Reduction of Insulin Clearance During Hyperglycemic Clamp: Dose-Response Study in Normal Humans

Abstract

Insulin secretion and clearance were studied in eight normal subjects who underwent hyperglycemie clamp studies at plasma glucose levels of 120, 225, and 300 mg/dl on three occasions. Insulin secretion rates were calculated during a 1-h baseline period and during 3 h of glucose clamping from a two-compartmental analysis of peripheral C-peptide concentrations with individual kinetic parameters derived after intravenous bolus injections of biosynthetic human C-peptide. At the 300-mg/dl clamp level, the insulin secretion rate increased to a value 9.9 ± 0.7 times that of basal at the end of the clamp (mean ± SE), whereas over the same period, the peripheral insulin concentrations increased to a greater extent, reaching a value 15.4 ± 1.2 times that of basal (P = .002). This greater relative increase in the insulin concentration in comparison with the corresponding insulin secretion rate suggests a reduction in the clearance of endogenous insulin. A similar trend was seen at the 225-mg/dl clamp level, but the relative increase in the insulin concentration (9.9 ±1.5 times that of basal) was not significantly higher than the relative increase in the insulin secretion rate (8.1 ± 0.5 times that of basal, P = .17). At the 120-mg/dl clamp level, the relative increases in the insulin secretion rate (2.7 ± 0.2 times that of basal) and the insulin concentration (2.4 ± 0.2 times that of basal) were similar (P = .26), indicating no reduction in endogenous insulin clearance during moderate stimulation of insulin secretion. In conclusion, a reduction in endogenous insulin clearance occurs during greater stimulation of insulin secretion at higher glucose-clamp levels. These data suggest that endogenous insulin clearance is nonlinear and shows evidence of saturation at high physiologic insulin concentrations.