Sarcopenia in type 2 diabetes mellitus is increasingly recognized as a mechanistic consequence of chronic metabolic stress rather than mere age-related comorbidity. This review synthesizes evidence demonstrating how insulin resistance, hyperglycemia, lipotoxicity, and inflammation converge on skeletal muscle mitochondrial proteostasis to drive progressive decline. We evaluate seven pathway modules—mitochondrial dynamics, mitophagy, biogenesis, oxidative phosphorylation, nicotinamide adenine dinucleotide (NAD+)/sirtuin (SIRT)-linked regulation, protein import, and the mitochondrial unfolded protein response (UPRmt)—across an evidence map encompassing basic, clinical, and multi-omics studies. Dynamics and mitophagy represent mechanistically central quality-control nodes; their impairment permits dysfunctional organelle accumulation and promotes atrophic cascades. Direct evidence density, however, remains weighted toward oxidative phosphorylation and mitochondrial biogenesis. NAD+/SIRT-linked regulation, protein import fidelity, and UPRmt represent mechanistically upstream but comparatively underinvestigated signals. We propose a diabetes-centered framework where mitochondrial proteostasis failure mediates atrophy and reinforces insulin resistance via a self-amplifying feed-forward loop, supported by pathway responsiveness to coherent interventions. Human multi-omics data highlight network-level dysregulation rather than isolated defects, underscoring module-based biomarker strategies. Translationally, exercise remains the mechanistic cornerstone, while pathway-directed adjuncts—NAD+ precursor repletion, mitophagy modulators, and emerging pharmacotherapeutics—are warranted for patients with identifiable module-specific failure patterns.
Incretin-based therapies have transformed the treatment of type 2 diabetes mellitus and obesity by producing a weight-loss magnitude that was previously achievable only through intensive caloric restriction or bariatric surgery. This therapeutic shift has moved the clinical focus from the quantity of weight loss to the quality of weight loss. Lean mass reduction is frequently observed during weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs), dual glucose-dependent insulinotropic polypeptide/GLP-1RAs, or emerging multi-agonists. However, loss of lean body mass does not necessarily indicate equivalent loss of contractile skeletal muscle or sarcopenia. Incretin-based therapy is generally associated with preferential fat mass reduction, relative preservation of lean mass, and potential improvement in muscle quality through reduced myosteatosis. Thus, the clinically relevant question is whether incretin-associated body-composition changes lead to deterioration in muscle strength or physical performance, an increased risk of falls or fractures, or impaired quality of life. Available evidence does not show obvious functional harm; however, long-term data remain limited, especially in people with reduced muscle reserve. A muscle-conscious approach that integrates body-composition assessment, functional monitoring, resistance training, nutritional optimization, and emerging pharmacologic muscle-preserving strategies is needed to achieve high-quality weight loss.
Aging is a major risk factor for type 2 diabetes mellitus (T2DM) and is accompanied by chronic, low-grade inflammation known as inflammaging. Emerging evidence indicates that the hypothalamus, a central regulator of energy and glucose homeostasis, undergoes age-associated inflammatory remodeling that contributes to metabolic dysfunction. In particular, glial cells, including microglia, astrocytes, tanycytes, and neural stem cells, acquire senescence-associated phenotypes characterized by impaired homeostatic functions and increased secretion of pro-inflammatory mediators. These changes disrupt hypothalamic neuronal circuits involved in glucose sensing, energy balance, and insulin responsiveness, thereby potentially promoting systemic insulin resistance and T2DM progression. In this review, we summarize current evidence on the cellular and molecular mechanisms of hypothalamic glial inflammaging and discuss how age-related glial dysfunction may contribute to metabolic abnormalities. We also highlight emerging therapeutic strategies targeting neuroinflammation and glial senescence for the prevention and treatment of age-associated T2DM.
