Characterization of the insulin resistance of aging.

Abstract

A B S T R A C T To clarify the nature of the insulin resistance of aging we studied the dose response for insulin-induced glucose disposal and the binding of insulin to circulating monocytes in healthy young and old men. A total of 49 two-hour euglycemic insulin clamp studies were performed in 17 young and 10 old healthy nonobese subjects. While the old group had lower estimates of lean body mass and greater estimates of total body fat than the young group, these differences did not exceed 5% and did not reach statistical significance. Insulin was infused at 20 mU/M2 per min (young = 8, old = 5); 80 rnU/M2 per min (young = 13, old = 9); 200 mU/m2 per min (young = 9, old = 5). Increasing levels of hyperinsulinemia were associated with dose-dependent increases in steady-state glucose infusion rates in young and old. The maximal glucose infusion rates (milligrams per kilogram body weight per minute) were the same for young and old. However, the dose-response curve was shifted to the right in the old subjects. In the four individuals in each age group in whom studies were performed at each dose level, the Km was 54±14 sU/ ml in the young and 113±11 MU/ml in the old (P <0.02). Correction of glucose infusion rate for lean body mass had no effect on comparisons between age groups. These data indicate an age-associated decline in sensitivity of peripheral tissues to insulin without a change in maximal tissue responsiveness. Studies of insulin binding with 14 young and 9 old subjects indicated no effect of age on the insulin binding to receptors on circulating monocytes (young = 5.25±0.35; old = 6.22±0.53% of 1251-insulin bound/107 cells).These studies suggest that aging may be associated with a postreceptor defect in insulin action manifested by decreased whole-body tissue sensitivity to insulin without a change in tissue responsiveness.

Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential

“…Ageing promotes a state of insulin resistance primarily by blunting the action of insulin on the uptake of glucose in liver and peripheral tissues [1,3]. Levels of GCK, a rate-limiting enzyme in glycolysis, are reduced in liver of patients with type 2 diabetes mellitus and in diabetic animals [17,40].…”

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

“…Ageing is associated with a moderate decrease in peripheral insulin sensitivity in humans (De Fronzo 1981, Fink et al 1983, Rowe et al 1983) and rodents (Goodman et al 1983, Narimiya et al 1984, Nishimura et al 1988, Escrivá et al 1997. It is also associated with changes in body composition, especially in adipose tissue, making it difficult to evaluate the role of ageing by itself in the impairment of insulin action.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Numerous studies have linked aging with development of insulin resistance (Rowe et al ., 1983; O'Shaughnessy et al ., 1992; Sczelecki et al ., 2013). In accord with this, we report a marked reduction in the ability of insulin to phosphorylate/activate PKB at its two key regulatory sites Thr 308 (by 1.7‐fold; P  < 0.05) and Ser 473 (by 1.6 fold; P  < 0.05) in aged versus young soleus tissue (Fig.…”

“…Consequently, impaired responsiveness to insulin, termed insulin resistance, is a key component of the metabolic syndrome and a prelude to type 2 diabetes mellitus (T2DM). Importantly, a number of studies have now linked aging with development of insulin resistance in rodents as well as obese and nonobese individuals (Rowe et al ., 1983; O'Shaughnessy et al ., 1992). However, those factors which contribute to aging‐related insulin resistance and metabolic dysfunction remain poorly understood.…”