Muscle fuel uptake : a result of hormone and substrate interaction affecting regional blood flow

Substantial evidence now exists for two distinct vascular circuits within skeletal muscle. The nutritive capillary circuit directly nourishes skeletal myocytes, whereas another slightly larger set of non-nutritive vessels is probably interspersed within connective tissue of the septa and tendons. The fluctuation of flow between these two circuits allows sensitive control of nutrient delivery, which is often independent of changes in total flow. These innate flow patterns can be manipulated in vitro by the infusion of vasoactive agents into the perfused rat hindlimb. Certain vasoconstrictors (including serotonin) increase connective tissue flow at the expense of muscle capillary flow, denying access of glucose and insulin to the myocytes and inducing acute insulin resistance. In vivo, insulin itself causes increased flow to the muscle capillaries, and this insulin-mediated capillary recruitment is often blocked in insulin resistant states. This thesis primarily investigates the uptake of blood-borne metabolites during serotonin infusion in the perfused rat hindlimb, including glucose, fatty acids (FFA, both albuminbound and derived from chylomicron-triglyceride) and amino acids. In addition, the effect of elevated plasma FFA on the action of insulin to recruit capillaries was investigated in the euglycaemic, hyperinsulinaemic clamp in vivo, from the metabolism of 1-methyl xanthine. When the ratio of non-nutritive to nutritive flow was increased in the perfused rat hindlimb, the insulin-mediated uptake of glucose, Na-palmitate (albumin-bound) and aaminoisobutyric acid were reduced. Unlike the other fuels tested, with high non-nutritive flow the uptake of FFA from chylomicron-triglyceride hydrolysis was increased. It was therefore reasoned that non-nutritive flow was accessing a population of adipocytes within the muscle connective tissue, most likely in the perimysium. This perimysial adipose tissue is responsible for muscle 'marbling'. In the experiments determining the effect of FFA on insulin-mediated glucose uptake in vivo, FFA inhibited both insulin-mediated capillary recruitment and glucose uptake, thus elevated FFA in vivo were able to induce a state of insulin resistance, likely to be partly mediated by reduced capillary recruitment or nutritive flow. Accordingly, elevated FFA prevent perfusion of the nutritive capillaries to some degree, resulting in predominantly non-nutritive flow. This likely results in the reduced access and uptake of insulin, glucose, amino acids and albumin-bound fatty acids by myocytes, contributing to their buildup in the plasma. However, increased flow through the non-nutritive vessels of the muscle connective tissue, increased the exposure of lipoproteins to lipolytic enzymes. Thus, non-nutritive flow probably nourishes connective tissue adipocytes and increases the potential for fat accretion within the muscle. The results within this thesis offer important insights into nutrient access in skeletal muscle, in particular with elevated FFA in vivo. A reduction in nutritive flow, caused by elevated plasma FFA, is likely to reduce the uptake of glucose, amino acids and FFA into the myocytes, however increase fat deposition in the muscle connective tissue. This may contribute to the reduction in oxidative capacity, and accelerated 'marbling' and insulin resistance of human muscle,