Introduction and Objective: Metformin improves glycemic control primarily by suppressing hepatic glucose production; however, its effects on skeletal muscle remain unresolved, particularly regarding insulin signaling and mitochondrial function. This study examined the impact of long-term metformin administration on skeletal muscle (SkM) insulin sensitivity, mitochondrial function, and endurance capacity. Methods: In a 40-week double-blind, placebo-controlled trial, 40 older adults (60-85 years) with overweight/obesity and impaired fasting glucose (100-140 mg/dL) were randomized to metformin or placebo. Systemic insulin sensitivity was assessed using a mixed-meal tolerance test, while hepatic insulin sensitivity and β-cell function were measured using a hyperinsulinemic-euglycemic clamp. Brain insulin sensitivity was inferred utilizing 18FDG glucose uptake. SkM insulin sensitivity was evaluated in biopsied tissue obtained before and 60 minutes after the mixed meal via pAKT Ser473. Mitochondrial function was assessed by oxygen consumption, and ATP/ROS production. Results: Compared to placebo, metformin improved systemic and hepatic insulin sensitivity (p0.05) and increased regional brain glucose uptake in insulin receptor-rich regions (p0.05). In contrast, metformin attenuated the postprandial increase in SkM pAKT Ser473 (p0.05) and did not alter any mitochondrial function parameters. Metformin was also associated with reduced leg lean mass and a modest decrease in VO2peak normalized to lean mass (p0.05). Conclusion: Long-term metformin therapy improved systemic, hepatic, and regional brain insulin sensitivity in insulin-resistant older adults without altering SkM mitochondrial function. Blunted skeletal muscle insulin signaling likely reflects reduced circulating insulin from improved β-cell function rather than intrinsic muscle insulin resistance. The modest reduction in endurance capacity is consistent with loss of lean mass rather than impaired mitochondrial efficiency. Disclosure R.G. Leija: None. M. Pataky: None. K. Klaus: None. A. Prabha Kumar: None. K. Sevits: None. K. Nair: None. Funding National Institute of Aging (R21 AG060139)
LEIJA et al. (Fri,) studied this question.