Decrease in Glucose-Stimulated Insulin Secretion With Aging Is Independent of Insulin Action

Abstract

While the incidence of diabetes increases with age, a decrease in ␤-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n ‫؍‬ 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF؊). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S i hyper clamp ) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats (ϳ50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes. Diabetes 53

Young capillary vessels rejuvenate aged pancreatic islets

“…In particular, aged mice were insulin-resistant and glucoseintolerant, although intolerance was only observed when aged mice were forced to release more insulin; for example, after a higher glucose load (37,38). Our results concur with those of several previous studies (3,5,6,39) but contrast with studies reporting insulin secretory defects with age (1,2,4,8). The discrepancies in the literature may be explained by the confounding influence of the systemic environment (10).…”

“…S3 (50)]. A dysfunctional vasculature also helps explain why there is a discrepancy between in vitro data showing no deterioration of insulin secretion with age (5) and in vivo studies reporting lower plasma insulin levels in response to hyperglycemia in aged mice (6,10).…”

“…Age-dependent dysfunction of islets and the concomitant dysregulation of blood glucose levels increase the risk for type 2 diabetes (1), which in turn contributes to other age-related chronic diseases. In general, it has been assumed that aging causes an intrinsic dysfunction of the insulin-secreting beta cells through reduced proliferative capacity and/or defective insulin secretion (1)(2)(3)(4)(5)(6)(7)(8)(9). However, there have been numerous reports that age-dependent impairment of glucose homeostasis is not just a result of intrinsic, age-dependent dysfunction of islets but is also caused by systemic factors.…”

β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults

“…Elevated blood lipids are known to impair insulin secretion. 27,28 In the current study, we observed a statistically significant correlation between TGs, total cholesterol, and HDL with the basal derived measures of b-cell function. However, the physiological relevance of this observation is uncertain given the weak correlation.…”

Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

“…This result is consistent with experimental data from different species showing that aging per se is associated with a continuous decrease in basal insulin release. The magnitude of this effect is enough to develop abnormalities in glucose metabolism [36][37][38] . Body weight increased in the Control and MS rats; nevertheless, the difference between the groups was not significant even though the diet of the sucrose-fed rats was hypercaloric ( Table 1).…”