Background:Diabetic kidney disease (DKD) remains a major cause of terminal renal failure, with residual risk remaining unacceptably high despite standard glucose control. Although the sodium-glucose co-transporter 2 (SGLT2) inhibitors have proven reno-protective properties extending beyond that explained by glucose lowering alone, unique glucose-independent molecular mechanisms are still incompletely defined. Unveiling these non-glycemic metabolic pathways is of paramount importance for new therapeutic targets and optimized clinical management. Methods:A systematic multi-omics triangulation framework integrating Mendelian randomization (MR) with tissue-specific transcriptomics was conducted. Two-sample MR and multivariable Mendelian randomization (MVMR) adjusted for fasting blood glucose were leveraged as a screening tool to detect glucose-independent serum metabolites in humans using large-scale genome-wide association study data. These findings were validated with transcriptomic signatures from both diabetic and non-diabetic mouse kidney models to identify conserved core genes and convergent metabolic pathways. Results:Genetically proxied SGLT2 inhibition associated with a reduced risk of DKD, with an odds ratio of 0.58, and improved renal function markers. MVMR highlighted 259 glucose-independent metabolites, covering systemic alterations in lipid and amino acid metabolism. A cross-model transcriptomic comparison revealed seven key genes functionally enriched in fatty acid oxidation and ketone body utilization. This convergence supports the concept of a fasting-like metabolic switch and coordinated downregulation of fibrosis-related extracellular matrix pathways irrespective of diabetic status. Conclusion:This study delineates a systemic-renal metabolic axis whereby SGLT2 inhibition drives renoprotection via metabolic reprogramming and anti-fibrotic mechanisms distinct from blood glucose lowering. These findings provide genetic evidence for specific non-glycemic targets and represent a novel mechanistic insight for precision therapeutic intervention in kidney disease.
Background:The pathophysiology of type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in peripheral tissues and dysfunction of β-cells. However, the molecular mechanisms underlying β-cell dysfunction remain incompletely understood. Methods:Analysis of single-cell RNA sequencing of T2DM islets was used to elucidate changes in family with sequence similarity 151 member A (Fam151a) expression. Deletion of Fam151a in INS-1E cells and mice was used to investigate the function of this gene in insulin secretion. Metabolic profiling and metabolomics analyses were used to decipher the effects of FAM151A on metabolic pathways. Results:Using single-cell RNA sequencing, we identified that Fam151a was significantly downregulated in pancreatic β-cells under T2DM conditions. We next investigated the potential functions of FAM151A in β-cells in vitro and in vivo. FAM151A was localized in the endoplasmic reticulum, and its expression was reduced by high-glucose treatment in INS-1E cells. Genetic deletion of Fam151a in INS-1E cells resulted in proinsulin accumulation, insulin vesicle retention, and impaired insulin secretion. A mouse model with pancreatic β-cell-specific deletion of Fam151a displayed reductions in glucose- and potassium chloride (KCl)-stimulated insulin secretion, and impaired glucose tolerance, without alterations in insulin sensitivity or islet morphology. Integrated metabolic profiling and metabolomics analyses revealed that cellular Fam151a deficiency affects the adenosine triphosphate/adenosine diphosphate ratio, glycolysis, the pentose phosphate pathway, and the purine synthesis pathway. Conclusion:Our study identifies FAM151A as a key regulator of insulin secretion in β-cells, providing a potential therapeutic target for the management of T2DM.
Background:Semaglutide, a glucagon-like peptide-1 receptor agonist, effectively promotes weight loss and improves metabolic parameters in individuals with obesity. However, its use is often accompanied by reductions in lean mass, raising concerns about long-term muscle health. This study explored whether combining semaglutide with exercise could preserve muscle mass and enhance metabolic outcomes. Methods:Ldlr-/-.Leiden mice with diet-induced obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis and atherosclerosis were either left untreated (control) or treated with semaglutide, exercise or the combination for 14 weeks. Histological and transcriptomic analyses were conducted on adipose tissue, muscle, liver and heart to explore underlying mechanisms. Results:Semaglutide significantly reduced fat mass (-31%) but also lean mass (-11%). Combining semaglutide with exercise further reduced fat mass (-45%) and lean mass as well but to a lesser extent (-8%). Semaglutide alone or with exercise improved insulin sensitivity and plasma lipids. The combination improved adipose tissue inflammation, liver steatosis, liver inflammation and atherosclerotic lesion area. Only combination treatment significantly improved grip strength and diameter of gastrocnemius myofibers. Multi-organ histological and transcriptomic analyses revealed organ-specific and synergistic effects of combination therapy, including activation of pathways involved in mitochondrial function, glucose metabolism, and inflammation resolution. Conclusion:Semaglutide improves metabolic, liver, vascular and adipose parameters but reduces lean mass and muscle strength. Combining semaglutide intervention with exercise enhances these benefits with partial preservation of muscle mass and function and activation of distinct molecular pathways not engaged by either monotreatment, thereby underscoring the potential of integrating lifestyle interventions with pharmacological treatment.
