Search Results (420)

To analyze, in an analytical cross-sectional observational study, the relationship between the plasma microRNA (miRNA) expression profile in children living with obesity and their metabolic health status. Based on body mass index percentiles (BMIp), the children were grouped into a control group (C) or an obesity group (Ob). Glucose, insulin, and low- and high-density lipoproteins (LDLs and HDLs, respectively), triacylglycerols (TG), and total cholesterol (TC) were measured. RNA from plasma was used for miRNA sequencing analysis (NextSeq 2000 platform). Differential miRNA expression was determined using counts obtained from the reference genome. Fifty controls (BMIp: 50.4 ± 23) and fifty children with obesity (BMIp: 97.54 ± 1.46) were included. The obese group presented hyperinsulinemia and insulin resistance. Sequencing revealed nine underexpressed and six overexpressed miRNAs in the obese group. In silico analysis suggested that these miRNAs may participate in regulating insulin secretion, protein synthesis, apoptosis, and the glycolytic pathway in pancreatic β-cells. Childhood obesity was associated with altered circulating levels of microRNAs linked to glucose metabolism, insulin resistance (IR) and β-cell survival. Reduced plasma levels of miR-126-3p, let-7a-5p, and miR-16-5p showed a high predictive value for hypertriglyceridemia and insulin resistance, indicating their potential relevance as early biomarkers or therapeutic targets in pediatric metabolic dysfunction. Full article

Obesity is increasingly recognized as a disease of dysregulated intercellular communication rather than merely an energy imbalance. Extracellular vesicles (EVs), membrane-bound nanoparticles (30–1000 nm) released by nearly all cell types, act as central mediators of this pathological crosstalk. In obesity, hypertrophic adipocytes, pro-inflammatory macrophages, and dysfunctional endothelial cells secrete EVs carrying altered cargo, including pro-inflammatory miRNAs (e.g., miR-34a, miR-155), bioactive lipids, and stress proteins, which propagate systemic metabolic dysfunction. Adipose tissue-derived EVs impair hepatic fatty acid oxidation, promote steatohepatitis, suppress pancreatic beta-cell insulin secretion, induce skeletal muscle insulin resistance via PPARγ repression, and contribute to endothelial dysfunction and atherosclerosis. EV-mediated adipocyte–macrophage crosstalk reinforces chronic adipose inflammation. Circulating EVs also provide biomarkers: subpopulation ratios, miRNA signatures, and tissue factor-positive EVs reflect disease severity, predict cardiovascular risk, and monitor therapeutic responses, with machine learning enhancing diagnostic precision. Therapeutically, EVs from mesenchymal stem cells, Wharton’s jelly MSCs, adipose progenitors, and M2 macrophages reverse insulin resistance, hepatic steatosis, and adipose inflammation in preclinical models. Engineering strategies improve EV potency and tissue targeting, and Phase I trials confirm safety, though manufacturing and cost remain barriers. Preclinical and early clinical studies of MSC-EVs confirm a favorable safety profile, though manufacturing scalability and cost remain barriers to widespread clinical adoption. Overall, EVs represent both diagnostic tools and therapeutic vehicles in precision obesity medicine, offering a pathway from symptom management toward true disease remission. Full article

Emerging evidence strongly suggests that gut microbiota dysbiosis plays a significant role in the development and progression of both type 1 and type 2 diabetes mellitus. Quantitative and qualitative changes in the intestinal microbiota’s composition are linked to these distinct pathomechanisms. In type 1 diabetes mellitus, dysbiosis is thought to initiate or accelerate the autoimmune destruction of pancreatic beta cells. This may occur through increased intestinal permeability, which allows microbial components and endotoxins to enter the systemic circulation. This exposure triggers inflammatory and autoimmune responses in individuals who are genetically predisposed. Conversely, in type 2 diabetes mellitus, gut dysbiosis contributes significantly to the characteristic metabolic derangements. Specific microbial shifts can lead to impaired energy metabolism, contributing to insulin resistance in peripheral tissues. Furthermore, dysbiosis is associated with the altered production of microbial metabolites, such as short-chain fatty acids, and the induction of low-grade chronic inflammation, which contribute to the pathogenesis of type 2 diabetes mellitus. Hyperglycemia, dyslipidemia and other metabolic changes also influence the gut microbiota. Understanding these type-specific microbial roles offers potential for novel diagnostic and therapeutic strategies. Full article

