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5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes—2026

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee for Diabetes, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee for Diabetes, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2026

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee for Diabetes, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Index

A1C, S7, S11, S12, S14–S15, S17–S18, S22, S27–S28, S40–S41, S54, S55, S56, S65, S66, S69, S72, S74, S81, S90–S91, S95, S101, S103, S104–S105, S110–S111, S114, S116, S144, S152, S153, S154, S155, S156, S158–S159, S171, S174, S176, S250, S254, S255correlation with BGM and CGM, S133–S134equivalent eAG levels, S133glycemic assessment with, S133hemodialysis and, S29in children and adolescents, S39–S40, S298, S300, S302–S303–S306in gestational diabetes mellitus, S41–S43in hospitalized patients, S339–S340, S346, S350in older adults, S281, S282–S283, S288, S290, S292in screening and diagnosis, S28–S30, S32in prediabetes, S28, S35–S36, S50–S51in pregnancy, S321–S322, S324, S326, S332–S333in type 1 diabetes, S32, S33, S35, S51, S177, S184, S188, S189, S261,in type 2 diabetes, S36, S38, S53, S190, S192, S196–S199,serum glycated protein assays as alternative to, S133

Metabolic and Paracrine Heterogeneity of Pancreatic Glucagon-Secreting α-Cells

By stimulating hepatic glucose production, glucagon (released by islet α-cells) restores normal blood glucose levels when they fall below the normal range. We used optogenetics in conjunction with electrophysiology, cytoplasmic free Ca 2+ concentration imaging, and hormone release measurements to explore the intrinsic and paracrine regulation of glucagon secretion. Many α-cells were spontaneously active at 1 mmol/L glucose. However, up to ∼50% of the α-cells were electrically silent. K ATP channel blockade, amino acids, and somatostatin receptor antagonism restored electrical activity in such α-cells. Termination of optoactivation resulted in K ATP channel–dependent (tolbutamide sensitive) membrane repolarization in active α-cells but long-lasting membrane depolarization and action potential firing in silent α-cells. The latter effect was associated with an increased cytoplasmic ATP:ADP ratio. Optoactivation or optoinhibition of somatostatin-releasing δ-cells inhibits and stimulates electrical activity in adjacent (but not distal) α-cells. There is an inverse relationship between basal glucagon secretion (a measure of the fraction active α-cells) and the relative stimulatory effects of amino acids. We conclude that islet α-cells are functionally heterogenous and that their electrical excitability and glucagon release are determined by K + channel activity due to variable mosaic of K ATP and somatostatin-sensitive K + channels reflecting metabolic state and proximity to δ-cells, respectively. Article Highlights A subpopulation of α-cells lack spontaneous electrical activity. K ATP channel blockers, somatostatin receptor antagonists, or amino acids activate silent α-cells. Stimulatory effects of amino acids are inversely related to basal glucagon secretion. Metabolic and paracrine heterogeneity determines glucagon secretion.

High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle

Treatment responses to behavioral, surgical, and pharmacological approaches in obesity are highly variable in quantity and quality. Here we refer to high-quality weight loss as a high proportion of fat to skeletal muscle mass lost. Given the role of skeletal muscle in energy expenditure, glucose homeostasis, metabolic flexibility, mobility, and strength, excessive loss of skeletal muscle during weight loss is a concern for overall health. Challenges in accurately measuring body composition, especially skeletal muscle, limit our understanding of muscle loss during obesity treatment. Recent incretin-related pharmacotherapies improve muscle metabolic health by enhancing glucose uptake and reducing muscle lipids but, like other weight loss interventions, are associated with muscle loss. Newer pharmacological interventions are being developed to minimize muscle loss, but many questions remain. This article examines the metabolic importance of skeletal muscle and its measurement clinically, as well as key genetic and metabolic factors influencing skeletal muscle and the quality of weight loss. Genetics can affect muscle composition (e.g., fiber types) and function. Together with metabolic factors, including neurohormonal responses and skeletal muscle metabolic efficiency and adaptation, there is variability in weight loss outcomes. In future research investigators should continue to focus on factors affecting skeletal muscle and on personalized strategies to optimize weight loss quality preserving the physical and metabolic functions of skeletal muscle. Article Highlights High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development. 10.2337/dbi25-0003Video 1. American Diabetes Association 84th Scientific Sessions: Diabetes Journal Symposium–Shifting from Quantity to Quality.d66be569-74dc-4ed8-9c83-67582847b6f7

