Improve Beta-cell Function Research Articles

Immune checkpoints and pancreatic beta cell dysfunction in HIV.

We explored the impact of immune dysregulation on pancreatic beta cell injury in HIV patients. Analyzing 105 participant samples, we observed lower IL-21 levels and elevated immune checkpoint levels (e.g. PD-1, CD27+, CD40+) in untreated HIV patients. Notably, soluble TIM-3 correlated positively with improved beta cell function and inversely with beta cell stress, suggesting its potential role in beta cell protection in untreated HIV.

The impact of time-restricted eating on beta-cell function in adults with type 2 diabetes: a randomized cross-over trial.

Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM. In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127. As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003). TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity.

Normalization of impaired glucose tolerance after kidney transplantation is associated with improved β-cell function.

Our previous study revealed that over 50% of recipients with pretransplant impaired glucose tolerance (IGT) improved to normal glucose tolerance after kidney transplantation. However, the mechanism is unclear. We aimed to investigate whether the changes in glucose tolerance are associated with β-cell function and insulin resistance in Japanese kidney transplant recipients with pretransplant IGT. Of the 265 recipients who received kidney transplantation, 54 with pretransplant IGT were included. We divided the recipients into improvement and nonimprovement groups according to the change in the area under the curve for glucose obtained from the oral glucose tolerance test (OGTT). β-Cell function was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and the disposition index (DI). Insulin resistance was estimated by the Matsuda index (MI) and the homeostasis model assessment of insulin resistance (HOMA-IR). ISSI-2 and DI increased significantly after transplantation in the improved group (P < 0.01, P < 0.05, respectively), but not in the nonimproved group. ΔISSI-2 and ΔDI were significantly and positively associated with pretransplant 60-min OGTT plasma glucose levels (both P < 0.01). There were no differences in MI or HOMA-IR between these two groups after transplantation. In recipients not on pretransplant dialysis, a significant negative association was found between Δblood urea nitrogen (BUN) and ΔDI (correlation coefficient = -0.48, P < 0.05). In pretransplant IGT recipients, improvements in glucose tolerance after kidney transplantation were linked to improvements in β-cell function. The higher the 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Improvements in BUN after transplantation were associated with improvements in β-cell function.NEW & NOTEWORTHY In recipients with pretransplant impaired glucose tolerance, improvements in glucose tolerance after kidney transplantation were associated with improvements in β-cell function. The higher the pretransplant 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Although glucose tolerance is known to be impaired after transplantation, the present study focused on the reason for the improvement in glucose tolerance rather than the development of posttransplantation diabetes mellitus.

Sex-dependent intra-islet structural rearrangements affecting alpha-to-beta cell interactions lead to adaptive enhancements of Ca2+ dynamics in prediabetic beta cells

Aims/hypothesisPrediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells’ functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes.MethodsIslets from male and female transgenic Ins1CreERT2-GCaMP3 mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca2+]i) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca2+]i dynamics in line with single beta cell [Ca2+]i analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca2+]idynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca2+]i dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10.ResultsMice fed a WD for 1 month displayed increased beta cell [Ca2+]i dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca2+]i dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes.Conclusions/interpretationWe identified increased coordination of [Ca2+]i dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca2+]i dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca2+]i dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca2+]i dynamics may thus serve as an early marker for beta cell failure in prediabetes.Graphical

Inhibition of de novo ceramide synthesis by sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular (CV) diseases. Dysregulated pro-apoptotic ceramide synthesis reduces β-cell insulin secretion, thereby promoting hyperglycaemic states that may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor CV outcomes. Sirtuin-1 (SIRT1) is a NAD + -dependent deacetylase that protects against pancreatic β-cell dysfunction; however, systemic levels are decreased in obese-T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycaemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. Circulating SIRT1 levels were reduced in obese-diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4 weeks prevented body weight gain and improved glucose tolerance, insulin sensitivity, and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin secretory function of β-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in β-cells, thereby decreasing the rate-limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among patients with T2D, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored β-cell function (HOMA2-β) and were more likely to have T2D remission during follow-up. Acetylation of TLR4 promotes β-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate CV complications of T2D.