The cytotoxic effect of islet amyloid polypeptide (IAPP) misfolding and aggregation has a well-recognized role in the pathogenesis of type 2 diabetes mellitus, mediated by failure of the beta cell’s protein quality control system to rescue the cell from overwhelming proteotoxic stress induced by IAPP aggregates, ultimately leading to apoptosis. A small but growing body of research also links IAPP-mediated proteotoxic stress to the pathogenesis of type 1 diabetes and to the functional decline of transplanted islets. Among the most promising therapeutic approaches under investigation are small organic molecules that may act as direct chemical chaperones to prevent IAPP aggregation, promote the activity of endogenous chaperones, or alter gene networks of the unfolded protein response (UPR) to promote pro-survival rather than pro-apoptotic pathways in response to IAPP-mediated proteotoxic stress. Compounds warranting special attention include 4-phenylbutyrate (PBA), tauroursodeoxycholic acid (TUDCA), and epigallocatechin gallate (EGCG), as each has a growing body of evidence supporting their ability to ameliorate this process, and given that each of these are already known to have good safety profiles in humans, potentially accelerating the timeline to interventional studies. This review explores the evidence for IAPP-mediated proteotoxicity in multiple forms of diabetes, the mechanisms of cytotoxicity at different levels of the cell’s protein quality control systems, how these small organic compounds may act on these processes including new insights on the role of thioredoxin-interacting protein (TXNIP), and the current evidence supporting each of these compounds in mitigating diabetogenesis. Full article

Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer’s disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood–brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations. Full article

Neonatal diabetes mellitus (NDM) is a rare monogenic disorder characterized by persistent hyperglycemia requiring insulin therapy, typically diagnosed within the first six months of life, and may be transient οr permanent. However, hyperglycemia in the neonatal population may be observed outside the NDM range. This narrative review aims to provide an overview of the genetic and molecular mechanisms underlying NDM, including both transient and permanent forms on the one hand and the developmental and regulatory pathways contributing to transient hyperglycemic states in neonates on the other. A comprehensive literature search of PubMed, Scopus, and Google Scholar was conducted, focusing on genetic and molecular mechanisms associated with NDM and transient neonatal hyperglycemia. Mutations in more than 40 genes or chromosomal loci have been implicated in the pathogenesis of NDM, affecting the development and function of pancreatic beta-cells, as well as insulin synthesis and secretion. Abnormalities of the 6q24 locus have been recognized as the most common cause of transient NDM, whereas mutations in genes encoding ATP-sensitive potassium (K_ATP) channels, particularly KCNJ11, are more commonly identified in permanent NDΜ cases. Transient hyperglycemia may occur in preterm and/or critically ill neonates due to immaturity and transient beta-cell dysregulation, insulin resistance, epigenetic modifications, or drug administration. In NDM cases, the clinical course, the presence of extra-pancreatic manifestations, and the optimal treatment depend on the causative gene. Therefore, genetic diagnosis is imperative, as it can facilitate individualized management strategies, long-term follow-up, and genetic counselling. Full article

Diabetes mellitus is a global healthcare issue of epidemic proportions. At the root of these disorders, characterized by poor glucose regulation and insulin deficiencies, is the pancreatic beta cell and insufficient insulin signal transduction in peripheral tissues. Residual c-peptide secretion and persisting beta cells have been found in patients who have been living with type 1 diabetes for over 50 years. Thus, beta cell regeneration has been vastly studied in rodents, and many agents to expand beta cell mass are under rigorous investigation for the treatment of diabetes. Multipotent stromal cells (MSC), isolated from human bone marrow, have an immunomodulatory and pro-regenerative secretome that can aid in repairing damaged tissues, including pancreatic islets. MSC transplantation has been shown to reduce hyperglycemia and orchestrate islet repair in experimental diabetes models and is currently being assessed in clinical trials. While the immunomodulatory mechanisms of MSC are well-studied, the beta-cell-regenerative mechanisms are unknown. MSC likely play a regenerative role by signaling to resident progenitor or precursor cells in the pancreas; however, the decades-long controversy surrounding the origin of regenerated adult beta cells remains unresolved. Herein, we take a deep dive into the role of MSC in the treatment of diabetes and the potential cellular mechanisms behind the MSC stimulation of beta cell regeneration. Full article