The Benefits of Exercise Training in Combination With Weight Loss Therapies

The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, while the addition of aerobic training (AT) further improves cardiorespiratory fitness. The individual benefits of RT and AT are complementary, and combining both exercise training modalities during CR provides the most optimal benefits for body composition and physical function. The World Health Organization recommends that adults engage in at least 150 min of moderate-intensity or 75 min of vigorous-intensity AT weekly and participate in RT activities involving major muscle groups at least 2 days per week. While this recommendation applies to the general adult population, regular exercise training that incorporates both RT and AT is particularly crucial for adults with obesity undergoing weight loss interventions. This clinical perspective highlights the benefits of exercise training alongside current weight loss strategies, such as lifestyle changes, bariatric surgery, and pharmacotherapy, with a focus on incretin-based therapies. Article Highlights Weight loss achieved through calorie restriction causes a decline in lean mass and bone mineral density. Progressive resistance training stimulates muscle protein synthesis even during negative energy balance and is particularly crucial for mitigating the loss of lean mass associated with calorie restriction. Aerobic training further improves cardiorespiratory fitness during calorie restriction. Combining both exercise training modalities during calorie restriction provides the most optimal benefits for body composition and physical function. 10.2337/dbi25-0001Video 1. American Diabetes Association 84th Scientific Sessions: Diabetes Journal Symposium–Shifting from Quantity to Quality.d66be569-74dc-4ed8-9c83-67582847b6f7

Treating Sarcopenic Obesity in the Era of Incretin Therapies: Perspectives and Challenges

Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future. Article Highlights Sarcopenic obesity, reduced muscle mass and strength coupled with obesity, poses significant health risks to older adults. Aging exacerbates sarcopenia and obesity due to metabolic, hormonal, inflammatory, and lifestyle changes. Traditional interventions emphasize exercise and diet to reduce fat mass while preserving muscle mass. Incretin therapies show promise in weight reduction and physical improvement in younger populations but are minimally studied in older adults. These medications can be used to treat several obesity-related complications, which older adults with sarcopenic obesity are prone to developing. These medications need to be used cautiously among older adults, considering potential muscle mass loss and adverse events. 10.2337/dbi25-0004Video 1. American Diabetes Association 84th Scientific Sessions: Diabetes Journal Symposium–Shifting from Quantity to Quality.d66be569-74dc-4ed8-9c83-67582847b6f7

Cushing Syndrome, Hypercortisolism, and Glucose Homeostasis: A Review

Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes. Article Highlights Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.

Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells

Ribosome profiling (Ribo-seq) measures translational regulation and reveals novel or unannotated open reading frames (nuORFs) otherwise difficult to identify. Recent reports demonstrate that nuORFs regulate gene expression and immune recognition, highlighting their emerging biological roles. Pancreatic β-cells are critical for maintaining euglycemic conditions, and β-cell impairment contributes to diabetes development. Identification of nuORF and protein/peptide products in human β-cells could reveal novel mechanisms that regulate β-cell function during homeostatic and disease conditions. Here, we applied a proteogenomic approach to human β-cells to define previously unknown protein/peptide products. First, we applied cell type–specific Ribo-seq to map the translatome of human stem cell–derived β-cells (sBCs). Pathways crucial for β-cell function and antigen presentation were subject to translational regulation. We detected a recently described immunogenic neoantigen, INS-DRiP, presumably originating from a downstream start site in INS mRNA. Moreover, our analysis revealed 965 novel nuORFs in sBCs, with a majority showing protein-level support. Comparison with primary human islets further validated nuORF translation and highlighted β-cell specificity. We identified a novel, primate-specific regulatory upstream ORF within TYK2, which is crucial for β-cell function and interferon response and has many variants strongly associated with type 1 diabetes. Finally, we used immunopeptidomics, HLA-binding prediction models, and T-cell coculture assays to validate the presentation and immunogenicity of preproinsulin peptides and nuORFs. Our findings underscore the importance of translational regulation in β-cell function and provide an important resource to the diabetes research community. Article Highlights We developed a cell type–specific proteogenomic approach to reveal novel or unannotated open reading frames (nuORFs) using transcriptomics, ribosomal profiling, and proteomic analysis of human pancreatic β-cells using stem cell–derived β-cells and/or cadaveric islets. Our analysis revealed translational regulation of β-cell–specific pathways during differentiation and identified 965 nuORFs, with a majority exhibiting protein support and substantial β-cell specificity. A primate-specific ORF located in the 5′ untranslated region of the type 1 diabetes risk gene TYK2 may act as a translational activator. We provide HLA class I immunopeptidomic data from cytokine-stimulated human β-cells and demonstrate their utility in coculture assays with autoreactive T-cell transductants. Taken together, our results define the human β-cell translatome, an important resource to the research field.

