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Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways

Ritu Malla1, Yu Wang2, William K Chan2

  • 1Department of Physiology and Pharmacology, T. J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, United States.

Biochemical Pharmacology
|May 2, 2015
PubMed

Insights

Deleting PRAS40 (proline-rich Akt substrate 40 kDa) protein reduces blood glucose and prevents hyperglycemia in a mouse model of diabetes. This suggests PRAS40 plays a role in glucose regulation.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Metabolic Diseases

Background:

  • The PI3K-AKT-mTOR signaling pathway is crucial for cellular metabolism and is frequently dysregulated in diabetes.
  • PRAS40 (proline-rich Akt substrate 40 kDa) is a key regulatory component of the mTORC1 complex and a substrate of AKT.
  • Understanding PRAS40's role in glucose homeostasis is vital for developing novel diabetes therapies.

Purpose of the Study:

  • To investigate the impact of PRAS40 gene ablation on glucose homeostasis and hyperglycemia.
  • To determine if PRAS40 disruption can prevent or mitigate hyperglycemia in a streptozotocin (STZ)-induced diabetes mouse model.

Main Methods:

  • Utilized PRAS40 gene knockout (PRAS40(-/-)) and wild-type (PRAS40(+/+)) mice.
  • Assessed glucose levels, glycated hemoglobin (HbA1C), and glucose tolerance in untreated mice.
  • Induced diabetes using streptozotocin (STZ) and evaluated hyperglycemia, signaling pathways (AKT, mTORC1), and glucose transporter expression in liver tissue.

Main Results:

  • PRAS40(-/-) mice exhibited improved glucose tolerance, lower blood glucose, and reduced HbA1C compared to wild-type mice.
  • Following STZ-induced diabetes, PRAS40(-/-) mice showed significantly attenuated hyperglycemia and lower HbA1C levels.
  • PRAS40 deletion led to increased hepatic AKT and mTORC1 signaling, altered AKT/IRS1 phosphorylation, and increased hepatic GLUT4 levels.

Conclusions:

  • PRAS40 ablation significantly ameliorates hyperglycemia in the STZ-induced diabetes model.
  • PRAS40 deletion enhances hepatic AKT and mTORC1 signaling, reduces insulin requirements, and alters glucose transporter expression.
  • Targeting PRAS40 may represent a novel therapeutic strategy for managing diabetes and hyperglycemia.
Keywords:
AKTDiabetesGLUT4InsulinPRAS40mTORC1

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