INSULIN MODULATION OF NA+/LI+ COUNTERTRANSPORT - IMPACT ON HYPERTENSION AND DIABETES

The presence in human red blood cells (RBC) of insulin receptors led us to examine the role of insulin in the regulation of Na/Li and Na/H exchanges (EXCs) that we previously reported to have high activity in hypertension and diabetic nephropathy. To this end, red cells of fasted normotensive subjects were incubated for 1 h with insulin (0-100 muU/ml) to study the external Na+ activation at ten Na+ concentrations. We found that insulin increased twofold the K(m) for Na+ to activate Na/H and Na/Li EXC. Insulin also modulated the activity of Na/Li EXC in vivo because the K(m) for Na was significantly higher in the fed than in the fasted state. In the fed state the high K(m) for Na+ caused an incomplete saturation of Li+ efflux between 70 and 150 mM Na+ which led to underestimation of the V(max) and K(m). To correctly determine the V(max) and K(m) for the extracellular Na+ of Na/Li EXC it is critical to control the feeding status of cases and controls and to ensure complete saturation of the flux. We have studied the Na+-activation kinetics of Na/Li EXC in fed normoalbuminuric and nephropathic patients, raising Na+ concentrations up to 280 mM under isosmotic conditions to avoid cell shrinkage. Under such conditions, Na/Li EXC shows significantly higher K(m) and V(max) values in nephropathic than in normoalbuminuric patients; this finding may explain the different results obtained by others in fed diabetic patients. The kinetic alterations of Na/Li EXC are also shared by patients with insulin-resistant hypertension as well as by red blood cells of fasted control subjects exposed in vitro to insulin action. We propose, therefore, that hyperinsulinaemia and/or a hyper-responsiveness of this Na+ antiporter to insulin are linked to the phenotypic alterations of Na/Li EXC in diabetes and hypertension.