Preservation Of Β-cell Function Research Articles

Vector of glycated hemoglobin in the formation of dysglycemia in postmenopause: Emphasis on early diagnosis and therapy

Introduction. The close relationship of postmenopause with insulin resistance (IR) and metabolic syndrome (MetS) marks a high cardiometabolic risk of dysglycemia, determining the need for its early diagnosis and therapy. Pathogenetically substantiated criteria for the diagnosis of prediabetes and the nature of early drug therapy for type 2 diabetes mellitus (T2DM) are debated. Information on the relationship between glucose homeostasis parameters and menopausal MetS is fragmentary.Aim. To evaluate the associations of glycated hemoglobin (HbA1c) levels with indices of IR, β-cell function and MetS character- istics in a cohort of postmenopausal women with different carbohydrate metabolic states.Materials and methods. In 94 Caucasian postmenopausal women 58.0 (53.0; 63.0) years old the following were determined: HbA1c, fasting glycemia (FG), TyG and HOMA2 indices, C-peptid, BMI, waist circumference (WC), blood pressure (BP), triglycerides (TG), HDL-C levels. When classifying women by HbA1c (ADA criteria), 15 had normoglycemia, 24 prediabetes, 55 T2DM. ME (25–75%) was assessed using SPSS (version 17); intergroup differences according to the Mann – Whitney test; Spearman and partial correlation analysis were performed.Results. HbA1c age independently correlated with IR parameters: TyG (R = 0.590; p < 0.001), HOMA2-IR (R = 0.318; p < 0.05) and beta cell function: HOMA2-B (R = -0.355; p < 0.001); with lipid markers of MetS (TG, HDL-C, respectively R = 0.382; -0.448; p < 0.001), anthropometric and blood pressure levels.Conclusion. Associations of HbA1c in postmenopausal women with a spectrum of glucose homeostasis parameters and MetS mark it as a vector of formation and progression of dysglycemia due to a close connection with the functional state of β-cells and the importance of lipoglucotoxicity in the dynamics of postmenopausal IR. The obtained data pathogenetically determine the use of HbA1c in the verification of dysglycemia and the early administration of combined antihyperglycemic therapy aimed at preserving β-cell function. The potential of dipeptidyl peptidase-4 inhibitors in slowing the progression of type 2 diabetes mellitus is considered

Pancreatic β-Cells, Diabetes and Autophagy.

Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.

TNF-α inhibitors for type 1 diabetes: exploring the path to a pivotal clinical trial.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate β-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived β-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving β-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNF-α) inhibitors have demonstrated efficacy at preserving β-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-α inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-α inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-α inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-α inhibitors in T1D and considerations for strategies collectively identified to advance TNF-α inhibitors beyond phase 2 clinical studies for stage 3 T1D.

HLA Genotyping in Children With Celiac Disease Allows to Establish the Risk of Developing Type 1 Diabetes.

Celiac disease (CD) and type 1 diabetes (T1D) often co-occur and share genetic components in the human leukocyte antigen (HLA) class II region. We aimed to study the usefulness of HLA genotyping in predicting the risk of developing T1D in patients with CD and the temporal relationship between these diseases. A cohort of 1,886 Sardinian patients, including 822 with CD, 1,064 with T1D, and 627 controls, underwent HLA class II typing. Seventy-six of 822 patients with CD were also affected by T1D (CD-T1D), and their HLA genotypes were analyzed for specific HLA associations with CD, T1D, and controls. High-risk HLA-DQ genotypes, including HLA-DQ2.5/DQ8, -DQ2.5/DQ2.5, and -DQ2.5/DQ2.3, were strongly associated with CD-T1D with frequencies of 34.5%, 15.9%, and 18.8%, respectively. Conversely, certain HLA genotypes associated with CD seemed to confer protection against T1D development. Therefore, HLA genotyping allows for the identification of those patients with CD who might develop T1D. The frequency of patients with CD preceding T1D is higher in younger children than older ones, with implications for the early childhood approach to diabetes prevention. CD is a condition for future T1D development, and specific HLA genotypes can predict this risk. Early screening for celiac autoimmunity and subsequent HLA typing in CD children could help identify those at high risk of T1D, allowing for proactive interventions and immunotherapies to preserve β-cell function. These findings may support the re-evaluation of HLA typing in children with CD.

INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes

IntroductionChildren and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving β-cell function...

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants. Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.

Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice

Mitochondrial dysfunction in pancreatic β-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment’s effects on mQC in diabetic β-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic β-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db β-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db β-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced β-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving β-cell function and effective glycemic control in T2D.

Preservation of β-Cells as a Therapeutic Strategy for Diabetes.

