The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action

Abstract

Evidence suggests that insulin delivery to skeletal muscle interstitium is the rate-limiting step in insulin-stimulated muscle glucose uptake and that this process is impaired by insulin resistance. In this review we examine the basis for the hypothesis that insulin acts on the vasculature at three discrete steps to enhance its own delivery to muscle: (1) relaxation of resistance vessels to increase total blood flow; (2) relaxation of pre-capillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular recruitment); and (3) the trans-endothelial transport (TET) of insulin. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. However, there is controversy as to whether this occurs at physiological concentrations of, and exposure times to, insulin. The microvasculature is recruited more quickly and at lower insulin concentrations than are needed to increase total blood flow, a finding consistent with a physiological role for insulin in muscle insulin delivery. Microvascular recruitment is impaired by obesity, diabetes and nitric oxide synthase inhibitors. Insulin TET is a third potential site for regulating insulin delivery. This is underscored by the consistent finding that steady-state insulin concentrations in plasma are approximately twice those in muscle interstitium. Recent in vivo and in vitro findings suggest that insulin traverses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET. Thus, muscle insulin delivery, which is rate-limiting for its metabolic action, is itself regulated by insulin at multiple steps. These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation.

Figures

Fig. 1

A euglycaemic-hyperinsulinaemic clamp (1 mU min-1 kg-1 insulin infusion) is initiated at time 0. The three lines illustrate the model-based time-course estimates for insulin concentration in three compartments (compartment 1, plasma; compartment 2, splanchnic bed; compartment 3, muscle). The shaded area illustrates the time-dependent changes in the rate of exogenous glucose infusion required to maintain euglycaemia during steady-state hyperinsulinaemia. Adapted from [1]

Fig. 2

A microvascular unit within muscle is composed of a terminal arteriole that feeds 12-20 capillaries and a draining vein. The capillary is the principal site of nutrient/hormone exchange between the muscle interstitium and blood. For insulin (I), the fraction that enters muscle interstitium may either be returned to the systemic circulation, through lymphatic drainage through reverse movement back across the EC (against a concentration gradient), or be taken up by the myocyte. via the insulin receptor (IR) and ultimately degraded

Fig. 3

The effect of increasing blood flow on the uptake of glucose and insulin by muscle tissue for post-absorptive and steady-state hyperinsulinaemic conditions. For glucose, after an overnight fast there is a very small concentration gradient between the arterial and venous ends of a capillary bed. Increasing the rate of blood flow will only minimally raise the mean capillary glucose concentration and will have a negligible effect on glucose uptake. In contrast, under high insulin conditions the glucose concentration gradient between arterial and venous plasma can reach 2-3 mmol/l. Increasing delivery of glucose from the arterial system by increasing flow could therefore substantially increase the mean capillary plasma glucose concentration and have a significant impact on trans-endothelial glucose uptake. For insulin, the circumstances that generate a concentration gradient are different. After an overnight fast the concentration of insulin in plasma draining skeletal muscle is 10-15% lower than that in arterial plasma. Increasing flow might be expected to produce a modest increase in mean capillary plasma insulin concentration and enhance insulin TET. When insulin concentrations are raised the total insulin uptake increases. However, the extraction fraction declines to approximately 7% at insulin concentrations of ~250 pmol/L (indicating that delivery alone is not determining insulin uptake) and any increases in flow would be predicted to have a minimally effect insulin TET

Fig. 4

Effect of increasing microvascular volume on the potential uptake of insulin or glucose by muscle tissue based on Fick's law. The architecture of the microvascular unit is shown within the myofibre bundle to the left of the white arrow. The terminal arteriole supplies a small network of capillaries that run longitudinally along the myofibre. The principal surface area available for nutrient exchange is within the endothelial surface of the capillary bed. In the presence of insulin the terminal arteriole relaxes and additional capillaries within the microvascular unit are more richly perfused. Using the contrast ultrasound method this is seen as an increase in microvascular volume

Fig. 5

The four potential pathways by which insulin may move from the vascular lumen to the interstitium of muscle. The possibility of movement via a paracellular pathway (1) through the junctional structure appears to be unlikely in either the arteriole or capillary bed within skeletal muscle, which has a continuous endothelium. This pathway may be open in small venules, or under circumstances where the endothelium is rendered `leaky'. Insulin could bind to a receptor anywhere on the plasma membrane, leading to internalisation, diffusion to the anti-luminal membrane of the EC and subsequent release into the muscle interstitium (2). Caveolae may allow the passage of insulin as part of a bulk fluid movement in the setting of vesicular trafficking (3). Because of the low plasma concentration of insulin, movement in this manner would be a relatively rare event. Caveolae may also function as areas of insulin receptor localisation. This would facilitate receptor-mediated association of insulin with transporting caveolae and increase the probability of insulin transiting the endothelium as part of a vesicular trafficking process (4)