Does skeletal muscle account for major glucose disposal and increase uptake during contraction?

Skeletal muscle is a central regulator of circulating glucose, and its ability to take up glucose during contraction has direct relevance to metabolic health, including in older adults and in insulin-resistant states.

Clinical and physiological evidence

• Human hyperinsulinemic–euglycemic clamp studies, supported by leg arterial–venous balance measurements, indicate that skeletal muscle accounts for approximately 70–80% of whole-body insulin-stimulated glucose disposal; some estimates exceed 80%, depending on study methods and clamp conditions.
• This proportion is state-dependent. After meals, tracer studies suggest that skeletal muscle and the splanchnic bed may each dispose of about 30% of meal-derived glucose, while the brain accounts for roughly 20%. Muscle nevertheless remains a major glucose-using tissue.
• In type 2 diabetes, impaired muscle glucose transport, phosphorylation, and glycogen synthesis contribute to hyperglycemia. Under postprandial-like hyperglycemic–hyperinsulinemic conditions, muscle glycogen synthesis has been reported to be approximately 50% lower in diabetes.

Contraction-mediated glucose uptake

• Muscle contraction increases glucose uptake without requiring insulin signaling. It promotes translocation of GLUT4 glucose transporters from intracellular stores to the sarcolemma and T-tubules, increasing glucose transport into active muscle.
• Insulin and contraction both enhance GLUT4 trafficking, but they do so through overlapping rather than identical signaling routes. Thus, contraction can facilitate muscle glucose disposal when insulin action is impaired.

Mechanistic interpretation

• AMPK, activated by contraction-associated energy stress, contributes importantly to this response, but is not the sole mechanism: experimental AMPK loss reduces rather than abolishes contraction-stimulated uptake.
• AMPK-associated TBC1D1/4 signaling and Rac1 provide parallel support for GLUT4 trafficking. In mouse muscle lacking AMPK and TBC1D1/4 signaling, Rac1 inhibition eliminated residual contraction-stimulated uptake.

Bottom line

• The claim is strongly supported: skeletal muscle is a major site of glucose disposal, and contraction can increase its glucose uptake through insulin-independent, multi-pathway GLUT4-trafficking mechanisms.