Microvascular dysfunction: An emerging pathway in the pathogenesis of obesity-related insulin resistance

Abstract

The prevalence of type 2 diabetes mellitus (T2DM) and its major risk factor, obesity, has reached epidemic proportions in Western society. How obesity leads to insulin resistance and subsequent T2DM is incompletely understood. It has been established that insulin can redirect blood flow in skeletal muscle from non-nutritive to nutritive capillary networks, without increasing total blood flow. This results in a net increase of the overall number of perfused nutritive capillary networks and thereby increases insulin-mediated glucose uptake by skeletal muscle. This process, referred to as functional (nutritive) capillary recruitment, has been shown to be endothelium-dependent and to require activation of the phosphatidylinositol-kinase (PI3K) pathway in the endothelial cell. Several studies have demonstrated that these processes are impaired in states of microvascular dysfunction. In obesity, changes in several adipokines are likely candidates to influence insulin signaling pathways in endothelial cells, thereby causing microvascular dysfunction. Microvascular dysfunction, in turn, impairs the timely access of glucose and insulin to their target tissues, and may therefore be an additional cause of insulin resistance. Thus, microvascular dysfunction may be a key feature in the development of obesity-related insulin resistance. In the present review, we will discuss the evidence for this emerging role for the microcirculation as a possible link between obesity and insulin resistance.

Determinants of microvascular function in individuals with and without type 2 diabetes

“…Microvascular endothelial dysfunction is an important underlying mechanism of common diseases which are (partly) of microvascular origin, such as heart failure, (lacunar) stroke, depression, cognitive decline, retinopathy, chronic kidney disease, and neuropathy [5][6][7][8][9][10]42,61 . Therefore, it is important to unravel determinants of microvascular (dys)function in the general population and specifically in individuals with T2D (who are at increased risk of developing these diseases), as it may highlight targets for the prevention of microvascular diseases.…”

“…Hyperglycemia may impair microvascular function, via the formation of advanced glycation end products and/or reactive oxygen species, both of which can lead to impaired nitric oxide bioavailability, by quenching endothelium-derived nitric oxide and directly inhibit nitric oxide synthase activity [55][56][57][58][59][60] . However, a vicious circle may exist between hyperglycemia and microvascular endothelial function 61 , as microvascular endothelial function can cause hyperglycemia by impairing insulin secretion 62 and/or by impairing the timely access of glucose and insulin to their target tissue 63 .…”

“…However, due to endothelial cell heterogeneity (i.e. endothelial cells differ remarkably in function and structure depending on their localization), this does not necessarily imply that microvascular endothelial function is affected similarly 66,67 .The pathophysiology of common diseases such as heart failure, (lacunar) stroke, depression, cognitive decline, retinopathy, chronic kidney disease, and neuropathy is thought to involve microvascular endothelial dysfunction [5][6][7][8][9][10]42,61 . As these diseases, which are (in part) of microvascular origin, affect both individuals with and without T2D, it is important to elucidate determinants of microvascular endothelial function in the general population.…”

“…The pathophysiology of common diseases such as heart failure, (lacunar) stroke, depression, cognitive decline, retinopathy, chronic kidney disease, and neuropathy is thought to involve microvascular endothelial dysfunction [5][6][7][8][9][10]42,61 . As these diseases, which are (in part) of microvascular origin, affect both individuals with and without T2D, it is important to elucidate determinants of microvascular endothelial function in the general population.…”

“…This is important, as it may help to unravel the etiology of (pre)diabetes-associated microvascular endothelial dysfunction. Microvascular endothelial dysfunction is thought to be involved in the pathophysiology of numerous common diseases such as heart failure, (lacunar) stroke, depression, cognitive decline, retinopathy, chronic kidney disease, and neuropathy [5][6][7][8][9][10]42,61 . The ultimate goal is to find targets for strategies to prevent or reduce these common diseases, which frequently occur in individuals with T2D 62 .…”