Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive

Aging Cell. 2013 Aug;12(4):712-8. doi: 10.1111/acel.12097. Epub 2013 Jun 7.

Abstract

Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the life span of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats, and humans is associated with insulin resistance (J Am Soc Nephrol., 19, 2008, 1411; Diabetes, 00, 2010, 00; Science, 335, 2012, 1638). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum life span. We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. To gauge the overall consequences of rapamycin treatment on average blood glucose levels, we measured HBA1c. Dietary rapamycin increased HBA1c over the first 3 weeks of treatment in young animals, but the effect was lost by 3 months, and no effect was detected in older animals. Our results demonstrate that the extended life span of HET3 mice on a rapamycin diet occurs in the absence of major changes in insulin sensitivity and highlight the importance of strain background and delivery method in testing effects of longevity interventions.

Keywords: aging; glucose tolerance; heterogeneous mice; insulin tolerance; rapamycin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blood Glucose
  • Diet
  • Female
  • Genetic Heterogeneity*
  • Genotype
  • Glucose / metabolism
  • Glucose Intolerance*
  • Glycated Hemoglobin A / analysis
  • Insulin Resistance*
  • Longevity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pyruvic Acid / metabolism
  • Sirolimus / administration & dosage*
  • Sirolimus / pharmacology
  • Species Specificity

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Pyruvic Acid
  • Glucose
  • Sirolimus