title: PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats.
abstract: mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPARγ activity. Herein, we tested the hypothesis that pharmacological PPARγ activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg·kg(-1)·day(-1)) in combination or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPARγ activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
authors.forename: Pierre-Gilles
authors.initials: PG
authors.lastname: Blanchard
authors.forename: Thiago
authors.initials: T
authors.lastname: Belchior
authors.forename: Patricia
authors.initials: P
authors.lastname: Chimin
authors.forename: Vivian A
authors.initials: VA
authors.lastname: Paschoal
authors.forename: Juliana
authors.initials: J
authors.lastname: Magdalon
authors.forename: Sandro M
authors.initials: SM
authors.lastname: Hirabara
authors.forename: Daniel
authors.initials: D
authors.lastname: Simões
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Pierre
authors.forename: Angelo
authors.initials: A
authors.lastname: Carpinelli
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004336:Drug Antagonism; D018149:Glucose Intolerance / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D020123:Sirolimus / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: gluconeogenesis; glucose uptake; insulin secretion; mechanistic target of rapamycin; peroxisome proliferator-activated receptor-γ; rapamycin; rosiglitazone