02Whole.pdf (1.18 MB)
Hemodynamic and metabolic changes in muscle in relation to insulin action
thesisposted on 2023-05-27, 15:33 authored by Mahajan, H
It is widely accepted that insulin increases total blood flow to muscle. This lab has demonstrated in a number of studies that insulin also recruits capillary flow in muscle by an unknown mechanism. This hemodynamic response to insulin is linked to its metabolic effects as it increases the access of glucose and insulin to muscle cells. It is possible that insulin may act on endothelial or vascular smooth muscle cells to release a vasodilator (NO, adenosine, prostaglandins or endothelium-dependent hyperpolarizing factor) causing capillary recruitment. The aim of this thesis was to look at possible mechanisms underlying insulin's hemodynamic and metabolic action in muscle. This was examined during hyperinsulinemic euglycemic clamps in anesthetized rats. To test the agents affecting insulin action at the local muscle level, a novel technique was developed wherein the epigastric artery (a branch of the femoral artery) was cannulated and test substances were infused into one leg to avoid any systemic effects; the contralateral leg served as control. Femoral artery blood flow and metabolism of exogenously infused 1-methylxanthine (1- MX) as an index of capillary recruitment were measured in both legs for comparison. There is some evidence that insulin's hemodynamic action on muscle is mediated by nitric oxide-cGMP pathway. T-1032, a phosphodiesterase-5 inhibitor, was infused systemically, to see whether NO-dependent insulin-mediated capillary recruitment in muscle could be enhanced by inhibiting cyclic GMP degradation. T-1032, however, produced an acute insulin resistance. In addition, NO production was enhanced using two endothelium-dependent nitro-vasodilators methacholine and bradykinin. Methacholine infused systemically caused MAP to fall and blood glucose to rise, resulting in a lower GIR. Local infusion of methacholine but not bradykinin in one leg significantly increased capillary recruitment and insulin-mediated glucose uptake. Furthermore, a NOS inhibitor, L-NAME, infused locally in one leg had no effect on insulin action in muscle. Systemic L-NAME infusion partially blocked the insulinmediated capillary recruitment without any effect on insulin-mediated glucose uptake. On the other hand, local infusion of calcium-dependent potassium channel (KCa) blocker TEA in one leg, almost completely blocked insulin's effects on capillary recruitment and attenuated insulin-mediated glucose uptake. Collectively these findings indicate that the action of insulin on muscle is the net result of a combination of effects. There is evidence for involvement of systemic NO and local KCa channels in insulin-mediated capillary recruitment. Hence, modulation of either of these components could potentially alter the hemodynamics and metabolism in muscle.
Rights statementCopyright 2005 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).