title: Chronic rapamycin treatment causes diabetes in male mice.
abstract: Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes.
authors: Department of Biology, Williams College, Williamstown, Massachusetts.
authors: Christine E
authors: CE
authors: Schindler
authors: Department of Biology, Williams College, Williamstown, Massachusetts.
authors: Uttara
authors: U
authors: Partap
authors: Department of Biology, Williams College, Williamstown, Massachusetts.
authors: Bonnie K
authors: BK
authors: Patchen
authors: Department of Biology, Williams College, Williamstown, Massachusetts sswoap@williams.edu.
authors: Steven J
authors: SJ
authors: Swoap
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control / Q000652:urine; D004958:Estradiol / Q000008:administration & dosage; D015914:Estrogen Replacement Therapy; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000139:chemically induced; D006029:Glycosuria / Q000139:chemically induced / Q000652:urine; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010052:Ovariectomy; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D019289:Pyruvic Acid / Q000378:metabolism; D012737:Sex Factors; D020123:Sirolimus / Q000008:administration & dosage / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D047428:Protein Kinase Inhibitors; D013739:Testosterone; D004958:Estradiol; D019289:Pyruvic Acid; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: diabetes; estradiol; hyperglycemia; mammalian target of rapamycin; rapamycin