Normalization of prandial blood glucose and improvement of glucose tolerance by liver-specific inhibition of SH2 domain-containing inositol phosphatase 2 (SHIP2) in diabetic KKAy mice : SHIP2 inhibition causes insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 9; pp. 2235 - 2241
• Main Authors: GREMPLER, Rolf, ZIBROVA, Darya, SCHOELCH, Corinna, VAN MARLE, André, RIPPMANN, Joerg F, REDEMANN, Norbert
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2007
• Subjects: Adenoviridae - enzymology; Adenoviridae - genetics; Animals; Biological and medical sciences; Blood Glucose - metabolism; Diabetes. Impaired glucose tolerance; DNA; Eating; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gluconeogenesis - physiology; Glucose - metabolism; Glucose Tolerance Test; Glycogen - metabolism; Glycolysis - physiology; Inositol Polyphosphate 5-Phosphatases; Insulin - pharmacology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Mice; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - antagonists & inhibitors; Phosphoric Monoester Hydrolases - genetics; Reference Values; Endocrinopathy; Pancreatic hormone; Inositol; Digestive system; Enzyme; Glycogen; Diabetes mellitus; Liver; Rodentia; Phosphoric monoester hydrolases; Tolerance; Esterases; B-Vitamins; Glucose; Metabolism; Insulin; Vertebrata; Mammalia; Mouse; Animal; Glycolysis; Hydrolases; Inhibition; Gluconeogenesis
• ISSN: 0012-1797; 1939-327X

Type 2 diabetes is characterized by a progressive resistance of peripheral tissues to insulin. Recent data have established the lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) as a critical negative regulator of insulin signal transduction. Mutations in the SHIP2 gene are associated with type 2 diabetes. Here, we used hyperglycemic and hyperinsulinemic KKA(y) mice to gain insight into the signaling events and metabolic changes triggered by SHIP2 inhibition in vivo. Liver-specific expression of a dominant-negative SHIP2 mutant in KKA(y) mice increased basal and insulin-stimulated Akt phosphorylation. Protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were significantly reduced, and consequently the liver produced less glucose through gluconeogenesis. Furthermore, SHIP2 inhibition improved hepatic glycogen metabolism by modulating the phosphorylation states of glycogen phosphorylase and glycogen synthase, which ultimately increased hepatic glycogen content. Enhanced glucokinase and reduced pyruvate dehydrogenase kinase 4 expression, together with increased plasma triglycerides, indicate improved glycolysis. As a consequence of the insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis, the liver-specific inhibition of SHIP2 improved glucose tolerance and markedly reduced prandial blood glucose levels in KKA(y) mice. These results support the attractiveness of a specific inhibition of SHIP2 for the prevention and/or treatment of type 2 diabetes.