The preservation of pancreatic islet β-cells is crucial in diabetes mellitus, encompassing both type 1 and type 2 diabetes. β-cell dysfunction, reduced mass, and apoptosis are central to insufficient insulin secretion in both types. Research is focused on understanding β-cell characteristics and the factors regulating their function to develop novel therapeutic approaches. In type 1 diabetes (T1D), β-cell destruction by the immune system calls for exploring immunosuppressive therapies, non-steroidal anti-inflammatory drugs, and leukotriene antagonists. Islet transplantation, stem cell therapy, and xenogeneic transplantation offer promising strategies for type 1 diabetes treatment. For type 2 diabetes (T2D), lifestyle changes like weight loss and exercise enhance insulin sensitivity and maintain β-cell function. Additionally, various pharmacological approaches, such as cytokine inhibitors and protein kinase inhibitors, are being investigated to protect β-cells from inflammation and glucotoxicity. Bariatric surgery emerges as an effective treatment for obesity and T2D by promoting β-cell survival and function. It improves insulin sensitivity, modulates gut hormones, and expands β-cell mass, leading to diabetes remission and better glycemic control. In conclusion, preserving β-cells offers a promising approach to managing both types of diabetes. By combining lifestyle modifications, targeted pharmacological interventions, and advanced therapies like stem cell transplantation and bariatric surgery, we have a significant chance to preserve β-cell function and enhance glucose regulation in diabetic patients.

Tofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis.

Background and Objectives: Recently, a randomized controlled trial suggested a potential benefit of baricitinib in patients with diabetes mellitus, preserving β-cell function. However, the clinical evidence currently available is limited. We aimed to assess the potential impact of tofacitinib and baricitinib on type 2 diabetes mellitus (T2DM) patients with rheumatoid arthritis. Materials and Methods: The candidates for this observational, retrospective, single-center study were selected from a cohort of 120 rheumatoid arthritis patients treated with tofacitinib or baricitinib between September 2017 and September 2023. The eligibility criteria included patients with T2DM who were receiving oral antidiabetic drugs (OADs). The primary outcome was the glycosylated hemoglobin (HbA1c) value after 6 months of a JAK inhibitor treatment. Secondary outcomes included body mass index (BMI) and rheumatoid arthritis disease activity. Differences were evaluated using Fisher's exact test, as well as the Mann-Whitney test or the Wilcoxon test. Results: Thirteen patients were included; 46.2% (6/13) underwent treatment with tofacitinib, while 53.8% (7/13) were treated with baricitinib. At 6 months, baricitinib treatment resulted in a reduction in HbA1c (p = 0.035), with 57.1% (4/7) of patients achieving values <7%, and 28.6% (2/7) of patients requiring a reduction in OAD dosage. Concerning BMI, an increase (p = 0.022) was observed at 6 months following baricitinib administration. All the patients treated with either tofacitinib or baricitinib achieved remission or low disease activity, without requiring statistically significant changes in concomitant rheumatoid arthritis treatment. Conclusions: In T2DM patients with rheumatoid arthritis, baricitinib can improve insulin sensitivity and glucose uptake, enabling the optimization of T2DM management.

Glycaemic abnormalities induced by small molecule tryosine kinase inhibitors: a review.

In light of the expected increase in the prevalence of diabetes mellitus due to an aging population, sedentary lifestyles, an increase in obesity, and unhealthy diets, there is a need to identify potential pharmacological agents that can heighten the risk of developing diabetes. Similarly, it is equally important to also identify those agents that show blood glucose-lowering properties. Amongst these agents are tyrosine kinase inhibitors used to treat certain types of cancers. Over the last two decades, there has been an increase in the use of targeted chemotherapy for cancers such as renal cell carcinoma, chronic leukaemia, and gastrointestinal stromal tumours. Small molecule tyrosine kinase inhibitors have been at the forefront of targeted chemotherapy. Studies have shown that small molecule tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which small molecule tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. In this review, the effort is directed at mapping mechanistic insights into the effect of various small molecule tyrosine kinase inhibitors on glycaemic dysregulation envisaged to provide a deeper understanding of these chemotherapeutic agents on glucose metabolism. Small molecule tyrosine kinase inhibitors may elicit these observed glycaemic effects through preservation of β-cell function, improving insulin sensitivity and insulin secretion. These compounds bind to a spectrum of receptors and proteins implicated in glucose regulation for example, non-receptor tyrosine kinase SRC and ABL. Then receptor tyrosine kinase EGFR, PDGFR, and FGFR.

Adipose Signals Regulating Distal Organ Health and Disease.

