Amylin influences insulin-stimulated glucose metabolism by two independent mechanisms

The effects of amylin on fiber type-specific muscle glucose metabolism under hyperglycemic (10 mmol/l) and hyperinsulinemic (2.1 nmol/l) conditions were investigated using a rat hindlimb perfusion system. Amylin concentration ranged from 1 to 100 nM. Efficacy for inhibition of glucose uptake traced with 2-deoxyglucose by amylin was demonstrated in all three fiber types. The incorporation of 2-deoxy-[H-3]glucose tracer decreased from control values by 41% in fast oxidative (FO), 36% in fast glycolytic (FG), and 37% in slow oxidative (SO) muscle with 100 nM amylin. Amylin increased intracellular glucose 6-phosphate (G-6-P), and G-6-P was negatively correlated with 2-deoxyglucose uptake in both FO (r = -0.65; P < 0.01) and FG (r = -0.53; P < 0.01) muscle. Muscle glycogen concentration increased under control conditions and decreased in the presence of 100 nM amylin. Lactate arteriovenous efflux across the hindlimb increased significantly above control with 100 nM amylin (5.03 +/- 0.81 to 11.28 +/- 0.94 mu mol . g(-1) . h(-1)). Adenosine 3',5'-cyclic monophosphate (cAMP) increased in FO and FG muscle with amylin. Salmon calcitonin-(8-32), an amylin antagonist, ameliorated the effect of amylin on all responses other than 2-deoxyglucose uptake and G-6-P concentration. These results suggest that amylin may work through at least two independent mechanisms, a cAMP-mediated effect on glycogen metabolism and a non-cAMP-mediated inhibition of glycolysis.