GLP-1 RECEPTOR AGONIST VS. EXERCISE: EFFECTS ON INSULIN GENE EXPRESSION AND Β-CELL RECOVERY IN DIABETIC RATS

Abstract

Background: Type 2 diabetes mellitus (T2DM) is estimated to affect 537 million adults worldwide, but the mechanisms at the molecular level whereby structured exercise and incretin-based pharmacotherapy affect pancreatic β-cell transcriptional activity and circulating microRNA (miRNA) profiles are not fully understood. In a diabetic rodent model, the effects of a GLP-1 receptor agonist (GLP-1 RA) were compared with those of aerobic and resistance exercise on glycemic control, β-cell function, and insulin-related miRNA expression. Methods: Forty male Wistar rats were randomly assigned to five groups (eight per group): healthy controls, STZ NA-induced diabetic, GLP-1 RA (semaglutide), aerobic exercise, and resistance exercise. Interventions were delivered for 12 weeks. Random blood sugar (RBS), glycated hemoglobin (HbA1c), serum C-peptide, insulin gene expression (RT-qPCR, 2⁻ΔΔCt method), and five miRNAs (miR-126, -128, -222, -375, -503) were measured by RT-PCR and gel electrophoresis. Results: All three interventions significantly decreased RBS levels compared with untreated diabetic animals (aerobic: 38.5%; resistance: 37.1%; GLP-1 RA: 39.3%; p<0.001). The HbA1c reductions were similar (~37%) for GLP-1 RA and aerobic exercise, and insulin gene expression was restored to ~70% of control values; resistance exercise had more modest improvements (25.9% reduction in HbA1c; 58% of control in insulin gene expression). Protective miRNAs (miR-126, -128, -222) increased in all treatment arms, pathological miRNAs (miR-375, miR-503) decreased, and resistance exercise normalized miR-503 the most. Conclusion: Structured exercise and GLP-1 RA therapy have similar effects on glycemic control, β-cell preservation, and epigenetic regulation via miRNAs, suggesting that exercise is a valid molecular therapy in addition to pharmacologic therapy.