Assessment Of Beta-cell Function Research Articles

Association between selenium biomarkers and insulin resistance in women with obesity: A case-control study.

Although literature demonstrates controversial results regarding the association between selenium and glucose metabolism, no studies have specifically targeted a population with obesity even though this group is vulnerable to insulin resistance. To evaluate the association between selenium biomarkers and insulin resistance in women with obesity. This case-control study recruited 84 women with obesity and 129 with healthy weight (control). Selenium intake was assessed by 3-day food record. Selenium concentration in plasma, erythrocyte, and urine was assessed by inductively coupled plasma optical emission spectrometry. Serum glucose, insulin, and glycated hemoglobin (HbA1c) were assessed in a fasting blood sample. Homeostasis Model Assessment of Beta Cell Function (HOMA-β) and Homeostasis Model Assessment of Insulin Resistance were calculated according to standard methods. Women with obesity had higher dietary selenium intake in comparison to the control group (p < 0.001). Further, the plasma and erythrocyte concentrations were lower in individuals with obesity (p < 0.001), while selenium in urine was higher (p < 0.001) than in controls. No significant differences in insulin resistance markers were observed between groups. Selenium intake was positively associated with HOMA-β in both groups. In women with obesity, selenium intake was also positively associated with insulin and HbA1c, while in the controls the clearance of selenium was negatively associated with insulin and HbA1c. There was a positive correlation between dietary selenium intake, fasting insulin, HbA1c, and HOMA-β (p < 0.05). Women with obesity present impaired selenium metabolism. Further, we observed an association between dietary selenium and markers of insulin resistance, which may reflect the possible negative action of selenium on insulin signaling.

12560 RIMOC1, A Novel Regulator Of Mitochondrial Function, And Its Role In Pancreatic Beta-cell Survival, Mitophagy, And Diabetogenesis

Abstract Disclosure: D. Filingeri: None. R. Liu: None. V. Negi: None. J. Lee: None. A. Kumar: None. V. Mandi: None. M. Moulik: None. V. Yechoor: None. Background: Literature supports preserving beta-cell function as an approach to slowing diabetes progression. Mitochondria emerge as an interesting area of focus, driving cellular respiration and glucose-stimulated insulin secretion (GSIS) within beta-cells in physiologic conditions, and leading to increased intracellular ROS generation when damaged. Damaged mitochondria are recycled via lysosomes by mitophagy, and defects in mitophagy have been linked to numerous disease states, with more recent data implicating impaired mitophagy with beta-cell death. Our previous work on the Hippo-TEAD pathway and beta-cell survival led to the isolation of the TEAD binding partner RIMOC1 (RAB7A-Interacting MON1-CCZ1 Complex Subunit 1), a protein highly expressed in pancreatic beta-cells, though its role in beta-cells remains unknown. The overarching hypothesis is that RIMOC1 is protective against the development of diabetes by preserving beta-cell mitophagy and mitochondrial function, and that impaired RIMOC1 function would lead to beta-cell failure and diabetes.Methods: We have generated both a stable INS2 RIMOC1 KO (knockout) cell line and an INS1-Cre RIMOC1 KO mouse model, that are beta-cell specific knockouts of RIMOC1. Mitochondrial membrane potentials were measured using TMRE and JC1 stains, and mitophagy was quantified using the mtKeima probe via flow cytometry. Protein expression was quantified via western blotting. Ongoing studies involving our mouse model include in vivo GTTs (glucose tolerance testing), ex vitro GSIS experiments to assess beta-cell function from mouse islets, and seahorse assays to quantify mitochondrial function. Results: Published GEO datasets show RIMOC1 expression is positively correlated with beta-cell maturity and negatively correlated with glucose load and HgbA1c. Our in vitro data demonstrates RIMOC1 knockout leads to decreased insulin mRNA expression, decreased insulin content, and increased beta-cell cycle inhibition. Early in vivo data shows worsened hyperglycemia with oral refeeding after fasting. In vitro mitophagy experiments demonstrate significantly diminished mitochondrial membrane potential in RIMOC1 KO INS2 cells. Conclusions: RIMOC1 is highly expressed in beta-cells and has a significant role in maintaining euglycemia through mitochondrial functioning, insulin processing, and altered mitophagy. This research highlights RIMOC1 as a promising target of further diabetes research. Presentation: 6/2/2024

