Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways.
Alterations in PI3K-AKT-mTOR signaling have been implicated in diabetes. This study assessed whether disruption of PRAS40, a substrate of AKT and component of mTORC1, would alter glucose homeostasis and prevent hyperglycemia in the streptozotocin (STZ)-induced diabetes mouse model. PRAS40 ablation resulted in a mild lowering of blood glucose levels and glycated hemoglobin (HbA1C), a lowered insulin requirement, and improved glucose tolerance in untreated PRAS40 gene knockout (PRAS40(-/-)) as compared to wild-type (PRAS40(+/+)) mice. Diabetes was then induced in these mice using STZ at 50mg/kg/day over five days. Following STZ-treatment, PRAS40(-/-) mice exhibited significantly lower blood glucose and HbA1C levels than PRAS40(+/+) mice. Liver tissue of PRAS40(-/-) mice and shPRAS40 Hep3B cells showed increased activation of AKT (p-AKT T308) and mTORC1 (p-p70S6K) signaling as well as decreased p-AKT (S473) and increased p-IRS1 (S612) protein levels. Altered tissue gene expression of several glucose transporters (GLUT) and increased hepatic GLUT4 protein levels were observed in PRAS40(-/-) as compared to PRAS40(+/+) mice. In summary, PRAS40 deletion significantly attenuates hyperglycemia in STZ-induced PRAS40(-/-) mice through increased hepatic AKT and mTORC1 signaling, a lowered serum insulin requirement, and altered hepatic GLUT4 levels.
Department of Physiology and Pharmacology, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, United States.
Ritu
R
Malla
Department of Pharmaceutics and Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, United States.
Yu
Y
Wang
Department of Pharmaceutics and Medicinal Chemistry, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, United States.
William K
WK
Chan
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, OH, United States.
Amit K
AK
Tiwari
Department of Physiology and Pharmacology, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, United States. Electronic address: jfaridi@pacific.edu.
Jesika S
JS
Faridi
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D017931:DNA Primers; D007328:Insulin; D010750:Phosphoproteins; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
AKT; Diabetes; GLUT4; Insulin; PRAS40; mTORC1