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

• Main Authors: Lamming, Dudley W. (Contributor), Ye, Lan (Author), Astle, Clinton M. (Author), Baur, Joseph A. (Author), Harrison, David E. (Author), Sabatini, David (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Whitehead Institute for Biomedical Research (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Sabatini, David M. (Contributor)
• Format: Article
• Language: English
• Published: Wiley Blackwell, 2015-04-23T16:59:47Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.)
National Institute on Aging (Grant AG 035860)
National Institute on Aging (Grant AG 022308)
National Cancer Institute (U.S.) (Grant CA 129105)
American Federation for Aging Research (Julie Martin Mid-Career Award in Aging Research)
National Institutes of Health (U.S.) (National Institute on Aging K00/R00 Award 1K99AG041765-01A1)