Correlation of Glycated Albumin With Glycated Hemoglobin as a Marker for Assessment of Beta Cell Function in Type 2 Diabetes

Objective: To evaluate a relationship between Glycated Albumin and Hba1c in comparison to Serum as predictor for Beta Cell Function in and type-2 diabetes population. Methodology: A descriptive cross-sectional study was conducted among 163 diabetic patients, aged 30 to 70 years and both genders who presented at the Lumhs Civil/Jamshoro OPD and wards with diagnosis of Diabetes Mellitus for at least 6 months or more. A 5cc blood sample was collected from each participant using EDTA tubes for the analysis of glycated albumin and glycated hemoglobin. All data collection procedures were conducted with utmost regard for participant privacy and confidentiality using study proforma and spss version 26 was used for analysis. Result: The mean age of the participants was 62.06±11.03 years. Out of 163 patients 50.3% were male and 49.6% were female. Correlation analyses of the findings had revealed that a significant correlations p&lt;0.001was present between HbA1C levels and glycated hemoglobin levels whereas a significant relation was also found between Body Mass Index and HbA1C and glycated hemoglobin levels. Conclusion: The study concludes that both glycated albumin were recorded high among diagnosed type 2 diabetic mellitus patients, with a strong correlation between HbA1C levels and glycated hemoglobin levels whereas a significant relation was also found between Body Mass Index and HbA1C and glycated hemoglobin levels.

A secondary analysis of indices of hepatic and beta cell function following 12 weeks of carbohydrate and energy restriction vs. free-living control in adults with type 2 diabetes

BackgroundSubstantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes.MethodsWe conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR: <50 g carbohydrates; ~850–1100 kcal/day; n = 20) versus treatment-as-usual (TAU; n = 16). Participants were people with T2D, using ≥ 1 glucose-lowering medication, and a body mass index of ≥ 30 kg/m2. Main outcomes were C-peptide to proinsulin ratio, circulating microRNA 375 (miR375), homeostatic model assessment (HOMA) beta-cell function (B), fatty liver index (FLI), hepatic steatosis index (HSI), HOMA insulin resistance (IR), and circulating fetuin-A and fibroblast growth factor 21 (FGF21). Data were analysed using linear regression with baseline as a covariate.ResultsThere was no observed change in miR375 (p = 0.42), C-peptide to proinsulin ratio (p = 0.17) or HOMA B (p = 0.15). FLI and HSI were reduced by -25.1 (p < 0.0001) and − 4.9 (p < 0.0001), respectively. HOMA IR was reduced by -46.5% (p = 0.011). FGF21 was reduced by -161.2pg/mL (p = 0.035) with a similar tendency found for fetuin-A (mean difference: -16.7ng/mL; p = 0.11). These improvements in markers of hepatic function were accompanied by reductions in circulating metabolites linked to hepatic insulin resistance (e.g., diacylglycerols, ceramides) in the Pharm TCR group.ConclusionsThe Pharm-TCR intervention did not improve fasting indices of beta-cell stress; however, markers of liver fat accumulation and and liver function were improved, suggesting that a LCER diet can improve some aspects of the underlying pathophysiology of T2D.Trial registrationClinicaltrials.gov (NCT03181165).

Interplay Between the American Diabetes Association's ABC Targets for Diabetes, Insulin Resistance Indices, and Dyslipidemia in Indian Type 2 Diabetes Patients.

