Pharmacological Effects of Antidiabetic Drugs on Skeletal Muscle Glucose Uptake and Metabolic Physiology: A Systematic Review

Abstract

Background: Skeletal muscle is a major site of insulin-stimulated glucose disposal and plays a central role in whole-body glucose homeostasis. In type 2 diabetes mellitus, impaired insulin signaling, defective GLUT4 translocation, mitochondrial dysfunction, altered substrate oxidation, and reduced metabolic flexibility contribute substantially to insulin resistance. Antidiabetic drugs differ in the extent to which they directly or indirectly modify these skeletal-muscle pathways.

Objective: To systematically evaluate the effects of antidiabetic drugs on skeletal muscle glucose uptake, insulin signaling, GLUT4 trafficking, AMP-activated protein kinase (AMPK) activity, mitochondrial function, substrate utilization, microvascular perfusion, and peripheral insulin sensitivity.

Methods: This systematic review followed PRISMA 2020 principles. MEDLINE/PubMed, Embase, Scopus, and Web of Science were used in the review framework, supplemented by citation searching. The PRISMA synthesis was restricted to adult human studies reporting skeletal-muscle or peripheral metabolic outcomes; animal and cell studies were used only for mechanistic context and were not counted as included studies. In the screening dataset, 2,250 database records and 28 citation-search records were identified. After duplicate removal, title/abstract screening, retrieval, and full-text assessment, 18 primary human studies were included in the qualitative synthesis. No quantitative meta-analysis was performed because of substantial clinical and methodological heterogeneity.

Results: Eighteen primary human mechanistic studies were included. Rosiglitazone and pioglitazone showed the most consistent non-insulin evidence for improving peripheral insulin sensitivity, insulin-stimulated glucose disposal, lipid handling, metabolic flexibility, and selected mitochondrial or signaling endpoints. Metformin activated skeletal-muscle AMPK in a small before-after study, although a randomized PET study did not demonstrate increased muscle glucose uptake. DPP-4 inhibitors improved clamp-derived peripheral insulin sensitivity in several trials. Liraglutide and exenatide improved whole-body insulin sensitivity or glucose fluxes, but direct muscle-specific evidence remained limited. SGLT2 inhibitor studies showed improved clamp-derived insulin sensitivity and vascular insulin responsiveness, whereas short-term PET data did not show increased skeletal-muscle glucose uptake. Imeglimin improved tissue-specific skeletal-muscle insulin sensitivity in a 2026 clamp study.

Conclusion: Antidiabetic drugs exert heterogeneous effects on skeletal-muscle metabolic physiology. Among non-insulin therapies, thiazolidinediones have the most consistent direct human evidence for improving muscle-related insulin sensitivity and glucose disposal. Metformin, incretin-based therapies, SGLT2 inhibitors, and imeglimin influence skeletal-muscle physiology through combinations of direct, systemic, vascular, and substrate-mediated mechanisms. Further human studies using muscle-specific imaging, biopsies, isotope tracers, and mitochondrial phenotyping are needed to define the tissue-level actions of newer therapies