Background: Diabetes mellitus is characterized by elevated blood sugar due to absolute or relative insulin deficiency. Diabetes is classified as type 1 (T1D) or type 2 diabetes (T2D), gestational diabetes, and other types, such as monogenic diabetes, exocrine pancreatic disorders, and medication-induced diabetes. Objectives: This review article provides an overview of diabetes genetics, covering polygenic, monogenic, and syndromic forms of the disorder with emphasis on aspects to help clinicians in diagnosis, management, and counseling, but also to foster valuable knowledge for diabetic researchers in identifying phenotypes that will help inform gene discovery. Key Findings: Most cases of T1D and T2D are polygenic with environmental triggers. T1D results from autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency. Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to T1D. Early studies showed a linkage between T1D and several human leukocyte antigen (HLA) susceptibility loci on chromosome 6. Genome-wide association studies (GWAS) have identified more than 100 HLA- and non-HLA loci that increase susceptibility to T1D. It has been well established that a substantial portion of the genetic risk for T1D is encoded in the HLA locus. The non-HLA loci INS, CTLA4, IL2RA, IFIH1, and PTPN22 make moderate contributions to T1D risk. Many other non-HLA loci have small effects to the phenotype and are relevant to autoimmunity, but they are yet to be identified. T2D, on the other hand, is associated with obesity and insulin resistance with relative insulin deficiency. Thousands of gene variants that are common and contribute small effects have also been identified through GWAS to contribute to T2D risk, but the rarer variants may confer significant risk to an individual’s risk. Common variants in the TCF7L2 locus consistently carry one of the largest risks associated with T2D with a reported 1.7-fold disease odds for homozygous carriers. The usefulness of individual variants for genetic counseling in the common forms of diabetes has been limited in clinical settings in the past. The development of polygenic risk scores (PRS) and partitioned polygenic risk scores (PPRS), statistics derived from GWAS, are being used to predict and classify diabetes. The performance of PRS and PPRS varies by ancestry and type of diabetes. The PRS performs better with T1D, with an area under the curve and receiver operating characteristics (AUC-ROC) ranging from 0.87 to 0.93, compared to 0.72–0.75 for T2D. The genetic architecture of T2D is markedly more polygenic than T1D, and the PPRS has been useful in assessing risk in that setting. Monogenic diabetes comprises several dysglycemic disorders that include neonatal diabetes, maturity-onset diabetes of the young (MODY), and other genetic syndromes that have diabetes either as an associated finding and/or as a complication. Some of the monogenic diabetes gene variants have incomplete penetrance and variable expressivity leading to different ages of onset and variable presentation even within the same family. Hence some patients with these conditions have been previously diagnosed as having T1D or T2D. Many monogenic disorders follow Mendelian inheritance patterns, so genetic counseling is relatively straightforward if pathogenic variants are found to be inherited from a parent. Counseling for forms of diabetes due to maternally inherited mitochondrial cytopathies, such as MELAS and Kearns–Sayres syndrome, is not straightforward due to the occurrence of two or more populations of genetically distinct mitochondrial DNAs in the cells (heteroplasmy); the higher the percent of pathogenic variants in a cell or tissue, the greater the chance for affectation of disorder. Implications: Early stages of diabetes may be asymptomatic, and improvement in methodologies to identify individuals at high risk is important so prevention strategies can be targeted to susceptible individuals to slow or obviate the onset of disease and to minimize complications. Conclusions: Diabetes is a heterogeneous disorder, and accurate definition of phenotypes in the setting of non-syndromic and syndromic forms, development of powerful statistical methodologies, use of next-generation sequencing applications to interrogate the genome, incorporation of epigenetic mechanisms in statistical modeling and accurate curation of gene variants, will help us to realize application of genomic medicine and to inform diabetes care. Full article

