Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 ± 0.9 yr n = 23)–and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 ± 0.9 ml · kg−1 · min−1P < 0.05)–and compared with these responses in nondiabetic young subjects (23.8 ± 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P < 0.001) in the elderly (plasma glucose recovery rate 29.4 ± 2.2 vs. 42.7 ± 5.0 μM/min, P < 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 ± 1.1 vs. 17.2 ± 1.1 μmol · kg−1 · min−1; P < 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 ± 122 vs. 940 ± 72 pM, P < 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 ± 6 vs. 66 ± 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly. Training had no effect on glucose recovery from or neuroendocrine responses to hypoglycemia in the elderly. Thus, we conclude that there is an age-associated impairment of glucose counterregulation best attributed to decreased insulin clearance, reduced glucagon secretion, or both. Delayed epinephrine secretion may also contribute. These are not the result of a sedentary life-style.

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