Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing

Abstract

This review concludes that a sedentary lifestyle, obesity and ageing impair the vasodilator response of the muscle microvasculature to insulin, exercise and VEGF-A and reduce microvascular density. Both impairments contribute to the development of insulin resistance, obesity and chronic age-related diseases. A physically active lifestyle keeps both the vasodilator response and microvascular density high. Intravital microscopy has shown that microvascular units (MVUs) are the smallest functional elements to adjust blood flow in response to physiological signals and metabolic demands on muscle fibres. The luminal diameter of a common terminal arteriole (TA) controls blood flow through up to 20 capillaries belonging to a single MVU. Increases in plasma insulin and exercise/muscle contraction lead to recruitment of additional MVUs. Insulin also increases arteriolar vasomotion. Both mechanisms increase the endothelial surface area and therefore transendothelial transport of glucose, fatty acids (FAs) and insulin by specific transporters, present in high concentrations in the capillary endothelium. Future studies should quantify transporter concentration differences between healthy and at risk populations as they may limit nutrient supply and oxidation in muscle and impair glucose and lipid homeostasis. An important recent discovery is that VEGF-B produced by skeletal muscle controls the expression of FA transporter proteins in the capillary endothelium and thus links endothelial FA uptake to the oxidative capacity of skeletal muscle, potentially preventing lipotoxic FA accumulation, the dominant cause of insulin resistance in muscle fibres.

Development of microdialysis methodology for interstitial insulin measurement in rodents

“…Further, HE clamp activated increased ser1177 phosphorylation of eNOS in terminal arterioles, but not capillaries of lean Zucker rats, whilst decreasing eNOS ser1177 phosphorylation in terminal arterioles and capillaries of obese Zucker rats (Cocks et al, 2013). Thus, it seems highly likely that the impaired transcapillary transport of insulin in obese Zucker rats during HE clamp is at least partly dependent on reduced ability of arteriolar insulin receptors to induce dilatation (Wagenmakers et al, 2016). Our results give no direct insight into differences in the insulin sensitivity of TET between lean and obese rats.…”

“…The relatively modest increase in ISF insulin we measured in the obese rats during HE clamp could be explained by an impaired insulin-induced dilatation of resistance and terminal arterioles and consequent blunted increase in muscle blood flow and recruitment of additional capillary surface area for transcapillary insulin transport, and/or by an impaired increase in TET of insulin (see Barrett et al, 2011;Wagenmakers et al, 2016). Insulin causes dilatation by activating eNOS via increased ser1177 phosphorylation (see Munyiappa et al, 2006), while NO-induced nitrosylation of proteins is critically important for insulin-induced increase in TET (Wang et al, 2013).…”

Age-related differences in skeletal muscle microvascular response to exercise as detected by contrast-enhanced ultrasound (CEUS)

“…Such capillary rarefaction may limit maximal vascular conductance as well as the size (exchange surface) of the fiber adjacent capillary network within a single microvascular unit (MVU), which upon exercise is considered recruite fiber-adjacent exchange surface by several mechanisms (see Discussion) at increased red blood cell (rbc) and/or plasma flux depending on proximal vasomotion of terminal arterioles or, if at all present, pre-capillary sphincters, though human data on the microvascular architecture are still lacking [25]. Beside age and sedentary life style, the metabolic syndrome as an age-immanent factor itself may contribute to capillary rarefaction [26].…”

Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle

“…It is not known whether TUG regulates contractionstimulated glucose uptake in muscle, or even whether the same GSVs are mobilized by contraction and insulin stimulation (39,40). A second possibility is that inactivation of vasopressin results in dilation of terminal arterioles and helps to recruit microvascular units and increase capillary blood flow in stimulated muscles (41,42). Although this may normally be a localized action, systemic effects of reduced vasopressin could also result because of the mass of skeletal muscle and the enormous surface area of the T-tubule system (43).…”