Increased susceptibility to insulin resistance associated with abdominal obesity in aging rats

Objective: Recent data have suggested that the insulin resistance observed with aging may be more related to adiposity than aging per se. We asked whether the insulin resistance observed in aged rats was comparable (both in magnitude and location) to that of fat-fed rats. Research Methods and Procedures: We performed hyperinsulinernic (5 mU/min per kg) euglycemic clamps with tracer in conscious, 6-hour fasted young (YL), fat-fed young (YF), fat-fed old (OF), and calorically restricted old (OL) rats. Results: Intraabdominal fat measurements showed that OF and YF rats were more obese than YL (p <= 0.001; YF > OF > YL). Caloric restriction not only prevented agerelated obesity but also reduced the ratio of intraabdominal fat to lean body mass (LBM) compared with YL (OL: 0.59 +/- 0.05 vs. YL: 1.07 +/- 0.04; p = 0.017). Despite similar incremental insulin, YF and OF rats required 40% less infused glucose to maintain euglycemia than YL and OL rats (p < 0.001). Insulin-stimulated glucose uptake (Si-Rd: Delta Rd/(Delta Insulin X Glucose(ss)) was impaired in OF rats (OF: 14.03 +/- 1.79 vs.YL: 23.08 +/- 1.87 X 10(3) dL/min X kg LBM per pM; p = 0.004) and improved in OL rats (29.41 +/- 1.84 X 10(3) dL/min X kg LBM per pM; p = 0.031) compared with YL. Despite greater obesity, YF rats did not exhibit lower Si-RD compared with OF rats (p = 0.58). In contrast, the ability of insulin to suppress endogenous glucose production (EGP; Si-EGP: Delta EGP/(Delta lnsulin X Glucosess) was not impaired in OF rats (OF vs. YL; p 0.61) but was markedly impaired in YF rats by similar to 75% (1.72 +/- 0.66 X 10(3) dL/min X kg per pM; p = 0.013). Surprisingly, separate regression analysis for old and young animals revealed that old rats exhibited a significantly steeper regression between Si (Rd and EGP) and adiposity than young rats (p < 0.05). Thus, older rats showed a proportionately greater decrement in insulin sensitivity with an equivalent increase in adiposity. Discussion: These data suggest that, in rodents, youth affords significant protection against obesity-induced insulin resistance.