Reduced Beta‐Cell Secretion and Insulin Hepatic Extraction in Healthy Elderly Subjects

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Abstract
One factor responsible for the altered carbohydrate metabolism in elderly subjects is impaired insulin release; however, difficulties in directly measuring insulin secretion have limited studies on pancreatic activity and on the contribution of the liver to insulin delivery. This study investigated beta‐cell performance and insulin hepatic extraction under dynamic conditions in normal elderly subjects. Two strictly comparable groups of 12 young controls (Y, 27 ± 1 (SE) years, 73 ± 3 kg) and 12 elderly men (E, 69 ± 2 years, 73 ± 3 kg) were chosen on the basis of normal OGTT and normal insulin sensitivity in order to investigate a “pure” age effect. The subjects underwent a 4‐hour frequently sampled intravenous glucose tolerance test (FSIGT) (dose 0.3 g/kg). Although no significant differences were found between the fasting levels of glucose and insulin (respectively: E: 89 ± 3 mg/dL versus Y: 87 ± 2, P > .1; and E: 5.0 ± 0.5 μU/mL versus Y: 6.8 ± 1.0, P > .05), basal C‐peptide was found to be lower in the old subjects: 0.43 ± 0.06 ng/mL versus 0.70 ± 0.11 (P < .025). The patterns of glucose and insulin during the FSIGT were similar, whereas C‐peptide concentration in E was systematically lower, suggesting a reduced insulin secretion. To verify this hypothesis, we analyzed FSIGT data with a mathematical model‐based method that provides a noninvasive direct measurement of the time courses of insulin secretion and hepatic extraction. Our results showed that age is associated with impaired beta‐cell secretion (the total amount of released hormone in 240 minutes was 4.8 ± 0.6 nM in E versus 7.5 ± 0.9 in Y, P < .025), and also that the hepatic extraction of the hormone was reduced in E compared to that of Y, yielding a total amount of insulin reaching the periphery in 240 minutes of 2.7 ± 0.2 nM, virtually the same as that of Y (2.9 ± 0.3, P > .3). We conclude that the normal peripheral insulin concentration observed during the FSIGT in our elderly subjects was due to a reduced hepatic insulin extraction that counterbalances the reduction in beta‐cell secretion.