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

Obesity (Silver Spring). 2019 Mar;27(3):434-443. doi: 10.1002/oby.22418.


Objective: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.

Methods: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps.

Results: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.

Conclusions: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adiposity / physiology*
  • Adult
  • Animals
  • Female
  • Humans
  • Insulin Resistance / genetics*
  • Male
  • Mice
  • Phenotype