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

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.