Grant: Canada Postdoctoral Research Award (CPRA) program

Type 2 diabetes (T2D) and obesity are leading global health concerns, contributing to high morbidity, mortality, and healthcare costs. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, have demonstrated remarkable efficacy in weight loss and glycemic control, making them an increasingly common therapy. However, recent evidence indicates that semaglutide-induced weight loss is accompanied by a disproportionate reduction in muscle mass, in some cases equivalent to a decade of aging-related decline. This loss of muscle mass poses significant risks for functional decline, frailty, and reduced quality of life, underscoring the urgent need for countermeasures. This project will test the hypothesis that B-hydroxy-B-methylbutyrate (HMB) supplementation, with or without resistance exercise, attenuates muscle mass loss and preserves strength in obese adults with T2D undergoing semaglutide therapy. We will conduct a 16-week, double-blind, randomized controlled trial enrolling 160 participants (40-65 years, ~50% women) newly prescribed semaglutide. Participants will be randomized into four groups: (1) semaglutide + placebo, (2) semaglutide + HMB, (3) semaglutide + resistance exercise, and (4) semaglutide + resistance exercise + HMB. Primary outcomes will be changes in thigh muscle mass. Secondary outcomes include changes in muscle strength (leg press, chest press, isometric knee extension), body composition, intramuscular fat infiltration (MRI), VO2peak, resting metabolic rate, inflammatory cytokines, and mitochondrial function. Mechanistic insights will be obtained using stable isotope tracers to measure protein synthesis and breakdown, along with muscle biopsy analyses for fibre type distribution and RNA sequencing to identify pathways involved in muscle preservation. This study will provide the first controlled evidence to guide strategies for preserving muscle in obese adults with T2D, informing guidelines, trials, and clinical practice.