Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Humans and Mice

Aims/hypothesis: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition. Methods: Cohorts of C57BL/6J male mice at 4-8 months of age (young) and 18-27 mo (aged) exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps. Results: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucose-stimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI. Conclusions/interpretation: This study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesity-associated insulin resistance are distinct.