Background The increasing incidence of type 2 diabetes (T2D) in India underscores the pressing need for effective management strategies. Meeting the American Diabetes Association (ADA) ABC targets for diabetes (glycated hemoglobin (HbA1c), blood pressure, and serum low-density lipoprotein cholesterol (LDL-C)) is crucial for effectively managing T2D, as it reflects the optimal control of key metabolic parameters. Insulin resistance (IR) and impaired beta cell function (BCF) have been found to have a significant impact on glycemic control, lipid metabolism, and hypertension, contributing to the complex cardiovascular risk profile of patients with T2D. This study aimed to explore the association between ABC targets for diabetes, IR, BCF, and dyslipidemia in a cross-sectional cohort of T2D patients. Methods This retrospective study examined data from 681 T2D patients with comorbid hypertension and dyslipidemia. The patients were part of a one-year online lifestyle intervention program for diabetes management at the Freedom from Diabetes Clinic in Pune, India, between January 2021 and December 2022. Baseline data (at the time of enrollment in the program) on medical history and anthropometric and biochemical parameters were retrospectively extracted from medical records and used to assess ABC targets and other clinical parameters. The ABC targets for diabetes include three goals: an HbA1c level of less than 7.0%, a blood pressure level of less than 140/90 mmHg, and an LDL-C level of less than 100 mg/dL. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic Model Assessment of Beta Cell Function (HOMA-B), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated using standard formulas. Results Cross-sectional analysis at baseline showed that 152 (22.3%) participants met all three ABC targets, 306 (45.0%) and 183 (26.8%) participants met two or one targets, respectively, and 40 (5.9%) did not meet any of the ABC targets. Participants meeting all three targets showed significantly lower IR, higher sensitivity (HOMA-IR, median 2.1; QUICKI, median 0.34), higher BCF (HOMA-B, median 62.9), and healthier lipid profiles (mg/dL) (total cholesterol, median 126; triglycerides, median 114; and non-high-density lipoprotein (HDL), median 84) than those who did not meet any of the ABC targets (HOMA-IR, median 3.4; QUICKI, median 0.31; HOMA-B, median 31.7; total cholesterol, median 221; triglycerides, median 187; and non-HDL, median 182) (p < 0.01). A significant association was observed between lower BMI (< 25 kg/m2), lower IR (HOMA-IR <2.5), and meeting all three ABC targets (p < 0.01). No significant association was observed between the duration of diabetes and ABC target status (p > 0.1). Lower IR was identified as a predictor of achievement of all three ABC targets (p < 0.01). Conclusion This study highlights the significance of meeting ABC targets for diabetes in relation to not only a better lipid profile but also lower IR and higher BCF. These preliminary findings provide novel insights into the interplay between IR, BCF, dyslipidemia, and meeting ABC targets in an Indian T2D population. These findings highlight the need for effective diabetes management strategies and improved patient outcomes, considering factors such as BMI and IR indices.

Zinc Alpha-2 Glycoprotein, Acylated Ghrelin, and Zinc Levels in Prediabetics.

Prediabetic stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) exhibit differences in the sites of insulin resistance. Serum Zinc α-2 glycoprotein (ZAG), acylated ghrelin (AG), and zinc (Zn) levels can affect IFG, IGT, and diabetic glucose tolerance (DGT) differently. This study examined the importance of ZAG, AG, and serum Zn levels in prediabetic individuals with IFG, IGT, and DGT, compared to those with normal glucose levels. The study was conducted at İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine. A total of n=151 volunteers were classified according to the WHO criteria for diabetes after undergoing an oral glucose tolerance test. Plasma and serum samples were measured by Inductively Coupled Plasma Optical Emission Spectroscopy, ELISA, and immunoassay. Prediabetic conditions became more prominent with the decrease in ZAG levels. ZAG levels showed a negative correlation with acylated ghrelin and Homeostatic Model Assessment for assessing beta-cell function and insulin resistance. Zinc levels were significantly lower in DGT. ZAG levels have regulatory effects on insulin resistance and plasma glucose levels are mediated by zinc and acylated ghrelin.

Autologous intraarterial pancreatic bone-marrow mononuclear cells infusion in T2D patients: Changes on beta-cells function, insulin resistance, and inflammatory marker

BackgroundType 2 diabetes (T2D) is a progressive disease. Many drugs currently being used for the management of T2D have minimal effect on pancreatic beta cells regeneration. Cell-based therapies might provide potential benefits in this aspect. MethodsA pilot study in five T2D patients with 12 months follow-up was performed to evaluate the effect of autologous bone marrow mononuclear stem cells (BM-MNCs) infusion into pancreatic arteries on the insulin requirement, beta-cell function, insulin resistance, and systemic inflammatory marker (CRP). ResultsThe primary endpoint, a 50 % reduction of total insulin doses from baseline, was not achieved in this study. However, a trend of increasing fasting C-peptide (p = 0.07) and C-peptide 60′ (p = 0.07) and 90′ (p = 0.07) after a mixed-meal tolerance test was observed 12 months post-infusion compared to baseline levels. A similar result was observed for the homeostatic model assessment of beta cell function (HOMA1-B), an index for beta cell function. No improvement was observed for insulin resistance measured by homeostasis model assessment of insulin resistance (HOMA1-IR) and systemic inflammatory parameter. ConclusionIntraarterial pancreatic autologous BM-MNCs infusion might potentially improve beta cell function in T2D patients, although further study is needed to confirm this finding.

