Abstract Overweight, obesity, and type 2 diabetes mellitus are metabolic health problems and diseases that affect billions of people worldwide. Studies in animals and humans suggest that stimulating global muscle hypertrophy could be a treatment for these diseases, as some key studies suggest that stimulation of global muscle hypertrophy commonly reduces fat mass and improves glucose homeostasis. To analyse the effect of muscle hypertrophy on fat and glucose homeostasis in more detail, we systematically searched the literature and quantitatively analyzed 122 studies (humans: n = 99; animals: n = 23). This analysis reveals that a 1.9–3.3% increase in global muscle mass in humans is associated with 4.1 ± 5.8% lower fat mass, a mean relative reduction in HbA1c of 4.1 ± 4.6% from baseline, and a reduction of fasting glucose concentrations by 5.8 ± 7.3% in studies lasting 2 weeks to 3 years. In the animal studies analyzed, the researchers increased muscle mass by transgenesis, drugs, or resistance training by 17.7 ± 18.4%. This increase of muscle mass was associated with 23.7 ± 22.3% less fat mass. In the second part of this review, we discuss mechanisms by which muscle hypertrophy can affect fat mass and glucose homeostasis. We also discuss the potential use of hypertrophy-focused resistance training and muscle hypertrophy-stimulating drugs as treatments for people with overweight, obesity, and type 2 diabetes.

Skeletal muscle is where the majority of insulin-stimulated whole-body glucose elimination takes place under normal circumstances. A significant risk factor for metabolic diseases is high dietary fat consumption, which also increases stored fat mass. Natural solutions with anti-diabetic effectiveness and fewer side effects are becoming more popular as a result of the conventional pharmacological treatments' numerous negative side effects and high rates of secondary failure. Cannabis and a variety of culinary herbs and spices may include the naturally occurring sequiterpene β-caryophyllene. Among other things, it has antioxidant, anti-inflammatory, and anti-lipidemic properties. However, it is not yet known how β-caryophyllene affects the uptake and oxidation of glucose. Determining if β -caryophyllene has anti-diabetic properties in type-2 diabetes brought on by a high-fat diet was the objective of the current investigation. A sufficient dose of β-caryophyllene (200 mg/kg b.w.t., orally for 30 days) was given to type-2 diabetic rats fed a high-fat diet and given fructose as an inducer of diabetes to assess its anti-diabetic activity. The treatment of diabetes-induced rats with β -Caryophyllene restored the altered levels of blood glucose, serum insulin as well as the lipid parameters, oxidative stress markers, antioxidant enzymes. Our findings show that β-caryophyllene improves glycemia control by enhancing glucose absorption and oxidation in the skeletal muscle of type-2 diabetic rats. From the present findings, it is evident that β -caryophyllene can be used as an anti-diabetic drug.

Resistance training (RT) promotes skeletal muscle (Skm) hypertrophy, increases muscular strength, and improves metabolic health. Whether changes in fat-free mass (FFM; a surrogate marker of muscle hypertrophy) moderate RT-induced improvements in glucose homeostasis has not been determined, despite extensive research on the benefits of RT for health and performance. The aim of this meta-analysis is to examine whether RT-induced Skm hypertrophy drives improvements in glucose metabolism and to explore confounders, such as biological sex and training parameters. Random-effects meta-analyses were performed using variance random effects. Meta-regressions were performed for confounding factors depending on the heterogeneity (<i>I</i>²). Analyses from 33 intervention studies revealed significant within-study increases in FFM with a moderate effect size (within-studies: (effect size; ES = 0.24 [0.10; 0.39]; <i>p</i> = 0.002; <i>I</i>²= 56%) and a tendency for significance when compared with control groups (ES = 0.42 [-0.04-0.88]; <i>p</i> = 0.07). Within-study significant increases in glucose tolerance (2 h glucose: ES = -0.3 [-0.50; -0.11]; <i>p</i> < 0.01; <i>I</i>²= 43%; glucose area under the curve (AUC): -0.40 [-0.66; -0.13] <i>I</i>²= 76.1%; <i>p</i> < 0.01) and insulin sensitivity (ES = 0.38 [0.13; 0.62]; <i>I</i>²= 53.0%; <i>p</i> < 0.01) were also apparent with RT. When compared to control groups, there was no significant difference in 2 h glucose, nor in glucose AUC from baseline in RT intervention groups. Meta-regression analyses failed to consistently reveal increases in FFM as a moderator of glucose homeostasis. Other mixed-effect models were also unsuccessful to unveil biological sex or training parameters as moderators of FFM increases and glucose homeostasis changes. Although Skm hypertrophy and improvements in glycemic control occur concurrently during RT, changes in these variables were not always related. Well-controlled trials including detailed description of training parameters are needed to inform RT guidelines for improving metabolic health. Registration and protocol number (Prospero): CRD42023397362.

Skeletal muscle is a vital metabolic organ that regulates systemic energy homeostasis by coordinating glucose uptake, fatty acid oxidation, and amino acid metabolism. Its remarkable capacity for dynamic adaptation, termed metabolic flexibility, underpins physical performance and protects against metabolic diseases such as obesity, type 2 diabetes, and sarcopenia. This review provides an integrative synthesis of the molecular and signaling networks that orchestrate skeletal muscle metabolism, focusing on key regulators including insulin, AMPK, mTOR, and PGC-1α. We also examine how disruptions in these pathways lead to mitochondrial dysfunction, lipid dysregulation, and muscle wasting. We explore the therapeutic landscape across pharmacological, exercise-based, and nutritional interventions, emphasizing mitochondrial-targeted strategies and myokine-mediated communication as emerging modalities for restoring metabolic resilience. Additionally, we emphasize the growing importance of multi-omics technologies and inter-tissue communication in improving mechanistic understanding and advancing precision medicine. This review integrates mechanistic, translational, and clinical perspectives to underscore the importance of a systems-level approach to skeletal muscle metabolism. This approach is essential for developing targeted, multidimensional therapies aimed at enhancing metabolic health and extending healthspan.