Hyperproinsulinaemia in elderly subjects: evidence for age-related pancreatic beta-cell dysfunction.

We investigated whether pancreatic beta-cell dysfunction has a role in the pathogenesis of glucose intolerance in the elderly by comparing plasma glucose, immunoreactive insulin, C-peptide and proinsulin concentrations during a 100-g oral glucose load in six healthy older male volunteers [aged 69 (65.9-74.9) years; median (95% confidence limits)] and seven young male controls [aged 24.0 (21.9-26.3) years]. Fasting and integrated concentrations of glucose and C-peptide were similar in the elderly and young. Although fasting, insulin and proinsulin levels were similar, integrated insulin (P=0.05) and proinsulin (P<0.05) concentrations were higher in the elderly than in controls. Insulin resistance, measured as homeostasis model assessment, was greater (P<0.05) in the elderly than in controls. Elderly men had greater molar ratios of integrated insulin:C-peptide (P<0.05) and proinsulin:C-peptide (P<0.01) but their respective fasting molar ratios were similar when compared with controls. Pancreatic beta-cell secretion in older subjects, as assessed by C-peptide concentrations, was inappropriately low in the presence of insulin resistance. Their post-prandial 'hyperinsulinaemia' is probably due to a combination of hyperproinsulinaemia and reduced metabolic clearance of insulin. Older subjects had disproportionately high proinsulin to C-peptide levels, suggesting pancreatic beta-cell dysfunction. These results are consistent with the notion that decreased insulin sensitivity and pancreatic beta-cell dysfunction may predispose the elderly to glucose intolerance.