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes.

Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

GDF15 Protects Insulin-Producing Beta Cells against Pro-Inflammatory Cytokines and Metabolic Stress via Increased Deamination of Intracellular Adenosine.

It has been proposed that antidiabetic drugs, such as metformin and imatinib, at least in part, promote improved glucose tolerance in type 2 diabetic patients via increased production of the inflammatory cytokine GDF15. This is supported by studies, performed in rodent cell lines and mouse models, in which the addition or production of GDF15 improved beta-cell function and survival. The aim of the present study was to determine whether human beta cells produce GDF15 in response to antidiabetic drugs and, if so, to further elucidate the mechanisms by which GDF15 modulates the function and survival of such cells. The effects and expression of GDF15 were analyzed in human insulin-producing EndoC-betaH1 cells and human islets. We observed that alpha and beta cells exhibit considerable heterogeneity in GDF15 immuno-positivity. The predominant form of GDF15 present in islet and EndoC-betaH1 cells was pro-GDF15. Imatinib, but not metformin, increased pro-GDF15 levels in EndoC-betaH1 cells. Under basal conditions, exogenous GDF15 increased human islet oxygen consumption rates. In EndoC-betaH1 cells and human islets, exogenous GDF15 partially ameliorated cytokine- or palmitate + high-glucose-induced loss of function and viability. GDF15-induced cell survival was paralleled by increased inosine levels, suggesting a more efficient disposal of intracellular adenosine. Knockdown of adenosine deaminase, the enzyme that converts adenosine to inosine, resulted in lowered inosine levels and loss of protection against cytokine- or palmitate + high-glucose-induced cell death. It is concluded that imatinib-induced GDF15 production may protect human beta cells partially against inflammatory and metabolic stress. Furthermore, it is possible that the GDF15-mediated activation of adenosine deaminase and the increased disposal of intracellular adenosine participate in protection against beta-cell death.

Tangeretin enhances pancreatic beta-TC-6 function by ameliorating tunicamycin-induced cellular perturbations.

Pancreatic beta cell health and its insulin-secreting potential are severely compromised under the diabetic condition. One of the key mediators of beta cell dysfunction is endoplasmic reticulum (ER) stress. Pharmacological intervention of ER stress and associated complications in pancreatic beta cells may be an effective strategy for the management of diabetes. In the present study, we evaluated the efficacy of tangeretin, a citrus pentamethoxyflavone, in the alleviation of ER stress and associated perturbations in pancreatic Beta-TC-6 cell lines. Tunicamycin (pharmacological ER stress inducer) at subtoxic levels was observed to induce beta cell dysfunction by upregulation of intracellular ROS levels, lowering mitochondrial number/biogenesis and membrane potential, elevation of UPR markers, XBP-1, GADD153, and ER resident chaperones. Treatment with tangeretin was successful in improving the beta cell function by lowering the ROS levels and improving the mitochondrial biogenesis and mitochondrial membrane potential. Tangeretin also downregulated the expression levels of XBP-1, GADD153, and ER resident chaperones. GLUT2 expression, however, did not undergo any significant change under ER stress. We also observed altered expression of Pdx-1, TRB3, and p-Akt under the ER stress condition. Tangeretin augmented the expression levels of Pdx-1, and p-Akt while curtailing the expression of TRB3 in beta cells. Tunicamycin treatment suppressed the insulin levels, however, co-treatment with tangeretin could only marginally improve the levels. Targeting ER stress and associated pathways in pancreatic Beta-TC-6 cell lines by tangeretin can be an effective strategy for improving beta cell function.

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.

Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis

Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398).Graphical

THU141 Clinical Characteristics Of Korean Youth-onset Type 2 Diabetes Patients With Remission

Abstract Disclosure: S. Shin: None. H. Kim: None. S. Kim: None. J. Kim: None. Backgrounds: Improvement of beta cell function can occur in some patients with type 2 diabetes mellitus (T2DM). However, studies on remission of youth-onset T2DM with pharmacotherapy are sparse. We aimed to identify the clinical characteristics of pediatric patients experiencing remission. Methods: Medical records of pediatric patients with T2DM who were followed up for at least 1 year at Seoul National Bundang Hospital (2015-2022) were retrospectively reviewed. Remission of T2DM was defined as a return of HbA1c to &amp;lt;6.5% that persists for at least 3 months after discontinuation of glucose-lowering pharmacotherapy. Clinical characteristics between the remission and non-remission groups were compared at three time points (at diagnosis, 3 months after diagnosis, and remission). Results: Among 66 patients with T2DM (46 males, 69.7%), the mean age at diagnosis was 14.6±0.5 years, and the mean follow-up duration was 3.0±0.5 years. One (1.5%) patient underwent lifestyle modification only, 13 (19.7%) were treated with oral hypoglycemic agents only, and 52 (78.8%) were combined with insulin therapy at diagnosis. Twelve patients (18.2%) attained remission after a mean of 1.4±0.4 years from the time of diagnosis (at a mean age of 16.1±1.1 years). The remission group showed a higher proportion of males (100.0% vs. 63.0%, P = 0.012). At diagnosis of T2DM, urinary microalbumin-to-creatinine ratio (ACR) was lower in the remission group than in the non-remission group (2.0±1.6 mg/g vs. 11.2±2.9 mg/g, P = 0.010). There were no significant differences between the groups in the presence of initial diabetic ketoacidosis, HbA1c levels at diagnosis, and type of initial treatment. At the time of remission, HbA1c levels were significantly decreased (from 11.8% to 5.4%), while high-density lipoprotein cholesterol levels were increased (from 40.1 mg/dL to 45.7 mg/dL) than those at the time of diagnosis (both P &amp;lt;0.05). Recurrence occurred in three of 12 (25.0%) patients after a mean of 1.9±1.7 years from the time of remission. Conclusion: In Korean youth with T2DM, remission was observed in 18.2% after a mean of 1.4 years of intervention with lifestyle and pharmacotherapy. Youth with T2DM remission showed male predominance, and lower ACR at the time of diagnosis. Further studies about underlying pathophysiology and long-term outcomes after remission are warranted. Presentation: Thursday, June 15, 2023

SAT679 Telehealth And Metabolic Health: Unraveling The Effects Of A 12-week Low-starch Diet On Homa2B IR In Overweight Women

Abstract Disclosure: G. Erta: None. G. Gersone: None. P. Tretjakovs: None. Background: Telehealth has emerged as a promising approach for delivering health care interventions remotely, allowing increased access and convenience, especially in the context of lifestyle interventions for metabolic health. In this study, our aim was to investigate the effects of a 12-week low-starch diet on HOMA2B IR (Homeostatic Model As-sessment for Beta Cell Function Insulin Resistance) in overweight women using tele-health consultations. Methods: A prospective single arm intervention study was conducted among 14 overweight women aged 18-48 years with a body mass index (BMI) of 25-29,9 kg/m^2. Participants received weekly telehealth consultations via video conference with an endocrinologist and were prescribed a low-starch diet for 12 weeks. The dietary intervention focused on reducing the intake of high-starch foods, such as refined grains, potatoes, and bread, while promoting the consumption of non-starchy vegetables, lean protein, and healthy fats. HOMA2B IR, a widely used surrogate marker of insulin resistance, was measured at baseline and after 12 weeks. Results: After 12 weeks of the low-starch diet intervention, there was a significant reduction in HOMA2B IR in overweight women (Mean ± SD: Baseline HOMA2B IR data (2.126 ± 1.909) improved to 1.522 ± 1.468 at 12 weeks (p &amp;lt; 0.05)), indicating improved beta cell function and decreased insulin resistance. Participants also showed reductions in bodyweight, waist circumference, and fasting blood glucose levels. The compliance with the low starch diet was generally high. Conclusion: Our findings suggest that a 12-week low-starch diet administered through telehealth consultations may have positive effects on HOMA2B IR, as well as bodyweight and fasting blood glucose levels, in overweight women. These results highlight the potential of telehealth as a convenient and effective mode of delivering lifestyle interventions to improve metabolic health. More research with larger sample sizes and longer follow-up periods is warranted to confirm these findings and explore the long-term effects of telehealth-based interventions on metabolic health outcomes. Presentation: Saturday, June 17, 2023

