Muscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within

Jia Liu,Zhenqi Liu

doi:10.3390/ijms20030562

Abstract

Insulin is a vascular hormone and regulates vascular tone and reactivity. Muscle is a major insulin target that is responsible for the majority of insulin-stimulated glucose use. Evidence confirms that muscle microvasculature is an important insulin action site and critically regulates insulin delivery to muscle and action on myocytes, thereby affecting insulin-mediated glucose disposal. Insulin via activation of its signaling cascade in the endothelial cells increases muscle microvascular perfusion, which leads to an expansion of the endothelial exchange surface area. Insulin’s microvascular actions closely couple with its metabolic actions in muscle and blockade of insulin-mediated microvascular perfusion reduces insulin-stimulated muscle glucose disposal. Type 2 diabetes is associated with chronic low-grade inflammation, which engenders both metabolic and microvascular insulin resistance through endocrine, autocrine and paracrine actions of multiple pro-inflammatory factors. Here, we review the crucial role of muscle microvasculature in the regulation of insulin action in muscle and how inflammation in the muscle microvasculature affects insulin’s microvascular actions as well as metabolic actions. We propose that microvascular insulin resistance induced by inflammation is an early event in the development of metabolic insulin resistance and eventually type 2 diabetes and its related cardiovascular complications, and thus is a potential therapeutic target for the prevention or treatment of obesity and diabetes.

Highlights

Diabetes prevalence continues to increase at an alarming rate and has become the most common and costly chronic disease worldwide
Insulin’s actions in the muscle microvasculature has garnered much attention in the past decade as it is in the muscle microvasculature that the exchanges of nutrients, oxygen, and hormones such as insulin between the plasma compartment and muscle interstitium take place and we and others have convincingly demonstrated that insulin resistance in the muscle microvasculature closely couples with impaired insulin-stimulated glucose use in muscle [8,9,10]
While both the endocrine effects of the circulating cytokines and FFAs and the paracrine effects of myokines from myocytes and cytokines and FFAs from muscle fat depots are important in microvascular inflammation and insulin resistance, the role of perivascular adipose tissue (PVAT), adipose tissues surrounding the small blood vessels, on microvascular function and insulin sensitivity must be emphasized [99]

Summary

Introduction

Diabetes prevalence continues to increase at an alarming rate and has become the most common and costly chronic disease worldwide. Mounting evidence has confirmed that insulin, in addition to stimulating tissue glucose uptake and use [6], is a vascular hormone that regulates vascular tone and tissue perfusion [7]. Endothelial dysfunction, characterized by abnormal vascular reactivity, increased production of reactive oxygen species (ROS), decreased nitric oxide (NO) bioavailability, and altered barrier function, is increasingly recognized as an early defect that leads to impaired vascular insulin responses and a contributing factor to the pathogenesis of T2DM and its cardiovascular complications [11,12,13]. We discuss available evidence on the regulation of insulin actions in muscle microvasculature in health and T2DM and the potential role of microvascular inflammation in the development of endothelial and metabolic insulin resistance in muscle

Vasculature is a Target for Insulin Action

Microvasculature Critically Regulates Insulin Action in Muscle

Findings

Conclusions