Involvement of the extracellular matrix and integrin signalling proteins in skeletal muscle glucose uptake

Abstract

Whole‐body euglycaemia is partly maintained by two cellular processes that encourage glucose uptake in skeletal muscle, the insulin‐ and contraction‐stimulated pathways, with research suggesting convergence between these two processes. The normal structural integrity of the skeletal muscle requires an intact actin cytoskeleton as well as integrin‐associated proteins, and thus those structures are likely fundamental for effective glucose uptake in skeletal muscle. In contrast, excessive extracellular matrix (ECM) remodelling and integrin expression in skeletal muscle may contribute to insulin resistance owing to an increased physical barrier causing reduced nutrient and hormonal flux. This review explores the role of the ECM and the actin cytoskeleton in insulin‐ and contraction‐mediated glucose uptake in skeletal muscle. This is a clinically important area of research given that defects in the structural integrity of the ECM and integrin‐associated proteins may contribute to loss of muscle function and decreased glucose uptake in type 2 diabetes.

Prediabetes-Associated Changes in Skeletal Muscle Function and Their Possible Links with Diabetes: A Literature Review

“…The chronic systematic inflammation associated with a high-fat diet [ 58 , 59 ] is suggested to heighten ECM protein synthesis and decrease ECM degradation, leading to increased deposition and ECM remodeling [ 60 , 61 ] ( Figure 5 ). The increased protein expression within the ECM is hypothesized to induce a physical barrier, impeding normal insulin action and glucose diffusion across the sarcolemma [ 55 , 62 ] ( Figure 5 ).…”

“…Another hypothesized factor that is suggested to be linked to the underlying mechanism of ECM-associated insulin resistance in DIO is that the muscle ECM may expand to disrupt vascular function and neovascular growth, provided there is close contact between the ECM and endothelium [ 62 ]. Nutrient delivery to the contracting muscle requires functional blood flow to establish sufficient glucose (during exercise) and insulin (post-exercise) availability to facilitate glucose uptake and glycogen resynthesis, respectively [ 61 ]. Hence, ECM vascular dysfunction and capillary rarefaction have been associated with insulin resistance and T2D [ 62 , 63 ].…”

“… Potential pathway linking integrins and their associated proteins in the regulation of glucose metabolism in skeletal muscle, adapted from Draicchio et al, 2022 [ 61 ]. ↓ = Decreased.…”