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin. This imbalance in adipokine secretion alters the physiological state of AT communication with target organs including pancreatic β-cells, heart, and liver. In the pancreatic β-cells, adipokines are known to have a direct effect on insulin secretion, gene expression, cell death, and/or dedifferentiation. For instance, impaired secretion of adipsin, which promotes insulin secretion and β-cell identity, results in β-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve β-cell function. The cardiac tissue is affected by both the classic white AT-secreted adipokines and the newly recognized brown AT (BAT)-secreted BATokines or lipokines that alter lipid deposition and ventricular function. In the liver, adipokines affect hepatic gluconeogenesis, lipid accumulation, and insulin sensitivity, underscoring the importance of adipose-liver communication in the pathogenesis of nonalcoholic fatty liver disease. In this perspective, we outline what is currently known about the effects of individual adipokines on pancreatic β-cells, liver, and the heart.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system

Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in β-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves β-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves β-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved β-cell function and survival under high-glucose conditions via the glutathione redox balance.

Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes

BackgroundJanus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves β-cell function in type 1 diabetes is unclear.MethodsIn this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration–time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring.ResultsA total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal–stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P=0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo.ConclusionsIn patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve β-cell function as estimated by the mixed-meal–stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.)

Anti-Inflammatory Properties of Eugenol in Lipopolysaccharide-Induced Macrophages and Its Role in Preventing β-Cell Dedifferentiation and Loss Induced by High Glucose-High Lipid Conditions.

Inflammation is a natural immune response to injury, infection, or tissue damage. It plays a crucial role in maintaining overall health and promoting healing. However, when inflammation becomes chronic and uncontrolled, it can contribute to the development of various inflammatory conditions, including type 2 diabetes. In type 2 diabetes, pancreatic β-cells have to overwork and the continuous impact of a high glucose, high lipid (HG-HL) diet contributes to their loss and dedifferentiation. This study aimed to investigate the anti-inflammatory effects of eugenol and its impact on the loss and dedifferentiation of β-cells. THP-1 macrophages were pretreated with eugenol for one hour and then exposed to lipopolysaccharide (LPS) for three hours to induce inflammation. Additionally, the second phase of NLRP3 inflammasome activation was induced by incubating the LPS-stimulated cells with adenosine triphosphate (ATP) for 30 min. The results showed that eugenol reduced the expression of proinflammatory genes, such as IL-1β, IL-6 and cyclooxygenase-2 (COX-2), potentially by inhibiting the activation of transcription factors NF-κB and TYK2. Eugenol also demonstrated inhibitory effects on the levels of NLRP3 mRNA and protein and Pannexin-1 (PANX-1) activation, eventually impacting the assembly of the NLRP3 inflammasome and the production of mature IL-1β. Additionally, eugenol reduced the elevated levels of adenosine deaminase acting on RNA 1 (ADAR1) transcript, suggesting its role in post-transcriptional mechanisms that regulate inflammatory responses. Furthermore, eugenol effectively decreased the loss of β-cells in response to HG-HL, likely by mitigating apoptosis. It also showed promise in suppressing HG-HL-induced β-cell dedifferentiation by restoring β-cell-specific biomarkers. Further research on eugenol and its mechanisms of action could lead to the development of therapeutic interventions for inflammatory disorders and the preservation of β-cell function in the context of type 2 diabetes.

Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves β-cells in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease associated with complications that reduce the quality of life of affected individuals and their families. The therapeutic options for T1D are limited to insulin therapy and islet transplantation; these options are not focused on preserving β-cell function and endogenous insulin. Despite the promising outcomes observed in current clinical trials involving allogeneic Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) infusion for the management of T1D, the precise underlying mechanism of action remains to be elucidated. In this correspondence, we propose prospective mechanisms of action of WJ-MSCs that may be mediating their observed capability to preserve β-cell function and prevent T1D progression and provide recommendations for further investigations in clinical settings. We also highlight the efficacy of WJ-MSCs for therapeutic applications in comparison to other adult MSCs. Finally, we recommend the participation of muti-centers governed by international organizations to implement guidelines for the safe practice of cell therapy and patients' welfare.

Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.

O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.

Teplizumab: A Disease-Modifying Therapy for Type 1 Diabetes That Preserves β-Cell Function.

In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10. To provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted. The primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted. These data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment.

Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.

Exercise improves glucose-stimulated insulin secretion through direct interorgan communication. Contracting skeletal muscle releases growth differentiation factor 15 (GDF15), which is required to synergistically enhance glucose-stimulated insulin secretion. GDF15 enhances glucose-stimulated insulin secretion by activating the canonical insulin release pathway. Increased levels of circulating GDF15 after exercise training are related to improvements in β-cell function in patients with type 2 diabetes.