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Aging Cell DOI:10.1111/acel.12097

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

Publication TypeJournal Article
Year of Publication2013
AuthorsLamming, DW, Ye, L, Astle, CM, Baur, JA, Sabatini, DM, Harrison, DE
JournalAging Cell
Volume12
Issue4
Pages712-8
Date Published2013 Aug
ISSN1474-9726
KeywordsAge Factors, Animals, Blood Glucose, Diet, Female, Genetic Heterogeneity, Genotype, Glucose, Glucose Intolerance, Hemoglobin A, Glycosylated, Insulin Resistance, Longevity, Male, Mice, Mice, Inbred C57BL, Pyruvic Acid, Sirolimus, Species Specificity
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.

URLhttp://dx.doi.org/10.1111/acel.12097
DOI10.1111/acel.12097
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23648089?dopt=Abstract

Alternate JournalAging Cell
PubMed ID23648089
PubMed Central IDPMC3727050
Grant ListAG 022308 / AG / NIA NIH HHS / United States
P30 CA034196 / CA / NCI NIH HHS / United States
CA 129105 / CA / NCI NIH HHS / United States
1K99AG041765-01A1 / AG / NIA NIH HHS / United States
AG 035860 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 AG038560 / AG / NIA NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
P30DK19525 / DK / NIDDK NIH HHS / United States
K99 AG041765 / AG / NIA NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
U01 AG022308 / AG / NIA NIH HHS / United States
R01 AG043483 / AG / NIA NIH HHS / United States