SAT035 Oligonucleotide IMT504 Markedly Improves Metabolic Sindrome And Type 2 Diabetes In High-Fat Diet Fed Mice

Abstract Disclosure: L. Domé: None. J.M. Riaño Gomez: None. M.M. Bonaventura: None. M.O. Fernandez: None. A.D. Montaner: None. V.A. Lux-Lantos: None. M.S. Bianchi: None. We have shown that the immunomodulatory oligonucleotide IMT504 (IMT) improves glucose homeostasis in several animal models of type 1 diabetes by regulating immunomodulatory factors and by improving beta-cell function. Here we evaluated the effects of IMT in a murine model of metabolic syndrome and type 2 diabetes induced by high-fat diet (HFD).Five weeks-old C57BL/6LP male mice were fed either standard diet (SD) or HFD (ResearchDiet, D12492) for 12 weeks. HFD mice showed higher non-fasting glycemia (NF-Gly: p&amp;lt;0.01), and body weight (BW: p&amp;lt;0.01). Thereafter, mice received one daily dose of IMT504 for 12 consecutive days [IMT(mg/kg/day), subcutaneous: 20, 6 or 2, only HFD mice) or saline (SD and HFD). Intraperitoneal glucose tolerance test (ipGTT, day 10), insulin secretion test (IST, day 10) and insulin tolerance test (ITT, day 11) were performed. On day 12, food intake (days 1-12), BW, and non-fasting Gly, were recorded; after 3 hours fasting, Gly were recorded, mice were sacrificed, and blood samples collected. Serum insulin levels were analyzed by ELISA.Food (F) and calories (C) consumed decreased with IMT treatment [F(g): ANOVA, p&amp;lt;0.001; HFD different from IMT6 and IMT20: p&amp;lt;0.05], [C (Kcal): ANOVA, p&amp;lt;0.001; HFD different from SD, IMT6, and IMT20: p&amp;lt;0.05]; BW also decreased [repeated measures ANOVA: interaction, p&amp;lt;0.05; SD: different from all on both days, p&amp;lt;0.01; IMT6: Day1 vs Day12, p&amp;lt;0.01; IMT20: Day1 vs Day12, p&amp;lt;0.002]. NF-Gly did not vary with time in SD and HFD mice (day 12 vs day 1), while it significantly diminished with IMT [NF-Gly (mg/dl): repeated measures ANOVA: interaction, p&amp;lt;0.05; IMT6: Day1 vs Day12, p&amp;lt;0.02; IMT20: Day1 vs Day12, p&amp;lt;0.02]. IMT also induced a significant recovery of glucose clearance [GTT-AUC: ANOVA, p&amp;lt;0.01; HFD different from SD, IMT6, and IMT20: p&amp;lt;0.01], as well as of insulin secretion in response to the glucose overload [IST-AUC: ANOVA: p&amp;lt;0.05; HFD different from SD, IMT6, and IMT20: p&amp;lt;0.05] and peripheral response to insulin [ITT- AUC: ANOVA, p&amp;lt;0.01; HFD different from SD, HFD, IMT6, and IMT20: p&amp;lt;0.01]. In addition, IMT decreased the higher Gly and insulinemia (Ins) present in fasting HFD mice [Gly: ANOVA: p&amp;lt;0.001; HFD different from SD, IMT6, and IMT20: p&amp;lt;0.005], [Ins (ng/mL): ANOVA p&amp;lt;0.05; SD vs HFD: p&amp;lt;0.06; HFD different from IMT6, and IMT20: p&amp;lt;0.05]. These effects were consistent with amelioration of peripheral insulin resistance [HOMA-IR index: ANOVA, p&amp;lt;0.006; HFD different from SD, IMT6, and IMT20: p&amp;lt;0.05], and insulin sensitivity [QUICKI: ANOVA, p&amp;lt;0.02; HFD different from SD and IMT20: p&amp;lt;0.05]. IMT treatment promotes a significant, dose-dependent, improvement in the diabetic condition and food intake in HFD mice. Further research is needed to understand its mechanism of action. Funding: CONICET, ANPCYT, Sidus Arg, F. R Barón, F. Williams. Presentation: Saturday, June 17, 2023