Multiomics Integration of Epigenetics, Proteomics, and Metabolomics Identifies Putative Drug Targets and Improves Early Prediction for Diabetes

Diabetes holds significant social importance due to its high incidence rate and multitude of associated complications. The identification of diabetes biomarkers and the understanding of the intricate biological mechanisms underlying diabetes are crucial for the early diagnosis and treatment of diabetes. In this study, we conducted comprehensive omics profiling of CpGs, plasma proteins, and serum metabolites in an National Survey of Physical Traits (NSPT) cohort of 3,451 individuals, among whom 293 were patients with diabetes. Global association analysis identified 175 CpGs, 29 proteins, and 93 metabolites significantly linked to diabetes, among which 43 CpGs and 25 metabolites were validated in an independent cohort comprising 532 individuals. Mendelian randomization and mediation analysis identified 20 causal biomarkers and 190 signaling pathways linking biomarkers from different layers. By integrating the cross-omics evidence, we provide a list of putative causal biomarkers of diabetes to serve as a valuable resource for the diabetes community. Cross-omics integration prioritized biomarkers for therapeutic targeting, highlighting COLEC11 as an example of a potential target and whose function was further validated in vitro. The early-prediction model using the prioritized biomarkers improved the area under the receiver operating characteristic curve by 27.5% compared with the baseline model, using clinical features alone. Our findings provide a comprehensive list of prioritized multiomics biomarkers and elucidate specific signaling pathways in diabetes, contributing significantly to the selection of therapeutic target and the understanding of diabetes pathophysiology. Article Highlights A total of 175 CpGs, 29 proteins, and 93 metabolites were identified as associated with diabetes, among which 43 CpGs and 25 metabolites were validated in an independent cohort. Causal and mediation analyses revealed 20 biomarkers and 190 signaling pathways involved in diabetes development. The integrative multiomics prioritization provides the community with an ordered list of diabetes biomarkers. We experimentally validated one of the prioritized proteins, COLEC11, and demonstrated its involvement in lipid metabolism. Our findings prioritize potential therapeutic targets and demonstrate that integrating multiomics biomarkers improves diabetes risk prediction beyond traditional clinical models.

Genome-Wide Association Study of Hypoglycemia in Adults With Diabetes in the Million Veteran Program

Hypoglycemia is a preventable adverse treatment effect in diabetes patients, but genetic markers to identify those with increased susceptibility are lacking. We performed a case/control genome-wide association study (GWAS) of hypoglycemia in U.S. Million Veteran Program (MVP) participants with medication-treated diabetes. Case participants had an outpatient random serum/plasma glucose <70 mg/dL or an emergency department visit for hypoglycemia. GWAS was stratified by race/ethnicity, adjusted for age at MVP enrollment, sex, and top 10 population-specific principal components, followed by multipopulation meta-analysis. Secondary analyses examined genetic associations with hypoglycemia stratified by diabetes medication exposure as well as replication in UK Biobank and the Action to Control Cardiovascular Risk in Diabetes clinical trial. The study included 72,244 (22,045 case participants) non-Hispanic White participants, 24,162 (10,441 case participants) non-Hispanic Black participants, and 9,196 (2,800 case participants) Hispanic participants. Four loci had genome-wide significant associations with hypoglycemia in multipopulation meta-analysis: rs12712928 (chromosome 2, SIX2/SIX3 locus), rs1064173 (chromosome 6, HLA-DQB1/DQA2 locus), rs35198068 (chromosome 10, TCF7L2 locus), and rs113748381 (chromosome 17, SCL16A11 locus). All four loci replicated in at least one independent cohort, and the magnitude of associations with hypoglycemia varied by diabetes type. Genome-wide analyses may complement candidate pharmacogenetic studies to identify risk markers of adverse drug effects. Article Highlights Genetic variants associated with hypoglycemia risk in individuals with medication-treated diabetes have not been evaluated genome-wide. The specific question we asked was whether common genetic variants are associated with hypoglycemia among individuals with diabetes treated with glucose-lowering medications. We found four genomic loci were associated with hypoglycemia in a genome-wide association study. One locus—on chromosome 6—was associated with hypoglycemia only in individuals with likely type 1 diabetes, and two loci—on chromosome 2 and chromosome 6—were associated with hypoglycemia only in the context of treatment with sulfonylureas (chromosome 2) or with insulin (chromosome 6). Genetic variants may help identify individuals with diabetes at increased hypoglycemia risk, but additional study is needed to address the clinical utility of genetic data to inform hypoglycemia risk.

