Pathogenesis of Age-Related Glucose Intolerance in Man: Insulin Resistance and Decreased β-Cell Function*

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Abstract
To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18−36 yr old) and 10 older (57−82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values.Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: S1, the insulin sensitivity index; φ1 and φ2, indices of first and second phase β-cell responsiveness to glucose; n, fractional insulin clearance, and SG, a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated β-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate, 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P < 0.01). This intolerance was the result of both a β-cell defect and insulin resistance. The potentiation slope (r = -0.67; P < 0.02) and φa (r = -0.47; P < 0.05) both decreased with age. In addition, S1 in the older group was diminished 63% (2.4 vs. 6.5; 10-4 min-1/μU/ml; P < 0.001) and was unrelated to differences in body fat. No differences were found in either n or SG. These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both β-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance,