The Gene INPPL1, Encoding the Lipid Phosphatase SHIP2, Is a Candidate for Type 2 Diabetes In Rat and Man
- 1 July 2002
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 51 (7) , 2012-2017
- https://doi.org/10.2337/diabetes.51.7.2012
Abstract
Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3′ untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans.Keywords
This publication has 18 references indexed in Scilit:
- The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actinThe Journal of cell biology, 2001
- SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubesDiabetologia, 2001
- The SH2 Domain Containing Inositol 5-Phosphatase SHIP2 Controls Phosphatidylinositol 3,4,5-Trisphosphate Levels in CHO-IR Cells Stimulated by InsulinBiochemical and Biophysical Research Communications, 2001
- Overexpression of SH2-Containing Inositol Phosphatase 2 Results in Negative Regulation of Insulin-Induced Metabolic Actions in 3T3-L1 Adipocytes via Its 5′-Phosphatase Catalytic ActivityMolecular and Cellular Biology, 2001
- Essential Role for the C-Terminal Noncatalytic Region of SHIP in FcγRIIB1-Mediated Inhibitory SignalingMolecular and Cellular Biology, 2000
- Molecular Cloning of Rat SH2-Containing Inositol Phosphatase 2 (SHIP2) and Its Role in the Regulation of Insulin SignalingBiochemical and Biophysical Research Communications, 1999
- Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive ratsNature Genetics, 1997
- Genetic analysis of non-insulin dependent diabetes mellitus in the GK ratNature Genetics, 1996
- Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK ratNature Genetics, 1996
- Two Binding Orientations for Peptides to the Src SH3 Domain: Development of a General Model for SH3-Ligand InteractionsScience, 1994