice and had a higher satiating value than noodle soup in T2D adults. Replacing common Asian breakfasts with DSF may improve glycemia and hunger control. Full article

To assess the effect of rice bran oil emulsified formulation (EMF) on cooked rice, a single-arm open clinical trial and in vitro testing for digestion and glycemic response were performed. Fifteen Japanese men consumed 200 g of packed rice, cooked with or without EMF. Blood samples were collected 0, 30, 60, and 120 min post-consumption and analyzed for glucose, insulin, and triglyceride levels. Continuous glucose monitoring (CGM) and sensory evaluation were also performed. A two-step in vitro digestion test, simulating gastric and small intestinal digestion was conducted. EMF-added rice group showed higher insulin response levels at 60 min than the placebo group. Stratification of participants with HbA1c ≥ 5.6 or an insulinogenic index ≤ 0.4 revealed a significant reduction in C_max glucose levels. A significant correlation was observed between venous and CGM blood glucose levels and no significant sensory differences were observed. The in vitro test revealed significantly lower C_∞, equilibrium starch concentrations, with EMF. Clinical trial suggests that EMF may stimulate insulin secretion and reduce blood glucose levels in participants with lower insulin responses. In vitro tests suggest that EMF inhibits glycemic digestion. This trial was registered at the UMIN Center (UMIN000053495; registered 31 January 2024). Full article

Adults with obesity have a reduction in branched-chain amino acid (BCAA) levels following metabolic and bariatric surgery (MBS), which is hypothesized to contribute to the metabolic advantages of MBS. We examined this relationship in 62 youth 13–24 years old with severe obesity (47 female) over 12 months. Thirty had sleeve gastrectomy (SG) and 32 were non-surgical controls (NS). We measured fasting insulin, glucose, glycated hemoglobin (HbA1c), isoleucine, leucine, and valine concentrations, and post-prandial insulin and glucose, following a mixed meal tolerance test. Twenty-four-hour food recalls were collected. At baseline, groups did not differ in the intake or the serum levels of BCAAs, HbA1C, HOMA-IR, Matsuda index, insulinogenic index, or oral Disposition index (oDI). Over 12 months, SG vs. NS had greater reductions in serum BCAAs, and SG had significant reductions in BCAA intake. SG vs. NS had greater reductions in HbA1c and HOMA-IR, with increases in the Matsuda index and oDI. In SG, baseline leucine and total BCAA concentrations were negatively correlated with the baseline Matsuda index. Reductions in serum leucine were positively associated with the reductions in HOMA-IR over 12 months. These associations suggest a potential role of BCAA in regulating metabolic health. Reducing dietary intake and serum BCAA concentrations may reduce insulin resistance. Full article

We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following a total pancreatectomy with islet autotransplantation (TPIAT). We investigated metabolic outcomes of this population at one-year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. We retrospectively reviewed 40 patients post-TPIAT previously studied at 10-days post-surgery (15 used MDI and 25 used pump therapy immediately post-ICU, and all were discharged on pump therapy). Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. one-year (via mixed meal testing) HbA1c, fasting glucose, insulinogenic index, and the area under the curve (AUC) for insulin and c-peptide. More patients were off insulin at one year in the early pump group compared to the MDI group (45% vs. 13%, p = 0.07). Of all patients off insulin, 100% of the early pump users weaned off by six months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg, were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97 vs. 122 mg/dL, p = 0.003), while AUC c-peptide was greater in early pump users at one-year post-TPIAT but did not reach significance (median 57.0 vs. 50.3 ng/mL × minutes, p = 0.14). Other metabolic outcomes did not differ between groups. Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Younger TPIAT age (p = 0.02) and early pump users (p = 0.04) were significantly associated with insulin independence at one year. This study was limited by sample size. Early pump use may have long-term benefits in post-TPIAT endogenous insulin secretion. Full article

