Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle

Abstract

Insulin has an exercise-like action to increase microvascular perfusion of skeletal muscle and thereby enhance delivery of hormone and nutrient to the myocytes. With insulin resistance, insulin's action to increase microvascular perfusion is markedly impaired. This review examines the present status of these observations and techniques available to measure such changes as well as the possible underpinning mechanisms. Low physiological doses of insulin and light exercise have been shown to increase microvascular perfusion without increasing bulk blood flow. In these circumstances, blood flow is proposed to be redirected from the nonnutritive route to the nutritive route with flow becoming dominant in the nonnutritive route when insulin resistance has developed. Increased vasomotion controlled by vascular smooth muscle may be part of the explanation by which insulin mediates an increase in microvascular perfusion, as seen from the effects of insulin on both muscle and skin microvascular blood flow. In addition, vascular dysfunction appears to be an early development in the onset of insulin resistance, with the consequence that impaired glucose delivery, more so than insulin delivery, accounts for the diminished glucose uptake by insulin-resistant muscle. Regular exercise may prevent and ameliorate insulin resistance by increasing "vascular fitness" and thereby recovering insulin-mediated capillary recruitment.

Fig. 1.

Proposed schematic blood flow patterns in muscle in vivo under basal conditions and following a physiological rise in plasma insulin. Insulin increases microvascular perfusion as a result of lowering the resistance in terminal arterioles and gives rise to increased perfusion of nutritive capillary beds. This is accompanied by a passive decrease in nonnutritive flow when bulk flow does not increase. Overall, there is an increase in perfused microvascular volume, as detected by contrast-enhanced ultrasound and laser Doppler flowmetry (LDF) and an average increase in available capillary surface area for 1-methylxanthine metabolism and glucose uptake. Insulin's increase in microvascular perfusion is also associated with an increase in vasomotion that is responsible for the rhythmic redistribution of blood flow throughout the muscle and which very likely contributes to the increase in microvascular perfusion. Wavelet analysis of the LDF signal reveals that insulin predominantly augments the myogenic component of vasomotion occurring at 0.1 Hz; hence, 3 different (random) patterns are shown to occur at intervals of 10 s. Perfused and unperfused capillaries are shown as solid and broken lines, respectively. During the increased rhythmic dilatation resulting from insulin, the arterioles allow greater penetration of blood flow into the microvasculature, analogous to “waves breaking further up the beach,” and more capillaries are perfused. In insulin resistance, insulin-mediated increase in microvascular perfusion and vasomotion are impaired, resulting in predominantly nonnutritive flow. With limited capillary recruitment and limited vasomotion, periodic blood flow to a capillary unit impacts more on glucose uptake than insulin signaling. Because the extraction fraction of glucose is high, interruption of blood flow leads to a decline in capillary blood glucose level sufficient to limit uptake. Periodic delivery of insulin may be sufficient to allow insulin signaling, which, once activated, continues unabated, increasing the demand for glucose that cannot be met.