A B S T R A C T In this study we examined the effect of age and various age-related environmental factors on maximal glucose-stimulated insulin release by the intact perfused pancreas. Male Sprague-Dawley rats were maintained from 40 d to 12 mo of age on standard chow, or on a sucrose-rich or calorie-restricted diet. At 12 mo, studies were carried out on the isolated pancreas of each animal to determine maximal (300 mg/ml) glucose-stimulated insulin secretion. After these studies were completed, each pancreas was perfused with formalin fixative and processed for morphometric estimation of the mass of the endocrine pancreas. Data from these older animals were compared with data from 2-mo-old control rats. The results indicate that maximal glucose-stimulated insulin secretion per unit endocrine pancreas was markedly reduced in all three groups of 12-mo-old rats, and was only 25-33% of that of 2-mo-old rats. Thus, aging led to a decline in insulin secretion per beta cell that was not modifiable by environmental manipulation. On the other hand, environmental factors can influence the development of endocrine tissue within the pancreas, and in so doing, modify total pancreatic insulin secretion. The mass of the endocrine pancreas of 12-mo-old rats fed either sucrose or chow was between three and four times that of 2-mo-old control rats, and these older rats were able to maximally secrete as much insulin per total pancreas as the young rats. In contrast, the endocrine cell mass of the calorie-restricted rats had not enlarged to this extent, and the maximally stimulated perfused pancreas from these rats secreted less insulin. These data suggest that the aging animal, challenged in vivo to secrete insulin, can overcome the loss of the beta cell response by expanding its pancreatic
Insulin secretion and in vivo insulin action were quantified in nonobese and moderately obese subjects (approximately 35% above desirable body weight) with normal glucose tolerance. Insulin secretion was estimated by determining plasma insulin responses to a 75-g oral challenge, and in vivo insulin-stimulated glucose uptake by the euglycemic clamp technique. Plasma glucose levels of the two groups were identical during the glucose tolerance test, but the plasma insulin response was significantly greater (P less than 0.01) in the obese subjects. However, insulin-stimulated glucose utilization by the two groups was equal during the euglycemic clamp studies. These results were supported by the fact that degree of obesity correlated significantly with insulin response (r = 0.61, P less than 0.005), but not with insulin-stimulated glucose utilization (r = -0.25, P greater than 0.2). Thus, indirect evidence that moderately obese subjects were more insulin-resistant based on measurement of plasma insulin response was not supported by direct quantification of insulin action. One explanation for these findings is that the height of the plasma insulin response bears no relationship to loss of in vivo insulin action, but that seems unlikely in view of the fact that there was a significant correlation (r = -0.52, P less than 0.01) between these two variables in the group as a whole. Therefore, it appears that the hyperinsulinemia seen in obese individuals may not be a simple function of insulin resistance, and that ability of insulin to stimulate glucose utilization is not significantly impaired in moderately obese subjects with normal glucose tolerance. Alternatively, the degree of impairment in insulin action seen in these individuals is insufficient to be detected by the euglycemic clamp technique.
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