The predictive factors for the progression from gestational diabetes mellitus (GDM) to type 2 diabetes remain incompletely elucidated. Our objective was to investigate the link between serum creatinine, a proxy for skeletal muscle mass, and the development of postpartum abnormal glucose metabolism (AGM). Methods: A retrospective review of the medical records of 501 women with GDM was conducted, all of whom underwent a 75 g oral glucose tolerance test (OGTT) between 4 and 12 weeks postpartum. Women were grouped based on quartiles of serum creatinine at the first antenatal visit to estimate the association between serum creatinine and postpartum AGM incidence. Results: Compared with the highest quartile of creatinine, lower quartiles were substantially linked to an increased incidence of postpartum AGM (adjusted odds ratios 3.37 [95% CI 1.77–6.42], 2.42 [95% CI 1.29–4.51] and 2.27 [95% CI 1.23–4.18], respectively). The generalized additive model suggested a linear relationship between serum creatinine levels and the risk of postpartum AGM below 68 µmol/L of serum creatinine levels. A decrease of 2 μmol/L in serum creatinine levels was found to be associated with a 10% increase in the odds of developing postpartum AGM. Linear regression revealed that a low serum creatinine level was linked to a higher postpartum 2-h glucose level and a decreased insulinogenic index (p = 0.007 and p = 0.027, respectively). Conclusions: An association was observed between lower serum creatinine levels in early pregnancy and an increased risk of postpartum AGM and poorer β-cell function in women with a recent history of GDM. Further research is needed to understand the mechanisms underlying our findings, as well as the role of skeletal muscle mass or nutritional status in early pregnancy on later glucose metabolism. Full article

Biliverdin reductase-A (BVRA) is involved in the regulation of insulin signaling and the maintenance of glucose homeostasis. Previous research showed that BVRA alterations are associated with the aberrant activation of insulin signaling in dysmetabolic conditions. However, whether BVRA protein levels change dynamically within the cells in response to insulin and/or glucose remains an open question. To this aim, we evaluated changes of intracellular BVRA levels in peripheral blood mononuclear cells (PBMC) collected during the oral glucose tolerance test (OGTT) in a group of subjects with different levels of insulin sensitivity. Furthermore, we looked for significant correlations with clinical measures. Our data show that BVRA levels change dynamically during the OGTT in response to insulin, and greater BVRA variations occur in those subjects with lower insulin sensitivity. Changes of BVRA significantly correlate with indexes of increased insulin resistance and insulin secretion (HOMA-IR, HOMA-β, and insulinogenic index). At the multivariate regression analysis, the insulinogenic index independently predicted increased BVRA area under curve (AUC) during the OGTT. This pilot study showed, for the first time, that intracellular BVRA protein levels change in response to insulin during OGTT and are greater in subjects with lower insulin sensitivity, supporting the role of BVR-A in the dynamic regulation of the insulin signaling pathway. Full article

The impact on body weight development is usually analysed by comparing different diet types. Our approach was to change only one component, namely bread, common to most diets. In a single-centre triple-blind randomised controlled trial the effects of two different breads on body weight were analyzed without further lifestyle modification. Overweight adult volunteers (n = 80) were randomised 1:1 to exchange previously consumed breads for either a rye bread from milled whole grain (control) or a medium-carbohydrate, low-insulin-stimulating bread (intervention). Pre-tests demonstrated that the two bread types strongly differed in the glucose and insulin response elicited, but had similar energy content, texture and taste. The primary endpoint was the estimated treatment difference (ETD) in change of body weight after 3 months of treatment. Whereas body weight remained unchanged in the control group (−0.1 ± 2.0 kg), significant weight reduction was observed in the intervention group (−1.8 ± 2.9 kg), with an ETD of −1.7 ± 0.2 kg (p = 0.007), that was more pronounced in participants ≥ 55 years (−2.6 ± 3.3 kg), paralleled by significant reductions in body mass index and hip circumference. Moreover, in the intervention group, the percentage of participants with significant weight loss (≥1 kg) was twice as high as in the control group (p < 0.001). No other statistically significant changes in clinical or lifestyle parameters were noted. Simply exchanging a common insulinogenic bread for a low-insulin-stimulating bread demonstrates potential to induce weight loss in overweight persons, especially those at older age. Full article