Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer's disease, and autism spectrum disorders.
Biochemical, epidemiological and experimental evidence suggests that cytosolic low molecular weight protein-tyrosine phosphatase (cLMWPTP) genetic variability may have a role in the clinical manifestations of diabetes mellitus.
Inappropriate regulation of the PI3-kinase/PTEN/Akt kinase-signalling cassette, a key downstream target of insulin/insulin-like growth factor signalling (IIS), is associated with several major human diseases such as diabetes, obesity and cancer.
In accordance with its ability to influence multiple crucial cellular processes, PTEN has a major role in the pathogenesis of numerous diseases such as diabetes, autism and almost every cancer examined.
Interestingly, five positional candidate genes for diabetes and related complications are located in our linkage region (the pituitary adenylate cyclase activating polypeptide (PACAP in 18p11); the peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGC1 in 4p15); PTEN, PPP1R5, and IDE located in 10q23.
Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population.
However, we did find interactions between GM, HLA-DR, and Type 1 diabetes (significant or of borderline significance after considering the effect of multiple tests): possession of Glm(2) appeared to increase susceptibility to diabetes in individuals who had HLA-DR3 but not HLA-DR4, while possession of G3m(5) appeared to increase susceptibility in individuals who had HLA-DR4 but not HLA-DR3.