title: Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes.
abstract: Numerous studies suggest that rapamycin treatment promotes insulin resistance, implying that rapamycin could have negative effects on patients with, or at risk for, type 2 diabetes (T2D). New evidence, however, indicates that rapamycin treatment produces somebenefitsto energy metabolism, even in the context of T2D. Here, we survey 5 mouse models of T2D (KK, KK-Ay, NONcNZO10, BKS-db/db, TALLYHO) to quantify effects of rapamycin on well-recognized markers of glucose homeostasis within a wide range of T2D environments. Interestingly, dietary rapamycin treatment did not exacerbate impaired glucose or insulin tolerance, or elevate circulating lipids as T2D progressed. In fact, rapamycinincreasedinsulin sensitivity and reduced weight gain in 3 models, and decreased hyperinsulinemia in 2 models. A key covariate of this genetically-based, differential response was pancreatic insulin content (PIC): Models with low PIC exhibited more beneficial effects than models with high PIC. However, a minimal PIC threshold may exist, below which hypoinsulinemic hyperglycemia develops, as it did in TALLYHO. Our results, along with other studies, indicate that beneficial or detrimental metabolic effects of rapamycin treatment, in a diabetic or pre-diabetic context, are driven by the interaction of rapamycin with the individual model's pancreatic physiology.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Reifsnyder
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Flurkey
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Austen
authors.initials: A
authors.lastname: Te
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000375:Aging / Q000187:drug effects*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: insulin sensitivity; pancreatic insulin content; rapamycin; strain survey; type 2 diabetes