PEGylated exenatide injection (PB-119) improves beta-cell function and insulin resistance in treatment-naïve type 2 diabetes mellitus patients.

Objective: PB-119, a PEGylated exenatide injection, is a once-weekly glucagon-like peptide-1 receptor agonist. In the present study, we aimed to evaluate the effects of PB-119 on insulin resistance and beta-cell function in Chinese patients with type 2 diabetes mellitus (T2DM) to uncover its antidiabetic characteristics. Methods: A total of 36 Chinese T2DM patients were randomized to receive 25μg and 50μg PB-119 once weekly and exenatide (5-10μg injected under the skin 2 times a day adjusted by the doctor) for 12weeks. Oral mixed meal tolerance tests were conducted before the study and on Day 79. The data were fitted to estimate beta-cell function and insulin sensitivity parameters using the SAAM II package integrating the oral minimal model (OMM), which was compared with Homeostatic Model Assessment (HOMA) analysis results. Results: Exenatide or PB-119 treatment, compared with their baseline, was associated with higher beta-cell function parameters (φb, φs and φtot), disposition index, insulin secretion rates, and a lower glucose area under the curve. High-dose PB-119 also has a higher insulin resistance parameter (SI) than the baseline, but HOMA-IR did not. For the homeostatic model assessment parameters, HOMA-IR showed no statistically significant changes within or between treatments. Only high-dose PB-119 improved HOMA-β after 12weeks of treatment. Conclusion: After 12weeks of treatment, PB-119 decreased glycemic levels by improving beta-cell function and insulin resistance.

In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome.

Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function. Because of the improved beta cell function the glycaemic control that occurs with pioglitazone is prolonged. Pioglitazone has positive effects not only on cardiac risk factors and surrogate measures of cardiovascular disease, it also lowers the incidence of cardiac events in patients with diabetes. The recurrence of transient ischaemic attack and ischaemic stroke is also reduced in non-diabetic, insulin-resistant subjects. Utilized at preclinical stages (but not later) of heart failure, pioglitazone improves diastolic function and avoids progression to heart failure. Pioglitazone, through suppression of atrial remodelling, also decreases the incidence of atrial fibrillation. The manifestations of diseases associated with insulin resistance (non-alcoholic steatohepatitis and polycystic ovary disease) are also improved with pioglitazone. Pioglitazone may possibly improve psoriasis and other dermopathies. Pioglitazone is therefore an inexpensive and efficacious drug for the insulin-resistant subject with diabetes that is underutilized because of biases that have evolved from the toxicities of other thiazolidinediones.

Beta-cell function in type 2 diabetes (T2DM): Can it be preserved or enhanced?

