Search Results (7)

Pancreatic beta cells regulate insulin secretion in response to glucose by generating ATP, which modulates ATP-sensitive potassium channels (K_ATP) channel activity and Ca²⁺ dynamics. We present a model of ATP production in pancreatic beta cells, focusing on ATP dynamics within the bulk cytosol, submembrane region, and microdomains near K_ATP channels. ATP is generated through glycolysis, mitochondrial oxidative phosphorylation (OxPhos), and glycolytic pyruvate kinase-mediated phosphoenolpyruvate (PEP) production, supported by PEP cycling between mitochondria and the cytosol. The model examines ATP production in relation to Ca²⁺ oscillations, elucidating their interdependent dynamics. Our findings demonstrate that both mitochondrial OxPhos and PEP-mediated ATP production contribute substantially to cellular ATP levels. Specifically, glycolysis and mitochondrial OxPhos are crucial for the initial (first-phase) increase in bulk and subplasmalemmal ATP, effectively “filling up” the ATP pool in beta cells. In the second phase, coordinated cycling between OxPhos and PEP pathways enables cost-effective fine-tuning of ATP levels, with localized effects in the K_ATP channel microdomains. This model addresses and clarifies the recent debate regarding the mechanisms by which sufficient ATP concentrations are achieved to close K_ATP channels in glucose-stimulated beta cells, offering novel insights into the regulation of energy production and K_ATP channel activity. Full article

Glucose homeostasis in the body is determined by four diabetes factors (DFs): insulin resistance (IR), glucose effectiveness (GE), and the two phases of insulin secretion—first phase (FPIS) and second phase (SPIS). Previous research points to a correlation between elevated levels of gamma-glutamyl transferase (γGT) and an increased risk of type 2 diabetes. This study investigates the relationship between γGT and the four DFs in older Chinese individuals. This study involved 2644 men and 2598 women, all of whom were relatively healthy Chinese individuals aged 60 years or more. The DFs were calculated using formulas developed by our research, based on demographic data and factors related to metabolic syndrome. Pearson’s correlation was utilized to assess the relationship between γGT and the four DFs. The findings suggested a positive correlation between γGT and IR, FPIS, and SPIS, but a negative correlation with GE in men. Among women, only SPIS and GE were significantly correlated with γGT. The factors showed varying degrees of correlation, listed in descending order as follows: GE, SPIS, FPIS, and IR. This study confirms a significant correlation between γGT and DFs in this population, highlighting the noteworthy role of GE. Full article

Aim: Several studies have demonstrated that factors including diabetes, including insulin resistance (IR), glucose effectiveness (GE), and the first and second phase of insulin secretion (FPIS, SPIS) could easily be calculated using basic characteristics and biochemistry profiles. Aging is accompanied by deteriorations of insulin resistance (IR) and insulin secretion. However, little is known about the roles of aging in the different phases of insulin secretion (ISEC), i.e., the first and second phase of insulin secretion (FPIS, SPIS), and glucose effectiveness (GE). Methods: In total, 169 individuals (43 men and 126 women) recruited from the data bank of the Meei-Jaw (MJ) Health Screening Center and Cardinal Tien Hospital Data Access Center between 1999 and 2008, with a similar fasting plasma glucose (FPG: 90 mg/dL) and BMI (men: 23 kg/m², women 22 kg/m²) were enrolled. The IR, FPIS, SPIS, and GE were estimated using our previously developed equations shown below. Pearson correlation analysis was conducted to assess the correlations between age and four diabetes factors (DFs: IR, FPIS, SPIS, and GE). The equations that are used to calculate the DF in the present study were built and published by our group. Results: The age of the participants ranged from 18 to 78 years. Men had higher FPIS but lower HDL-C levels than women (2.067 ± 0.159, 1.950 ± 0.186 μU/min and 1.130 ± 0.306, 1.348 ± 0.357 mmol/dl, accordingly). The results of the Pearson correlation revealed that age was negatively related to the IR and GE in both genders (IR: r = −0.39, p < 0.001 for men, r = −0.24, p < 0.003 for women; GE: r = 0.66, p < 0.001 for men, r = 0.78, p < 0.001 for women). At the same time, the FPIS was also only found to be negatively correlated with age in females (r = −0.238, p = 0.003), but there was no difference in the SPIS and age among both genders. Conclusions: We have found that in Chinese subjects with a normal FPG level (90 mg/dL) and body mass index (men: 23 kg/m², women: 22: kg/m²), age is negatively related to the IR and GE among both genders. Only the FPIS was found to be negatively related to age in women. The tightness of their relationships, from the highest to the lowest, are GE, FPIS, and IR. These results should be interpreted with caution because of the small sample size. Full article