Critical Evaluation of Indices Used to Assess β-Cell Function.

The assessment of beta-cell function-defined as insulin secretion rate (ISR) in relationship to plasma glucose-is not standardized and often involves any of a number of beta-cell function indices. We compared beta-cell function by using popular indices obtained during basal conditions and after glucose ingestion, including the HOMA-B index, the basal ISR (or plasma insulin)-to-plasma glucose concentration ratio, the insulinogenic and "ISRogenic" indices, the ISR (or plasma insulin)-to-plasma glucose concentration areas (or incremental areas) under the curve ratio, and the disposition index, which integrates a specific beta-cell function index value with an estimate of insulin sensitivity, in 50 lean people with normal fasting glucose (NFG) and normal glucose tolerance (NGT) and four groups of people with obesity (n=188) with: i) NFG-NGT; ii) NFG and impaired glucose tolerance (IGT); iii) impaired fasting glucose and IGT, and iv) type 2 diabetes. We also plotted the ISR-plasma glucose relationship before and after glucose ingestion and used a statistical mixed effects model to evaluate group differences in this relationship (i.e. beta-cell function). Index-based group differences in beta-cell function produced contradicting results and did not reflect the group differences of the actual observed ISR-glucose relationship, or, in the case of the disposition index, group differences in glycemic status. The discrepancy in results is likely due to incorrect mathematical assumptions that are involved in computing indices, which can be overcome by evaluating the relationship between ISR and plasma glucose with an appropriate statistical model. Data obtained with common beta-cell function indices should be interpreted cautiously.

A Cross-sectional Study to Assess Beta-Cell Function in Individuals with Recently Diagnosed Young-Onset Type 2 Diabetes Mellitus and Its' Complications.

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

Circulating acyl-CoA-binding protein/diazepam-binding inhibitor in gestational diabetes mellitus

BackgroundAcyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has recently been characterized as an endocrine factor affecting energy balance and lipid metabolism. However, regulation of ACBP in women with gestational diabetes mellitus (GDM) during pregnancy, as well as postpartum, has not been investigated, so far.MethodsACBP was quantified in 74 women with GDM and 74 healthy, gestational age-matched, pregnant controls using an enzyme-linked immunosorbent assay. Furthermore, ACBP was quantified post-partum in 82 women (i.e. 41 women with previous GDM vs. 41 previous control women). ACBP was related to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation during pregnancy and postpartum.ResultsDuring pregnancy, median [interquartile range] ACBP levels were not significantly different in women with GDM (40.9 [40.0] µg/l) compared to healthy, pregnant controls (29.1 [32.3] µg/l) (p = 0.215). ACBP serum concentrations increased from 30.3 [40.5] µg/l during pregnancy to 59.7 [33.2] µg/l after pregnancy in the entire cohort (p < 0.001). This observed elevation was consistent across both subgroups of women, those with prior GDM and those without. Multivariate analysis revealed that homeostasis model assessment of beta cell function (HOMA2-B) and creatinine positively and independently correlated with serum ACBP after pregnancy, while multivariate analysis during pregnancy showed no significant correlations.ConclusionsCirculating ACBP is not a marker of GDM status, but ACBP is decreased during pregnancy, irrespective of GDM status. Furthermore, ACBP is related to beta cell function and renal markers in women after pregnancy.

