Unlocking the secrets of exercise: A pathway to enhanced insulin sensitivity and skeletal muscle health in type 2 diabetes

Abstract

1. •

   Exercise impacts skeletal muscle and systemic metabolism, yet understanding the complex molecular mechanisms behind these effects remains a key research challenge.

2. •

   Mapping the molecular effects of exercise with advanced “omics” can advance our understanding of muscle function and metabolism.

3. •

   Exercise holds promise for managing and preventing type 2 diabetes, emphasizing the need for more research on individualized training and its molecular effects.

Fig. 1

Activation of energy sensing pathways can by-pass defects in insulin signaling in skeletal muscle from people with type 2 diabetes. Glucose uptake is a tightly regulated process that is influenced by insulin- and exercise-dependent signaling pathways. In response to a meal, the rise in the systemic level of insulin lowers the glucose concentration by activating cellular signaling events via a canonical protein phosphorylation cascade involving IRS1, PI3K and AKT, that promotes GLUT4 translocation to the plasma membrane to mediate glucose uptake and metabolism. In people with type 2 diabetes, insulin signaling, and glucose transport is impaired, giving rise to hyperglycemia. Notably, exercise mediates an insulin-independent increase in GLUT4 translocation and enhances insulin sensitivity. While the molecular transducers of exercise-mediated glucose transport are still under investigation calcium- and ATP-sensitive kinases (CaMKII and 5′, AMPK, respectively) play a role. Insulin and exercise-mediated signaling pathways can converge at the level of TBC1D1 and TBC1D4 to promote GLUT4 translocation and glucose uptake. Thus, activation of energy sensing pathways can by-pass defects in insulin signaling in skeletal muscle from people with type 2 diabetes. In addition to the acute effects of exercise/muscle contractions on glucose uptake, regular exercise training has a genomic effect to remodel skeletal muscle and boost the abundance of proteins that confer improved insulin sensitivity. Figure schematic was created with BioRender.com. AKT = protein kinase B; AMPK = AMP-activated protein kinase; CaMKII = Ca2 +/calmodulin-dependent protein kinase; GLUT4 = glucose transporter 4; IRS1 = insulin receptor substrate 1; PI3K = phosphatidylinositol 3-kinase; TBC1 = Tre-2/BUB2/cdc 1; TBC1D1 = TBC1 Domain Family Member 1; TBC1D4 = TBC1 Domain Family Member 4.