Impact of Transgenic Overexpression of SH2-Containing Inositol 5′-Phosphatase 2 on Glucose Metabolism and Insulin Signaling in Mice

Abstract

SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a 5'-lipid phosphatase hydrolyzing the phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P(3) to PI(3,4)P(2) in the regulation of insulin signaling, and is shown to be increased in peripheral tissues of diabetic C57BL/KSJ-db/db mice. To clarify the impact of SHIP2 in the pathogenesis of insulin resistance with type 2 diabetes, we generated transgenic mice overexpressing SHIP2. The body weight of transgenic mice increased by 5.0% (P < 0.05) compared with control wild-type littermates on a normal chow diet, but not on a high-fat diet. Glucose tolerance and insulin sensitivity were mildly but significantly impaired in the transgenic mice only when maintained on the normal chow diet, as shown by 1.2-fold increase in glucose area under the curve over control levels at 9 months old. Insulin-induced phosphorylation of Akt was decreased in the SHIP2-overexpressing fat, skeletal muscle, and liver. In addition, the expression of hepatic mRNAs for glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was increased, that for sterol regulatory element-binding protein 1 was unchanged, and that for glucokinase was decreased. Consistently, hepatic glycogen content was reduced in the 9-month-old transgenic mice. Structure and insulin content were histologically normal in the pancreatic islets of transgenic mice. These results indicate that increased abundance of SHIP2 in vivo contributes, at least in part, to the impairment of glucose metabolism and insulin sensitivity on a normal chow diet, possibly by attenuating peripheral insulin signaling and by altering hepatic gene expression for glucose homeostasis.

LL5β Directs the Translocation of Filamin A and SHIP2 to Sites of Phosphatidylinositol 3,4,5-Triphosphate (PtdIns(3,4,5)P3) Accumulation, and PtdIns(3,4,5)P3 Localization Is Mutually Modified by Co-recruited SHIP2

“…Therefore, it is likely that SHIP2, Filamin A, and LL5␤ help a cell to move in one direction smoothly. Moreover, the ability of PtdIns(3,4,5)P 3 and SHIP2 to regulate various cellular responses, such as the insulin response (27), and the reciprocal regulation of PtdIns(3,4,5)P 3 with Filamin A-LL5␤ reported here suggest that these findings are significant for the general understanding of such events, and possibly, for the understanding of related diseases.…”

Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase–Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance

“…PI(3,4,5)P 3 accumulation promotes the activity of signaling molecules, such as Akt; by reducing PI(3,4,5)P 3 accumulation, SHIP2 acts as a negative regulator of insulin-induced Akt signaling (7). Indeed, transgenic mice overexpressing SHIP2 have reduced glucose tolerance and blunted Akt activation in classic insulin target tissues (8).…”

Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes

“…Lipid phosphatase SHIP2 downregulates PI3K mediated signalling, induced by insulin and other growth factors, by hydrolyzing PI(3,4,5,)P 3 to PI(3,4)P 2 (Blero et al 2001. SHIP2 overexpression in mice has a negative effect on glucose tolerance (Kagawa et al 2008,Fukui et al 2005 and SHIP2 knockout mice appear resistant to high fat diet-induced obesity and insulin resistance (Sleeman et al 2005), and in addition, inhibition of SHIP2 in the liver has been shown to improve glucose tolerance in diabetic mice (Grempler et al 2007). Taken together, SHIP2 is a downregulator of PI3K mediated insulin signalling, that is known to function in liver, muscle and adipose cells, but its role in the kidney has not been studied previously.…”