mTORC1 inhibitors rapamycin and metformin affect cardiovascular markers differentially in ZDF rats.
Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency. Rapamycin and metformin improved proteinuria, and rapamycin also reduced urinary gamma glutamyl transferase (GGT) indicating improvement of tubular health. Metformin reduced food and water intake, and urinary sodium and potassium, whereas rapamycin increased urinary sodium. Metformin reduced plasma alkaline phosphatase, but induced transaminitis as evidenced by significant increases in plasma AST and ALT. Metformin also induced hyperinsulinemia, but did not suppress fasting plasma glucose after ZDF rats reached 17 weeks of age, and worsened lipid profile. Rapamycin also induced mild transaminitis. Additionally, both rapamycin and metformin increased plasma uric acid and creatinine, biomarkers for cardiovascular and renal disease. These observations define how rapamycin and metformin differentially modulate metabolic profiles that regulate cardiorenal pathology in conditions of severe type 2 diabetes.
a Division of Nephrology, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.|b Department of Medicine, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.|c Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65201, USA.
Ravi
R
Nistala
b Department of Medicine, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.|c Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65201, USA.|d Division of Cardiology, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Ahmad
A
Raja
b Department of Medicine, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.|c Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65201, USA.|d Division of Cardiology, Columbia School of Medicine, University of Missouri, Columbia, MO 65212, USA.|e Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.
Lakshmi
L
Pulakat
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002318:Cardiovascular Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011507:Proteinuria / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Zucker diabetic fatty rat; cardiorenal pathologies; metformin; metformine; pathologies cardio-rénales; rapamycin; rapamycine; rat Zucker diabétique obèse