Sex-specific differences exist in insulin secretion (ISec) and sensitivity (IS) in humans. However, current fasting indices used to estimate them, such as HOMA and QUICKI, are not sex-specific. We aimed to develop sex-specific models to improve the prediction of ISec and IS by fasting measures in adults with overweight/obesity. A post hoc analysis was conducted on baseline data of two clinical trials completed between 2010 and 2020 (37 men and 61 postmenopausal women, 45–73 years, BMI > 25 kg/m², without chronic disease). Glucose-induced insulin or C-peptide secretions and IS were measured using gold-standard Botnia-clamps, which is a 1 h intravenous glucose tolerance test followed by a 3 h hyperinsulinemic–euglycemic clamp. Stepwise regression analysis using anthropometric and fasting plasma glucose, insulin, and lipoprotein-related measures was used to predict ISec and IS. First-phase, second-phase and total glucose-induced ISec were predicted by a combination of fasting plasma insulin and apoB without or with plasma glucose, triglyceride, and waist circumference in women (R² = 0.58–0.69), and by plasma insulin and glucose without or with BMI and cholesterol in men (R² = 0.41–0.83). Plasma C-peptide, alone in men or followed by glucose in women, predicted C-peptide secretion. IS was predicted by plasma insulin and waist circumference, followed by HDL-C in women (R² = 0.57) or by glucose in men (R² = 0.67). The sex-specific models agreed with the Botnia-clamp measurements of ISec and IS more than with HOMA or QUICKI. Sex-specific models incorporating anthropometric and lipoprotein-related parameters allowed better prediction of ISec and IS in subjects with overweight or obesity than current indices that rely on glucose and insulin alone. Full article

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants. Full article

Secretagogin (SCGN) is a calcium binding protein related to insulin release in the pancreas. Although SCGN is not co-released with insulin, plasma concentrations have been found to be increased in type 2 diabetes mellitus patients. Until now, no study on SCGN levels in pregnancy or patients with gestational diabetes mellitus (GDM) has been published. In 93 women of a high-risk population for GDM at the Medical University of Vienna, secretagogin levels of 45 GDM patients were compared to 48 women with a normal glucose tolerance (NGT). Glucose tolerance, insulin resistance and secretion were assessed with oral glucose tolerance tests (OGTT) between the 10th and 28th week of gestation (GW) and postpartum. In all women, however, predominantly in women with NGT, there was a significant positive correlation between SCGN levels and Stumvoll first (r_p = 0.220, p = 0.032) and second phase index (r_p = 0.224, p = 0.028). SCGN levels were not significantly different in women with NGT and GDM. However, SCGN was higher postpartum than during pregnancy (postpartum: 88.07 ± 35.63 pg/mL; pregnancy: 75.24 ± 37.90 pg/mL, p = 0.004). SCGN was directly correlated with week of gestation (r_p = 0.308; p = 0.021) and triglycerides (r_p = 0.276; p = 0.038) in women with GDM. Therefore, SCGN is related to insulin secretion and hyperinsulinemia during pregnancy; however, it does not display differences between women with NGT and GDM. Full article

In this study, two capsaicin analogues, N-eicosapentaenoyl vanillylamine (EPVA) and N-docosahexaenoyl vanillylamine (DHVA), were enzymatically synthesized from their corresponding n-3 long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both dietary relevant components. The compounds significantly reduced the production of some lipopolysaccharide (LPS)-induced inflammatory mediators, including nitric oxide (NO), macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1 or CCL2), by RAW264.7 macrophages. Next to this, only EPVA increased insulin secretion by pancreatic INS-1 832/13 β-cells, while raising intracellular Ca²⁺ and ATP concentrations. This suggests that the stimulation of insulin release occurs through an increase in the intracellular ATP/ADP ratio in the first phase, while is calcium-mediated in the second phase. Although it is not yet known whether EPVA is endogenously produced, its potential therapeutic value for diabetes treatment merits further investigation. Full article