Combined Weight Loss and Exercise Training Alters Skeletal Muscle Subcellular Lipid Localization and Intermuscular Adipose Tissue Cellular Composition

Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipids and IMAT cellular composition is not known. Twenty-one adults with obesity (18 female and 3 male; 46 ± 2 years; 35.0 ± 0.9 kg/m 2 ) completed a 3-month supervised weight loss and exercise training intervention. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp, and basal and insulin-stimulated vastus lateralis biopsies were collected pre- and postintervention. After the intervention, body weight and body fat decreased (11 ± 1% and 9 ± 1%, respectively), while VO 2 peak and insulin sensitivity increased (14 ± 3% and 68 ± 14%, respectively). Lipidomics revealed reduced sarcolemmal and nuclear triglycerides, with unchanged whole-muscle triglycerides. Whole-muscle diacylglycerols increased because of increased nuclear 1,2-diacylglycerols without PKCε, PKCθ, or PKCδ activation. Whole-muscle sphingolipid levels increased because of cytosolic accumulation. Single-nuclei RNA sequencing showed altered IMAT cellular composition, including increased fibro-adipogenic progenitors, vascular cells, and macrophages, and decreased preadipocytes. Bulk muscle RNA sequencing indicated upregulation of genes related to muscle remodeling and cellular respiration, and there were changes in the relationship between nuclear diacylglycerols and gene expression postintervention. These findings dissociate improvements in insulin sensitivity from total muscle diacylglycerol and sphingolipid levels and highlight roles for subcellular lipid redistribution and IMAT remodeling in insulin sensitization. Article Highlights Evaluation of subcellular fractionated muscle revealed decreases in sarcolemmal and nuclear triglycerides and increases in nuclear diacylglycerols and cytosolic sphingolipids postintervention. Weight loss revealed alteration in the cellular composition of intermuscular adipose tissue and upregulation of genes related to muscle remodeling and cellular respiration. These findings dissociate improvements in insulin sensitivity from total muscle 1,2-diacylglycerol and sphingolipid levels and highlight roles of intermuscular adipose tissue remodeling for enhanced insulin sensitivity.

Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance

Heterozygous inactivating mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (GCK-MODY). We identified a novel variant of uncertain significance in the GCK gene (c.77A>T, p.Q26L) in two family members exhibiting contrasting diabetic phenotypes. To explore the diabetogenic potential of the GCK-Q26L mutation and investigate the mono- and polygenetic factors contributing to different phenotypes, whole-exome sequencing and polygenic risk score (PRS) assessments were conducted on three family members. We found that the proband inherited the GCK-Q26L mutation from her father (who had mild, stable hyperglycemia) but exhibited more severe diabetic symptoms, including polydipsia, polyuria, weight loss, ketosis, and significant dyslipidemia. Genetic analysis linked the proband’s severe phenotypes to her high PRS for insulin resistance (IR) and type 2 diabetes. A global knock-in mouse model expressing GCK-Q26L presented mild hyperglycemia, impaired glucose tolerance, reduced serum insulin, and impaired glucose-stimulated insulin secretion. Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. This study demonstrates that GCK-Q26L is a pathogenic GCK-MODY mutation, and its associated phenotypes are influenced by PRS for IR and type 2 diabetes. Article Highlights This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.

Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1

Osteoprotegerin (OPG) has emerged as a pivotal factor in metabolic disease pathology; however, its role in hepatic glucose metabolism remains poorly understood. We demonstrated a pronounced reduction in hepatic OPG expression in obese mice, attributable to DNA hypermethylation mediated by DNMT3α. Opg overexpression in the liver reduced the basal metabolic rate and exacerbated glucose metabolism disorders in mice with high-fat diet–induced obesity, whereas Opg knockout yielded opposite effects. Furthermore, mammalian target of rapamycin complex 1 (mTORC1; Raptor)/S6K1/IRS1/AKT signaling was found to be required for the regulation of hepatic glucose metabolism. Mechanistic investigations revealed that OPG interacts with Raptor within the mTORC1 complex, facilitating its phosphorylation at Ser863 and Ser877, influencing the mTORC1 (Raptor)/S6K1/IRS1/AKT signaling pathway, and thereby affecting glucose metabolism and insulin sensitivity. These findings underscore the integral role of OPG in glucose homeostasis and suggest it as a novel therapeutic target in type 2 diabetes.Article HighlightsMethylation of the Opg promoter inhibits hepatic OPG expression in obese mice.Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice.OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor).Opg deficiency in mice reduces age-related metabolic dysfunction.