Background: The pancreatic beta-cell hormone insulin regulates the metabolism of carbohydrates, as well as fats and protein. While the insulin response to a carbohydrate challenge is well defined in normoglycaemic as well as dysglycaemic (prediabetes and type 2 diabetes (T2DM)) individuals, the response of co-secreted beta-cell products (C-peptide, proinsulin and proinsulin intermediates) is less well defined. This analysis aimed to establish the expected glycaemic and pancreatic beta-cell responses to a standardised mixed meal in individuals with impaired glucose tolerance (IGT) and T2DM alongside reference ranges established in normoglycaemic individuals (NGT). Methods: A total of 743 adults (104 NGT, 85 IGT and 554 T2DM) were included, none of whom were on any anti-diabetic medication at the time of initial testing. All attended following a 10 h fast, before consuming a 500 kcal solid mixed meal (calorie contribution: 58% carbohydrates, 22% fat and 20% protein). Blood samples were collected every 30 min for the 4.5 h duration of the test for the determination of plasma glucose, insulin, C-peptide and intact and total proinsulin. Median profiles with corresponding 2.5th and 97.5th percentile lines to display the expected range were calculated and plotted for the three participant groups. Results: Median profiles with ranges over a 4.5 h meal period have been created for glucose, insulin, C-peptide and intact and total proinsulin, along with respective fasting and post-meal intervals in the three participant groups with differing glycaemic status. Conclusions: The resulting profiles and ranges allow for comparison in responses to a carbohydrate challenge in individuals across the glycaemic spectrum. Full article

Glycogen synthase kinase-3 beta (GSK-3β) is a multifunctional serine/threonine kinase mediating multiple cellular functions, such as differentiation, apoptosis, and cell proliferation. Because of their ability to alter carcinogenic pathways, GSK-3β inhibitors are being explored for the development of anticancer molecules. In the present study, we synthesized and evaluated the cytotoxic properties of a series of twenty indole–triazole-linked pyrazolone derivatives, 10Aa–Ed. All derivatives were characterized by FTIR, ¹H/¹³C NMR, and high-resolution mass spectrometry (HRMS) methods. All compounds and standards, sunitinib and 5-Fluorouracil (5-FU), were screened against four adherent cell lines, including pancreatic adenocarcinoma (Capan-1), colorectal carcinoma (HCT-116), glioblastoma(LN229), and lung carcinoma (NCI-4460), and four non-adherent cell lines, including acute myeloid leukemia (HL-60), chronic myeloid leukemia (K562), T lymphoblast (MOLT4), and non-Hodgkin lymphoma (Z138). Among the screened derivatives, molecule 10Aa showed cytotoxicity against MOLT 4, Z138, and HL60 with CC₅₀ values of 14.45 μM, 15.34 μM, and 17.56 μM, respectively. GSK-3β kinase inhibition was evaluated with the 10Aa, which is capable of inhibiting GSK-3β in a dose-dependent manner. Additionally, molecular docking was performed to estimate the correlation between invitro data and GSK-3β binding affinity. The outcomes of the invitro experiments demonstrated strong concordance with the insilico data. The discovery yielded compounds 10Aa and 10Cd, which can be modified to create effective anticancer agents that target GSK-3β. Full article

Prediabetes is accompanied by early β-cell stress and oxidative imbalance before overt hyperglycemia. Circulating extracellular vesicle (EV) microRNAs (miRNAs) may capture early metabolic disturbances, but their mechanistic relevance remains unclear. Plasma EV miRNA profiles were analyzed across normoglycemia, prediabetes, and newly diagnosed type 2 diabetes, with validation in an independent cohort (n = 150). Functional studies were performed in pancreatic β-cells exposed to glucolipotoxic stress to examine miRNA regulation, IFN-α signaling, mitochondrial redox status, and insulin secretion. Six EV miRNAs, including miR-186-5p, were consistently reduced in prediabetes and correlated with glycemic and insulin resistance indices. In β-cells, glucolipotoxic stress selectively suppressed miR-186-5p, leading to derepression of IFNA2, activation of IFN-α–JAK/STAT signaling, increased mitochondrial ROS, impaired ATP/ADP dynamics, and reduced glucose-stimulated insulin secretion. Restoration of miR-186-5p or pharmacologic JAK inhibition mitigated these defects, and luciferase assays confirmed IFNA2 as a direct target of miR-186-5p. EV-associated miR-186-5p represents an early marker of metabolic stress in prediabetes and provides mechanistic insight into IFN-α–driven oxidative and secretory dysfunction in β-cells. Full article

