Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling.

Abstract

Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K--a master regulator of endocytosis, endosomal sorting and autophagy--provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)-associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance.

• Authors: Ivan Nemazanyy, Guillaume Montagnac, Ryan C Russell, Lucille Morzyglod, Anne-Françoise Burnol, Kun-Liang Guan, Mario Pende, Ganna Panasyuk
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 8283 (Sep 21 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26387534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Tumor Suppressor Proteins
• UVRAG protein, mouse
• Phosphatidylinositol 3-Kinases
• Receptor, Insulin
• Vacuolar Sorting Protein VPS15
• Glucose

Topics

• Animals
• Diabetes Mellitus (metabolism)
• Feedback, Physiological
• Glucose (metabolism)
• Homeostasis
• Humans
• Insulin (metabolism)
• Insulin Resistance
• Liver (enzymology, metabolism)
• Male
• Mice
• Mice, Knockout
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Receptor, Insulin (genetics, metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (genetics, metabolism)
• Vacuolar Sorting Protein VPS15 (genetics, metabolism)