GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes

Abstract

Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.

Keywords: GLP-1; cardiac muscle; endothelium; insulin resistance; microvascular perfusion; skeletal muscle; 内皮; 微血管灌注; 心肌; 胰岛素抵抗; 骨骼肌.

FIGURE 1

Muscle microvasculature regulates tissue perfusion, health, and function

FIGURE 2

Muscle microvascular insulin resistance and capillary rarefaction in type 2 diabetes mellitus

FIGURE 3

Muscle oxygen demand and supply mismatch in type 2 diabetes mellitus

FIGURE 4

Microvascular actions of glucagon-like peptide (GLP)-1 and GLP-1R agonists in type 2 diabetes mellitus. VEGF, vascular endothelial growth factor