We present a simplified phenomenological computational framework that integrates the GABA shunt into established metabolic mechanisms underlying pancreatic beta cell insulin secretion. The GABA shunt introduces carbon into the tricarboxylic acid (TCA) cycle via succinate, thereby functioning as an anaplerotic pathway. This anaplerotic input is coupled to oscillatory cataplerotic fluxes, primarily involving α-ketoglutarate, whose effective extrusion requires coordinated counter-fluxes of malate and aspartate. Within the model, these cataplerotic exchanges are facilitated by UCP2-mediated transport processes and necessitate complementary anaplerotic replenishment through pyruvate carboxylase (PC). Based on this functional interdependence, we introduce the Dual Anaplerotic Model (DAM), which conceptually links two anaplerotic routes—the GABA shunt-mediated pathway and the glucose-dependent PC pathway—into a unified metabolic response module. DAM describes a coordinated, breathing-like redistribution of carbon between mitochondrial and cytosolic metabolite pools, while efficient oxidative metabolism of glucose-derived carbon entering the TCA cycle via pyruvate dehydrogenase is maintained. The model is driven by experimentally observed ATP/ADP and Ca²⁺ dynamics and is not intended to generate autonomous oscillations. Instead, it enables qualitative, phase-dependent visualization of how dual anaplerotic fluxes constrain and shape oscillatory metabolic states in beta cells. DAM provides an integrative conceptual scaffold for interpreting experimental observations and for motivating future quantitative modeling and experimental studies addressing metabolic regulation in physiological and pathophysiological contexts. Full article

Diabetes mellitus encompasses a heterogeneous group of metabolic disorders defined by abnormalities in insulin secretion, function, or both. Exogenous insulin therapy has long been the principal treatment strategy for patients with type 1 diabetes and for those in advanced stages of type 2 diabetes. Stem cell therapy has gained significant attention in recent years as a potential curative approach for several life-threatening disorders. In this review, we focus on the use of induced pluripotent stem cells as an alternative source for beta-cell generation, offering a solution to organ scarcity and providing a sustainable supply of insulin-producing cells. We further evaluate current developments in encapsulation technologies and transplantation sites, while noting that the issue of immune-mediated graft rejection continues to be widely debated. The aim of this review is to outline encapsulation techniques and transplantation approaches explored in animal models, and to discuss the risks and challenges anticipated in human clinical trials. Full article

Autoimmune type 1 diabetes (T1D) results from the failure of the physiologic regulatory mechanisms that are designed to maintain immune tolerance to pancreatic beta cells. Consequently, the design of strategies to restore tolerance to beta cell antigens is an attractive objective of translational research. We have designed ultrasmall nanoparticles (NPs) loaded with a proinsulin (PI) fusion protein and an agonist for the aryl hydrocarbon receptor (AhR), a transcription factor promoting tolerance induction by different immune cells. We report that a 4 week-treatment with these NPs in non-obese diabetic (NOD) mice starting at disease onset induces temporary and sometimes durable disease remission. Mechanistically, short-term NP treatment induces a rapid depletion of islet infiltrates with a dramatic reduction in the number of CD8⁺ T cells and dendritic cells. This is accompanied by the emergence of B lymphocytes producing IL-10. In the rare mice that undergo durable disease remission, the disappearance of islet infiltrates is associated with the emergence of Foxp3⁺ CD4⁺ regulatory T cells, IFN-γ-producing memory T cells in the spleen, and draining lymph nodes (LNs). We conclude that treatment with these NPs could be of interest in the treatment of recent-onset autoimmune diabetes, but is unlikely to be sufficient for the induction of long-term remission as a stand-alone therapy. Full article

Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not always lead to a precise diagnosis, as novel variants are often classified as variants of unknown significance. Variant interpretation requires collation of a framework of evidence, including population, computational, and segregation data, and can be assisted by functional analysis. The inclusion of functional data can be challenging, depending on the number of benign and pathogenic variants available for benchmarking assays. Glucokinase is the rate-limiting step for glucose metabolism in the pancreatic beta-cell and governs the threshold for glucose-stimulated insulin release. Loss-of-function alleles in the glucokinase (GCK) gene are a cause of stable fasting hyperglycemia from birth and/or diabetes. In this study, we functionally characterized 25 variants identified during diagnostic testing or in exome sequencing studies. We assessed their kinetic characteristics, stability, and interaction with pharmacological and physiological regulators. We integrated our functional data with existing data from the ClinGen Monogenic Diabetes Variant Curation Expert Review panel using a gene-specific framework to assist variant classification. We show how functional evidence can aid variant classification, thus enabling diagnostic certainty. Full article