A DESCRIPTIVE COMPARISON OF RESPONSE OF ORAL HYPOGLYCEMIC AGENTS AMONG T2DM IN A BACKDROP OF INSULIN RESISTANCE

Introduction:Different homeostatic models for the assessment of beta cell function in patients with insulin resistance in type 2 diabetes mellitus suggest that Dipeptidyl Peptidase (DPP-4) inhibitors cause less beta cell stress. Aims: The present study aimed to compare and contrast insulin resistance in two groups of patients taking oral hypoglycemic agents, DPP-4 plus metformin and glimepiride plus metformin, on the basis of fasting and postprandial c-peptide and insulin resistance estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Methods: This preliminary descriptive observational study was conducted from 2018 to 2019 in the service Laboratory of the Department of Biochemistry, in collaboration with the Endocrinology Department, Nil Ratan Sircar Medical College and Hospital, Kolkata. Serum C-peptide, serum insulin, and plasma glucose levels were measured in both fasting and post-prandial states along with glycated hemoglobin. Result: In the fasting and fed state, the secretagogue effect of glimepiride-metformin combination was significantly higher (p = 0.017) than that of the linagliptin-metformin combination. Conclusion: Patients treated with glimepiride showed high post prandial insulin levels and high post prandial glucose excursion. This finding can be explained by the probable increase in insulin resistance, which is reflected in their post-prandial C peptide level. However, in the case of linagliptin, one mechanism of decreased post-prandial glucose is believed to be the inhibition of α-cell glucagon release, thereby relieving β-cell stress

Hand grip strength is inversely associated with total daily insulin dose requirement in patients with type 2 diabetes mellitus: a cross-sectional study.

Short-term (2 weeks to 3 months) insulin intensive therapy using continuous subcutaneous insulin infusion (CSII) can improve islet beta cell function and prolong glycemic remission in patients with newly diagnosed type 2 diabetes mellitus (T2DM). However, the total daily insulin dose (TDD, IU/kg/d) required to achieve near-normoglycemic control with CSII still needs to be frequently adjusted based on blood glucose monitoring. Although real-time continuous glucose monitoring (rtCGM), which measures the interstitial fluid glucose concentration continuously without much difficulty, facilitates the adjustment of insulin dosage, its adoption in the T2DM population is strictly limited by insurance coverage and lack of awareness of rtCGM among clinicians. Thus, it is of clinical significance to identify easy-to-use parameters that may allow a more rapid and accurate prediction of TDD requirement. This study aimed to explore the association between hand grip strength (HGS) and TDD requirement in patients with T2DM receiving CSII therapy. A total of 180 eligible patients with T2DM were enrolled in the study and divided into three groups based on their HGS: low (L), medium (M), and high (H). The TDD requirement was calculated on day 7 or 8 of CSII treatment. Anthropometric parameters, including HGS, skeletal muscle mass, skeletal muscle index (SMI) and 6-m gait speed, and laboratory data, were collected on the morning of the second day after admission, within the first 24 h of CSII therapy. These parameters were used to identify significant predictors of TDD requirement using Pearson or Spearman correlation test, and stepwise multiple regression analysis. There were no significant differences in age, duration of T2DM, waist-to-hip ratio (WHR), body mass index (BMI), blood pressure, liver function, estimated glomerular filtration rate, triglyceride, total cholesterol, glycosylated hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta cell function (HOMA-β) among the groups. The H group had higher body muscle mass-to-fat ratio (BMFR), skeletal muscle mass-to-fat ratio (SMFR), SMI, 6-m gait speed, and lower TDD requirement than the M and L groups. The HGS negatively correlated with TDD requirement (r = -0.33, p < 0.001) after adjusting for sex, age, BMI, WHR, HbA1c, Ln (HOMA-β), Ln (HOMA-IR), Ln (BMFR), Ln (SMFR), SMI, and 6-m gait speed. Multivariate stepwise regression analysis indicated that HGS was an independent predictor of TDD requirement in patients with T2DM (β = -0.45, p < 0 001). Lower HGS is associated with an increased TDD requirement in T2DM patients. HGS may facilitate the prediction of TDD requirement in T2DM patients receiving CSII therapy.

1553-P: Postprandial C-Peptide–to–Glucose Ratio Is Valuable in Assessing Beta-Cell Function in Japanese Patients with Type 2 Diabetes