Finerenone reduces kidney and cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and albuminuric chronic kidney disease (CKD). Recent Asian subgroup, pooled, combination-therapy, Asian versus non-Asian, and real-world analyses have expanded the evidence base relevant to Asian practice. These data support the consistency of finerenone efficacy and safety in Asian patients and do not support withholding treatment on the basis of Asian ethnicity alone. However, the central question in Asia is shifting from whether finerenone is effective to how eligible patients can be identified, treated, monitored, and continued on therapy in routine care. This review summarizes Asian evidence from the FIDELIO-DKD, FIGARO-DKD, FIDELITY, and CONFIDENCE programs and emerging Asian real-world data. Focus is placed on persistent albuminuric risk, potassium monitoring, treatment sequencing with sodium-glucose cotransporter 2 inhibitors, and implementation feasibility across heterogeneous health-care systems. Finerenone should be considered an evidence-based add-on therapy when baseline potassium and kidney function are appropriate and early laboratory monitoring can be delivered. Simultaneous or early combination therapy may be appropriate in selected high-risk patients, but is not a universal default strategy. The practical priority is to strengthen CKD phenotyping, albuminuria testing, structured potassium monitoring, and care pathways that support sustained use of trial-proven therapy.
Background: Exercise positively influences glycemic control. Some individuals experience greater glycemic stability on the day after exercise, even without additional physical activity. However, the mechanisms underlying this delayed glycemic improvement remain unclear. Methods: Seventy-one patients with type 2 diabetes mellitus were assigned to either a 60-minute exercise group or a resting group. Serum fibroblast growth factor 21 (FGF21) levels and untargeted metabolomic profiles were assessed at multiple time points before and after exercise. Interstitial glucose levels were monitored using continuous glucose monitoring system. FGF21 knockout mice and wild-type littermates fed a high-fat diet underwent a 3-week exercise intervention and received FGF21 supplementation. Results: Individuals exhibiting delayed glycemic improvement (responders) displayed a significantly stronger FGF21 response than non-responders. Baseline metabolites, including p-cresol sulfate and dimethylglycine, differed between responders and non-responders and were associated with the FGF21 response. Longitudinal time-series analyses revealed post-exercise differences in acylcarnitines, fatty acids, and complex lipids between responders and non-responders. Dynamic correlation and mediation analyses supported the role of FGF21 in modulating delayed glycemic improvement through regulation of lipid metabolism. In vivo FGF21 knockout and rescue experiments demonstrated that FGF21 is necessary for these metabolic shifts and the associated improvements in glucose tolerance and insulin sensitivity. Conclusion: This study suggests that the baseline metabolome is associated with the magnitude of the post-exercise FGF21 re-sponse, which influences delayed glycemic improvement through regulation of lipid metabolism pathways.
Type 2 diabetes mellitus (T2DM) is increasingly recognized as a heterogeneous, multisystem disease that extends beyond chronic hyperglycemia to encompass cardiovascular disease, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease. Central to this expanded disease spectrum is insulin resistance arising from coordinated metabolic, inflammatory, neuroendocrine, and immune disturbances across multiple organs. Rather than a uniform defect in insulin signaling, insulin resistance represents a dynamic, tissue-specific, and stage-dependent process involving multiorgans, with substantial interorgan crosstalk. This review synthesizes contemporary mechanistic insights into the pathogenesis of insulin resistance in T2DM, integrating molecular pathways, organ-specific dysfunction, and systemic metabolic networks. Ectopic lipid accumulation, mitochondrial dysfunction, chronic low-grade inflammation, immune dysregulation, and gut dysbiosis are highlighted as convergent processes that impair insulin action and drive clinical heterogeneity. Insulin resistance is further contextualized within the cardiovascular-kidney-metabolic syndrome framework, which unifies metabolic, renal, and cardiovascular disease through shared upstream mechanisms. In addition, how contemporary glucose-lowering therapies exert benefits beyond glycemic control by targeting insulin resistance, metabolic reprogramming, and interorgan crosstalk is discussed. Collectively, insulin resistance is positioned as a central pathophysiological driver of T2DM and its complications, supporting a shift toward mechanism-based, organ-protective, and precision-oriented therapeutic strategies.
