G. Accardi, C. Caruso, G. Colonna Romano, R. Monastero, G. Candore

Phosphoinositides are components of the cell membrane and act as fundamental signaling molecules for regulation of cell proliferation and survival, cytoskeletal reorganization, and vesicular trafficking by recruiting effector proteins to cellular membranes. To regulate the cellular levels of lipid secondary messengers such as PtdIns(3,4,5)P3, cells use two major types of phosphoinositide phosphatases: the inositol polyphosphate 3-phosphatase PTEN and SH2 domain-containing inositol 5-phosphatases 1 and 2 (SHIP1 and SHIP2). SHIP2 is a protein that catalyzes the degradation of lipid secondary messenger phosphatidylinositol 3,4,5-triphosphate (PIP3) to produce phosphatidylinositol 3,4-diphosphate (PIP2). Thus SHIP2 is an antagonist phosphatidylinositol 3-kinase (PI3K) that takes part to the insulin signaling phosphorylating PIP2 to obtain PIP3. Because the PI3K pathway plays a key role in the biological effects of insulin, it is possible that the attenuation of the PI3K-mediated insulin signaling is associated with the insulin resistance in type 2 diabetes. Many studies underlying the role of SHIP2 as a negative regulator of insulin signaling. Its overexpression reduces both insulin-stimulated MAP kinase and AKT activation, leading to downregulation of glucose uptake towards failed recruitment of GLUT4 in cell membrane and glycogen synthesis in 3T3-L1 adipocytes and L6 myotubes Expression of SHIP2 was greatly increased in the skeletal muscle and fat tissue of diabetic mice. In addition, INPPL1, the SHIP2 gene coding, is in human chromosome 11q13-14, which is suggested to be linked to type 2 diabetes with insulin resistance and hypertension. Therefore, it is possible that SHIP2 is involved in the pathogenesis of insulin resistance of type 2 diabetes mellitus in humans. A study of 2004 has demonstrated that two SNPs of INPPL1, rs2276047 in intron 9 and rs9886 in the 3’ untranslated region and an insertion/deletion polymorphism in intron 1 found in British and French type 2 diabetes people are associated with metabolic syndrome including type 2 diabetes and hypertension. Our aim is to study the prevalence of these three SNPs in Sicilian population in a case-control study, analyzing Alzheimer’s patients as case and healthy people as control. Also we are analyzing the association between these polymorphisms, singularly and as haplotype, in Alzheimer’s disease patients with and without diabetes because it is known that Alzheimer’s disease is associated with metabolic syndrome. Preliminary results show the presence of these SNPs in Sicilian population.

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age-ralated disease