Onset of type 2 diabetes (T2D) is based on the insulin secretion (loss of β-cell function) and resistance. Residual β-cell function is a key factor in achieving optimal glycemic control in T2D patients. Glucagon stimulates insulin, therefore glucagon stimulation test (GST) is a reliable marker for β-cell function. Fasting C-peptide (CPR) to glucose ratio (CPR[ng/ml] to glucose[mg/dl] x100; F-CPR-index) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio (P-CPR-index) for evaluating β-cell function in T2D. Japanese T2D patients with inadequate glycemic control (HbA1c&amp;gt;7.0) were enrolled in the study (n=500, insulin therapy=283). HbA1c, fasting CPR and glucose, postprandial (120 min after breakfast) CPR and glucose were measured, and F-CPR-index and P-CPR-index were calculated. GST was performed as follows: 1mg of glucagon was injected intravenously, CPR was determined before and 6 min after injection, GSTΔCPR (CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTΔCPR were analyzed using simple and multiple stepwise regression analysis. P value&amp;lt;0.05 was defined as statistically different. F-CPR-index, P-CPR-index and GSTΔCPR were 1.60±0.95, 2.67±1.92 and 1.93±1.21, respectively. Simple regression analysis showed that GSTΔCPR was significantly correlated with age, height, body weight (BW), BMI, waist circumference, duration of diabetes, retinopathy, insulin therapy, urinary CPR, F-CPR-index and P-CPR-index. Multiple stepwise regression analysis revealed that independent factors contributing to GSTΔCPR were BW (β=0.336), duration of diabetes (β= −0.107), presence of retinopathy (β= −0.121), use of DPP-4i (β= −0.099), metformin (β= −0.109), SGLT2i (β= −0.108, p=0.002) and P-CPR-index (β=0.432)(R2=0.453). Our date demonstrated that P-CPR-index was valuable and simple method in assessing residual β-cell function with/without insulin therapy in daily clinical practice. Disclosure Y.Matsuhashi: None. T.Abe: None. T.Fujita: None. S.Mizushiri: None. S.Chikazawa: None. M.Daimon: None.

96-LB: Dorzagliatin Improves Beta-Cell Function in Patients with Type 2 Diabetes

Objective: The oral minimal model (OMM) is a powerful tool to assess beta-cell function, including both the dynamic and static states. Dorzagliatin, a novel dual-acting glucokinase activator, has been reported the potential to improve pancreatic function in patients with type-2 diabetes mellitus (T2DM). In this study, we aimed to evaluate the effects of dorzagliatin on beta-cell function by using OMM. Methods: A randomized, double-blind, placebo-controlled study of dorzagliatin following multiple ascending doses in T2DM was completed (NCT02077452) and the data collected were used for beta-cell function parameters (Φb, Φd, Φs, and Φtot) estimation by using the SAAM II package integrating OMM. These parameters represent the non-glucose stimulated index, the dynamic responsivity of insulin secretion, the static responsivity of insulin secretion, and the global index of beta-cell responsivity, respectively. Results: All treatments except for the 200 mg dose group, compared with baseline, were associated with higher beta-cell function indices. Among them, Φb was significantly higher in the 25, 50, 100, and 150 mg dose groups (p &amp;lt; 0.05, p &amp;lt; 0.01, or p &amp;lt; 0.001), indicating basal beta-cell responsivity improved. Φd has an increase in the 25 and 100 mg dose groups (p &amp;lt; 0.05), indicating promptly releasable insulin responsivity improved. Φs was higher in the 25, 50, 100, and 150 mg dose groups (p &amp;lt; 0.05 or p &amp;lt; 0.01), indicating insulin secretion responsivity at steady state improved. Φtot significantly increased in the 25, 50, 100, and 150 mg dose groups (p &amp;lt; 0.05 or p &amp;lt; 0.001), indicating total beta-cell responsivity improved. No statistically significant difference was observed within the placebo group. Conclusions: This study suggested dorzagliatin can improve postprandial glucose control through its positive effects on beta-cell function. Disclosure Y. Zhang: None. L. Feng: Employee; Hua Medicine. L. Chen: Employee; Hua Medicine. D. Liu: None.

Effect of Tinospora cordifolia on gestational diabetes mellitus and its complications

