The Metabolic Clearance of Insulin and the Feedback Inhibition of Insulin Secretion Are Altered with Aging

Elevated basal and stimulated insulin levels have been previously demonstrated in elderly human subjects. To see whether these elevated insulin levels are due to alterations in either the metabolic clearance rate (MCR) for insulin or the feedback inhibition of insulin secretion, we have studied 14 elderly and 19 nonelderly subjects, mean age 70 ± 2 and 35 ± 2 yr, respectively. Fasting serum insulin and C-peptide levels were elevated in the elderly compared with the nonelderly, 17 ± 2 versus 11 ± 1 μU/ml, P < 0.01 and 0.95 ± 0.12 versus 0.47 ± 0.07 pmol/ml, P < 0.001. Euglycemic hyperinsulinemia created by insulin infusion rates of 15, 40, and 1200 mU/m²/min with glucose held constant resulted in steady-state serum insulin levels of 65 ± 4, 109 ± 8, and 11,316 ± 890 versus 34 ± 2, 96 ± 5, and 11,083 ± 1079 μU/ml in the elderly and nonelderly subjects, respectively. The MCR of insulin was decreased by 46% in the elderly compared with the nonelderly (10.1 ± 0.7 versus 18.7 ±1.4 ml/kg/min) at the insulin infusion rate of 15 mU/m²/min with no difference observed between the two groups at the higher insulin infusions. Steady-state suppression of C-peptide by exogenous insulin was similar, 73 ± 2% versus 72 ± 2% and 70 ± 3% versus 64 ± 5% in the nonelderly and elderly groups during the 15 and 40 mU/m²/min insulin infusions, respectively. However, 50% suppression was achieved within 30 min in the nonelderly group compared with 70 min in the elderly group during the low-dose infusion. While the maximal percent C-peptide suppression was comparable for the nonelderly and elderly, absolute C-peptide levels were increased at all times in the elderly during both infusions. In elderly subjects, a significant inverse relationship (r = −0.81, P < 0.01) was observed between the MCR of insulin and the total insulin response during a 7-h meal tolerance test. In summary, (1) aging is associated with a decrease in the MCR of insulin at low physiologic insulin levels. At higher serum levels, this effect is blunted, possibly due to a decreased role of hepatic uptake as a primary removal mechanism. (2) The decreased clearance rate of insulin and a defect in feedback inhibition of insulin secretion may also contribute to the hyperinsulinemia associated with aging.