Aging is associated with hyperinsulinemia, but reports vary on the contributions of altered insulin clearance versus insulin secretion to this phenomenon. To elucidate the role of insulin secretion in the hyperinsulinemia of aging, 10 elderly (age 66 ± 4 yr, body mass index 25 ± kg/m2) and 8 young (age 30 ± 5 yr, body mass index 24 ± 3 kg/m2) subjects were studied to determine rates of insulin secretion in response to fasting, mixed meals, and intravenous glucose administration. Insulin secretion was determined with a two-compartment model based on individual C-peptide kinetic parameters derived after bolus injection of biosynthetic human C-peptide. Basal insulin secretion rates were increased in elderly subjects (82.5 ± 9.0 vs. 62.8 ± 6.1 pmol · min−1 · m−2; P < .05). This was reflected in elevated serum insulin levels in elderly subjects (62.8 ± 10.1 vs. 41.1 ± 5.0 pM, P < .05). During a 24-h mixed-meal profile, elderly subjects had an increase in their glucose response (P < .01 by analysis of variance [ANOVA]) and total insulin secretion (261 ± 28 vs. 195 ± 22 nmol · 24 h−1 · m−2; P < .05) compared with young subjects. However, the relative total increases in both glycemia and insulin secretion, calculated as a function of basal levels, were similar between the groups (both NS). To experimentally control for differences in glycemia, both groups underwent a 16.8-mM hyperglycemic clamp and a stepped intravenous glucose infusion to match glycemia. Under these steady-state and dynamic conditions, insulin secretion profiles were nearly identical (NS by ANOVA). However, during the stepped infusion, relative insulin secretion in elderly subjects, calculated as a function of basal levels, was significantly lower than insulin secretion in young subjects (change from basal 209 vs. 322%; P < .05). These changes could not be accounted for by relative differences in glycemia. To determine if diminished insulin clearance is present and contributes to hyperinsulinemia, endogenous insulin clearance was calculated from the ratio of total area under the insulin-secretion rate curve to the peripheral insulin-concentration curve during basal and mixed-meal conditions. Basal endogenous insulin clearance was 1.38 ± 0.22 L · min−1 · m−2 in elderly subjects vs. 1.34 ± 0.14 L · min−1 · m−2 in young subjects (NS). In response to mixed meals, endogenous insulin clearance was also similar between groups (0.813 ± 0.100 vs. 0.876 ± 0.048 L · min−1 · m−2 in elderly and young subjects, respectively; NS). In conclusion, physiological hyperinsulinemia of aging is caused by increased insulin secretion rather than decreased insulin clearance as demonstrated under basal conditions and in response to mixed meals. Under physiological conditions, the insulin-secretion response is appropriate for the prevailing level of glucose. However, although the β-cell secretory response to intravenous glucose is normal in absolute terms, it is disproportionately low when relative differences in glycemia and insulin sensitivity between elderly and young subjects are considered and may indicate reduced insulin secretion with aging under such conditions.

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