Type 2 diabetes (T2DM) is a complex metabolic disorder manifested by hyperglycemia, insulin resistance, and deteriorating beta-cell function. A way to prevent progression of the disease might be to enhance beta-cell function and insulin secretion. However, most previous studies examined beta-cell function while patients were using glycemia-lowering agents without an adequate period off medications (washout). In the present review we focus on studies with a washout period. We performed a literature search (2010 to June 2021) using beta-cell function and enhancement. The evidence shows that beta-cell function can be enhanced. Bariatric surgery and very low calorie diets show improvement in beta-cell function in many individuals. In addition, use of glucagon-like peptide-1 receptor agonists for prolonged periods (3 years or more) can also lead to improvement of beta-cell function. Further research is needed to understand the mechanisms leading to improved beta-cell function and identify agents that could enhance beta-cell function in patients with T2DM.

1780-P: Assessment of Toll-Like Receptor Expression and Signaling in Islets under Metabolic and Inflammatory Conditions

Pancreatic beta cells undergoing metabolic and inflammatory stress express islet-derived cytokines or “isletokines” which can induce immune cell infiltration and cellular damage leading to loss of islet cell function. We and others have shown that toll-like receptor (TLR) 4 in islets can mediate metabolic and inflammatory response to DAMPs under diabetic conditions and in islet cell transplantation. Here we show that metabolic and inflammatory conditions result in induction and suppression of expression of multiple members of the TLR family in both MIN6 beta-cell line and mouse islets. Among upregulated TLRs, the endosomal nucleic acid-sensing TLR3 was most highly induced (up to 5 fold) in response to cytokine cocktail IL-1beta, TNF-alpha, and IFN-gamma in the presence of high glucose. Induction of TLR3 expression was blocked by PI3 kinase inhibitor wortmannin and unaffected by mTOR inhibitor rampamycin, calcineurin inhibitor FK506, and NF-κB inhibitor BMS345541. Immunoblot analyses confirmed that TLR3 but not TLR4 protein expression was wortmannin sensitive. These data indicate that TLR3 is upregulated by PI3 kinase signaling in islet beta cells in response to inflammatory conditions. As the endosomal TLR3 signaling is known to sense nucleic acids as well as influence glucose homeostasis, we propose that beta cells may sense DNA damage to induce isletokines to mediate local inflammatory responses during metabolic and inflammatory stress. Further investigations are warranted to decipher signaling pathways and molecular targets of TLR3 signaling to alleviate islet inflammation and improve beta-cell function. Disclosure J.D.Mattke: None. B.Naziruddin: None. M.C.Lawrence: None.

233-OR: The Beta-Cell Specific Deletion of Complement 1q-Like-3 Secreted Protein Improves Beta-Cell Function and Glucose Homeostasis

Using bioinformatics network analysis, we identified complement-1q like-3 (C1ql3) as a secreted protein that affects pancreatic islet function in obese mice. Previously, we showed that the recombinant C1ql3 protein inhibits insulin secretion stimulated by exendin-4 (an agonist for GLP-1 receptor) from human and mouse islets. Currently, we are elucidating the role of C1ql3 in pancreatic β-cell function by using mice with β-cell-specific deletion of the C1ql3 (βKO) gene on a standard chow diet. C1ql3βKO mice showed significantly improved glucose clearance after oral glucose challenge than the control mice, whereas no difference in insulin sensitivity was observed. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. However, islets isolated from C1ql3βKO significantly increased insulin secretion stimulated by cAMP and Exendin-4 than control islets. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. Adenovirus-mediated overexpression of C1ql3 in islets showed increased ER stress and decreased expression of genes involving β-cell function and maintenance. In pathophysiological conditions, increased C1ql3 expression coupled to secretion was observed from both T2D donor islets and obese mouse islets. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased glucose-stimulated insulin secretion from islets of C1ql3βKOLeptinob/ob compared to Leptinob/ob control mice. These findings suggest that the loss of β-cell C1ql3 maintains ER stress and increases insulin secretion to maintain glucose homeostasis. Our work shows that an autocrine regulation of the C1ql3-signaling pathway contributes to β-cell dysfunction in obesity and type 2 diabetes. Disclosure M.Rahman: None. H.Alsharif: None. A.Michl: None. S.Bhatnagar: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK120684-01)

Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial

Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose–response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).

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).