ABSTRACT Ayurvedic system of medicine uses giloy or guduchi, also known as Tinospora cordifolia (TC), to treat diabetes and related diseases like hyperglycemia and hyperlipididemia. However, its usage in gestational diabetes mellitus (GDM) is not well studied. The primary objective of the study was to examine the effects of water extract of TC called satva, essential oil, and hydroalcoholic (HA) extract on GDM and its complications and to explore their mechanism of action using mice model. We used streptozotocin-induced diabetes in pregnant mice as murine model and tested TC preparations for anti-GDM activities. Blood glucose, insulin, litter size, and placental weight were assessed. ELISA method was used to measure plasma insulin level to compute homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and homeostatic model assessment for assessing beta cell function (HOMA-Beta) levels to estimate insulin resistance, insulin sensitivity, and beta cell function respectively. TC-treated groups had significantly higher serum insulin levels, QUICKI, average litter size, and lower placental weight (p < .001). TC oil and HA extract increased pancreatic beta cell activity according to the level of HOMA-Beta. TC lowered placenta weight and increased litter size significantly compared to control group. Our findings suggest that TC preparations preserve pancreatic beta cells, increase insulin production, decrease insulin resistance, and improve beta cell function, hence preventing GDM. TC preparations also reduced placental weight and increased litter size in mice. Based on these results, we recommend the clinical trial and testing of TC preparations for management of GDM and associated complications. Refer graphical abstract (Figure S1).

Ispitivanje beta ćelijske funkcije pacijenata sa novootkrivenim dijabetes melitusom tip 2 u kliničkoj praksi

Dysfunctions underlining type 2 diabetes mellitus (DM2) evolution are insulin resistance and beta-cell secretory insufficiency. Practical but reliable beta-cell function (BCF) testing is still elusive. Methods of BCF measurement include the homeostasis model assessment (HOMA), glucagon stimulation test (GST), oral glucose tolerance tests (OGTT), intravenous glucose tolerance tests (IVGTT), meal tolerance tests (MTT) and the hyperglycemic clamp procedure. Oral tests have the advantage of simpler use and superior approximation of real-life stimulation inclusive for incretin activation effects. The advantage of the test meal over the OGTT incudes a more adequate simulation of nutrients effect on incretin secretion. Therefore, a standardized test meal (STO) would best reflect the spike in insulin secretion after a meal in real life. Conclusion: Standardized test meal, as potent stimulus of C-peptide secretion, is a promising simple and naturalistic alternative to in vivo assess beta-cell function in an affordable outpatient setting, through analysis of C-peptide response in newly diagnosed diabetic patients, as potent stimulus of C-peptide secretion.

Age-Related Sex Differences in Glucose Tolerance by 75 g Oral Glucose Tolerance Test in Japanese.

To elucidate the age-related sex difference in glucose tolerance, we conducted 75 g oral glucose tolerance tests in 1156 participants. Participants were divided into four groups, namely, young (22-29) males, young females, middle-aged (&gt;50) males, and middle-aged females. According to the Japanese Clinical Practice Guideline for Diabetes 2019, the prevalence of normal glucose tolerance (NGT) was significantly lower in middle-aged than in young participants. The prevalence of high-normal fasting plasma glucose (FPG) was higher, and NGT was lower in young males (high-normal FPG 15.2%, NGT 82.0%) than young females (high-FPG 3.9%, NGT 94.3%). Combined glucose intolerance (CGI) was higher and NGT was lower in middle-aged males (CGI 10.2%, NGT 25.2%) than in middle-aged females (CGI 3.3%, NGT 39.8%). FPG and body mass index (BMI) were the lowest and Homeostatic model assessment beta cell function (HOMA-β) was the highest in young females, followed by young males, middle-aged females, and middle-aged males. Multiple linear regression analysis revealed that BMI weakly correlated with HOMA-β and Matsuda index in all subjects except young females. The superior glucose tolerance in females was apparent in young, but attenuated in middle-aged females. The differences are due to the higher insulin secretion potential and lower BMI in young females.

Validity and reliability of simple surrogate indexes to evaluate beta-cell function and insulin sensitivity.

Simple surrogate indexes (SSI) to assess beta-cell function, insulin sensitivity (IS) and insulin resistance (IR) are an easy and economic tool used in clinical practice to identify glucose metabolism disturbances. To evaluate the validity and reliability of SSI that estimate beta-cell function, IS and IR using as a reference the parameters obtained from the frequently sampled intravenous glucose tolerance test (FSIVGTT). We included 62 subjects aged 20-45 years, with a normal body mass index and without diabetes or prediabetes. SSI were compared with the acute insulin response to glucose (AIRg), insulin sensitivity index (Si) and disposition index (DI) obtained from the FSIVGTT using the minimal model approach. Half of the participants (n = 31) were randomly selected for a second visit two weeks later to evaluate the reliability of all the variables. HOMA1-%B and HOMA2-%B had a significant correlation with AIRg (Spearman Rho (rs) = 0.33 and 0.37 respectively, p < 0.01). The SSI evaluating IS/IR that showed stronger correlation (rs > 0.50) with Si were fasting insulin, HOMA1-IR, HOMA2-IR, HOMA1-%S, HOMA2-%S, QUICKI, and the McAuley index. The parameters that showed good reliability with an intraclass correlation coefficient (ICC) > 0.75 were AIRg, HOMA1-%S, HOMA2-%S, and QUICKI. Our results suggest that most of the SSI are useful and reliable.

