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.

Insulin Clearance in Obesity and Type 2 Diabetes

“…However, it is not clear whether the slower rise in interstitial insulin was due to impaired transendothelial transport or reduced muscle perfusion, or possibly (though unlikely) even faster interstitial insulin removal. Reduced muscle perfusion during a hyperinsulinemic clamp is often observed in people with obesity, and is due to both capillary rarefaction and impaired insulin-mediated vasodilation [ 155 , 156 , 157 , 158 ]. In addition, results from studies conducted in mice suggest that obesity results in ultrastructural alterations to the muscle capillary endothelium which delay endothelial insulin transport [ 159 ].…”

Type 2 Diabetes Complicated With Heart Failure: Research on Therapeutic Mechanism and Potential Drug Development Based on Insulin Signaling Pathway

“…And liraglutide can also reduce the NF-KB activation, thus reducing inflammatory cytokines ( Li et al, 2018 ). Importantly, GLP-1 may improve insulin sensitivity, glycemic control, and endothelial function, increase muscle microvascular perfusion, and stimulate angiogenesis, and these effects are retained in IR ( Hagve et al, 2019 ; Love et al, 2020 ).…”

“…At present, GLP-1 agonists have been used for the treatment of chronic IR. They have beneficial cardiovascular effects for T2DM patients and are very suitable for T2DM patients with cardiomyopathy ( Hagve et al, 2019 ; Love et al, 2020 ). Intervention of GLP-1 RA to CRTd therapy in diabetic patients significantly improved LVEF and the 6 min walking test, reduced the arrhythmic burden, and reduced hospital admissions for heart failure worsening by increasing the CRTd responder rate ( Sardu et al, 2018 ).…”

The Effects of Curcuma longa in Insulin Resistance

“…Insulin resistance (IR) is a consequence of abnormal functioning and signaling of insulin receptors, an excessively high level of insulinbinding antibodies, or an abnormal insulin molecule structure [1]. This condition manifests impaired insulin action in all insulin target organs and tissues as skeletal muscle, cardiac muscle, liver, adipose tissue, the brain as well as the vasculature [2,3]. Therefore it is clinically seen as metabolic stress that leads to high blood glucose, obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), and cardiovascular diseases (CVD) [1,4,5].…”

“…The usual metabolism is disturbed in the state of IR due to elevated plasma free fatty acids and inflammatory cytokines, like tumor necrosis factor-alpha (TNFα), which induces microvascular IR, seen in obesity and T2DM [2].Furthermore, the p110α, catalytic subunit of phosphatidylinositol 3-kinase, mediates the cellular responses to insulin [5,6]. Its inhibition blocks insulin signaling, leading to glycogen breakdown in the liver and decreased glucose uptake in skeletal muscle and adipose tissue, resulting in a state of IR, hyperglycemia, and hyperinsulinemia [3].…”