Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women.

Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes.

“…However, the incidence of diabetes tended to be higher in carriers of the D1057D genotype of the IRS-2 gene and in the carriers of the M326 allele of the PI3K gene than it was in non-carriers of these polymorphisms. This is in accordance with previous findings [16,29]. Although carriers of the Q121 allele of the PC-1 gene are insulin-resistant and potentially at high risk of developing diabetes [11,12], there was no difference in incidence of diabetes between carriers and non-carriers of the Q121 allele.…”

“…Mice lacking PI3K p85α subunit have increased insulin sensitivity and hypoglycaemia [28]. In addition, the I326I genotype carriers have been reported to have lower prevalence of Type 2 diabetes than carriers of the M326 allele of PI3K p85α [29]. However, results suggesting the opposite have also been reported [30,31].…”

Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity

“…Analysis of the p55a splice variant of p85a, which contains a unique 32 amino acid N-terminal extension, showed no additional SSCP variants. In agreement with others we also found that all cDNA samples sequenced at amino acid residue 330 coded for Asp suggesting that there is an error in the published sequence of p85a [32]. Also of note was the absence of mutations in the p85a gene in the pseudoacromegalic patients whom we have previously reported to have impaired insulin-stimulated PI 3K activity in their cultured dermal fibroblasts [15].…”

“…Two reports suggest that the Met 326 Ile variant is not associated with Type II diabetes [34,38], whereas another has reported that in female Pima Indians it is associated with a lower prevalence of Type II diabetes and a higher early phase insulin response [32]. In our group of people with severe insulin resistance we found a similar allelic frequency for the Met 326 Ile allele to that reported for Pima Indians (25 %) [32]. The small sample size, however, and mixed racial origin of our group precludes any definite conclusions being drawn from this observation.…”

“…Association studies examining the consequences of the Met 326 Ile polymorphism have resulted in variable findings; one study has reported that in the homozygous form it is associated with a reduced insulin sensitivity index, glucose disappearance constant and glucose effectiveness [38] whereas another report showed no association with insulin sensitivity [32]. Two reports suggest that the Met 326 Ile variant is not associated with Type II diabetes [34,38], whereas another has reported that in female Pima Indians it is associated with a lower prevalence of Type II diabetes and a higher early phase insulin response [32]. In our group of people with severe insulin resistance we found a similar allelic frequency for the Met 326 Ile allele to that reported for Pima Indians (25 %) [32].…”