Predictors of acarbose therapeutic efficacy in newly diagnosed type 2 diabetes mellitus patients in China

BackgroundAcarbose is one of the optimal drugs for patients with the first diagnosis of type 2 diabetes mellitus (T2DM). But what kind of emerging patients has the best therapeutic response to acarbose therapy has never been reported. To this end, we investigated predictors of acarbose therapeutic efficacy in newly diagnosed T2DM patients in China.MethodsA total of 346 T2DM patients received acarbose monotherapy for 48 weeks as part of participating in the Study of Acarbose in Newly Diagnosed Patients with T2DM in China (MARCH study) from November 2008 to June 2011. Change in glycated hemoglobin (ΔHbA1c) served as a dependent variable while different baseline variables including sex, age, disease duration, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, fasting plasma glucose (FPG), 2-h postprandial blood glucose (2 h PG), fasting insulin (FINS), 2-h postprandial insulin (2 h INS), early insulin secretion index (IGI), homeostasis model assessment of insulin resistance index (HOMA-IR), homeostasis model assessment of beta cell function (HOMA-B), area under the curve (AUC) of glucagon, insulin and GLP-1 were assessed as independent predictors. Step-wise multiple linear regression was employed for statistical analysis.ResultsThe results suggested that independent predictors of ΔHbA1c at 12 weeks included baseline body weight (β = − 0.012, P = 0.006), DBP (β = 0.010, P = 0.047), FPG (β = 0.111, P = 0.005) and 2 h PG (β = 0.042, P = 0.043). Independent predictors of ΔHbA1c at 24 weeks included disease duration (β = 0.040, P = 0.019) and FPG (β = 0.117, P = 0.001). Finally, independent predictor of ΔHbA1c at 48 weeks was disease duration (β = 0.038, P = 0.046).ConclusionsAcarbose may be more effective in newly diagnosed T2DM patients with low FPG, low 2 h PG and obesity. The earlier T2DM is diagnosed and continuously treated with acarbose, the better the response to therapy.

Pancreatic beta-cell function dynamics in youth with GCK, HNF1A, and KCNJ11 genes mutations during mixed meal tolerance test.

The aims were (1) to assess beta-cell function in GCK diabetes patients over 2-year period; (2) to evaluate the dynamics of beta-cell function in HNF1A and KCNJ11 patients after treatment optimization; using mixed meal tolerance test (MMTT) as a gold standard for non-invasive beta-cell function assessment. Twenty-two GCK diabetes patients, 22 healthy subjects, 4 patients with HNF1A and 2 with KCNJ11 were recruited. Firstly, beta-cell function was compared between GCK patients versus controls; the dynamics of beta-cell function were assessed in GCK patients with two MMTTs in 2-year period. Secondly, the change of beta-cell function was evaluated in HNF1A and KCNJ11 patients after successful treatment optimization in 2-year period. GCK diabetes patients had lower area under the curve (AUC) of C-peptide (CP), average CP and peak CP compared to controls. Also, higher levels of fasting, average, peak and AUC of glycemia during MMTT were found in GCK patients compared to healthy controls. No significant changes in either CP or glycemia dynamics were observed in GCK diabetes group comparing 1st and 2nd MMTTs. Patients with HNF1A and KCNJ11 diabetes had significantly improved diabetes control 2 years after the treatment was optimized (HbA1c 7.1% vs. 5.9% [54 mmol/mol vs. 41 mmol/mol], respectively, p=0.028). Higher peak CP and lower HbA1c were found during 2nd MMTT in patients with targeted treatment compared to the 1st MMTT before the treatment change. In short-term perspective, GCK diabetes group revealed no deterioration of beta-cell function. Individualized treatment in monogenic diabetes showed improved beta-cell function.