Influence of Aging on Hepatic and Peripheral Glucose Metabolism in Humans

Mechanisms of glucose intolerance with aging were studied by comparing the metabolic response to glucose ingestion in 10 young (20–23 yr) and 10 elderly (73–80 yr) normal men with the simultaneous application of the forearm and double-isotope techniques. The latter technique consisted of a primed-constant infusion of [3-³H]glucose followed by the administration of an oral glucose load (mean ± SE, 90.7 ± 0.7 g) containing [1-¹⁴C]glucose. Fasting plasma glucose and insulin concentrations were similar in young and elderly subjects, but in the elderly, glucose tolerance was markedly impaired. Although in the elderly the initial rise in insulin levels (∆, i.e., the incremental area under the curve) from 0 to 30 min was delayed (P < .02), the response from 0 to 45 min, 0 to 60 min, and thereafter equaled that in the young group, and from 90 to 240 min insulin concentrations in the elderly exceeded those in young subjects. Basal hepatic glucose output (HGO) was similar in young and elderly men (2.13 ± 0.10 and 1.97 ± 0.14 mg.· kg⁻¹ · min⁻¹, respectively). Similar proportional reductions in HGO from 0 to 270 min after glucose loading occurred in young (59.7 ± 10.3%) and elderly (50.3 ± 4.9%) subjects but was delayed in the elderly. Suppression of HGO was observed in the young 30 min after glucose ingestion (P < .02), but not before 60 min in the elderly subjects (P < .05). The systemic appearance of ingested glucose (0–270 min) was slowed with age (80.7 ± 3.1 and 66.9 ± 4.3% of the oral load in the young and elderly groups, respectively; P < .02). Initial increments in both total glucose disappearance (R_d) and forearm glucose uptake (FGU) from 0 to 60 min after glucose loading were decreased in the elderly (R_d, 4.1 ± 0.7 vs. 11.5 ± 1.3 g, P < .001; FGU, 17.2 ± 1.4 vs. 24.6 ± 2.5 md/dl forearm, P < .02). The overall increment (∆, 0–270 min) in R_d was reduced with age (47.2 ± 2.9 and 34.5 ± 3.6 g, P < .02 in the young and elderly, respectively), but the corresponding data for FGU were similar in the two groups. However, the ratios of ∆R_d and ∆FGU to the corresponding insulin responses (∆l), mainly reflecting peripheral insulin sensitivity, were reduced in the elderly (∆R_α/∆I, 1.3 ± 0.2 vs. 3.0 ± 0.6 U, P < .01; ∆FGU/∆I, 0.7 ± 0.1 vs. 1.2 ± 0.2 U, P < .05). Assessment of the relative contribution by the liver and peripheral tissues to age-related glucose intolerance suggested that the deficit in R_d was twofold greater than that due to the delayed fall in HGO. We conclude that age-related glucose intolerance 1) develops despite slowed glucose absorption; 2) is characterized by delays in the initial rise in insulin levels, the suppression of HGO, and the rise in peripheral glucose uptake; but 3) is predominantly the result of impaired peripheral glucose utilization. While the latter reflects increased tissue insulin resistance, the delayed fall in HGO may be mainly the consequence of delayed insulin secretion.