IDENTIFICATION OF A COMMON AMINO-ACID POLYMORPHISM IN THE P85-ALPHA REGULATORY SUBUNIT OF PHOSPHATIDYLINOSITOL 3-KINASE - EFFECTS ON GLUCOSE DISAPPEARANCE CONSTANT, GLUCOSE EFFECTIVENESS, AND THE INSULIN SENSITIVITY INDEX

Phosphatidylinositol 3-kinase (PI3-K) may regulate the basal plasma me mbrane glucose transporter recycling and the organization of the trans porter intracellular pool in addition to being an insulin signal for t ranslocation of glucose transporters to the plasma membrane. The objec tives of the present study were to examine for genetic variability in the human regulatory p85 alpha subunit of PI3-K, to look for an associ ation between gene variants and NIDDM in a case-control study, and to relate identified variability to potential changes in whole-body insul in sensitivity and glucose turnover in a phenotype study. Single-stran d conformational polymorphism and heteroduplex analysis of the coding region of the regulatory p85 alpha subunit in cDNA isolated from human muscle tissue from 70 insulin-resistant NIDDM patients and 12 control subjects revealed three silent polymorphisms and a missense mutation at nucleotide position 1020 (G-->A), changing a Met to Ile at codon 32 6. Using allele-specific oligohybridization, we found a similar alleli c frequency of the codon 326(Met-->Ile) variant in 404 NIDDM patients (0.15 [95% CI 0.13-0.17]) and 224 matched glucose tolerant control sub jects (0.16 [0.13-0.19]). In a random sample of 380 unrelated healthy young Caucasians aged 18-32 years, in whom we have performed a tolbuta mide modified intravenous glucose tolerance test, we identified 263 wi ldtype subjects, 109 heterozygous subjects, and 8 subjects homozygous for the codon 326 variant (allelic frequency = 0.16 [0.13-0.19]). No d ifference in glucose disappearance constant (K-G), insulin sensitivity index (S-I), and glucose effectiveness (S-G) was observed between wil dtype and heterozygous subjects. However, compared with the combined v alues for wildtype and heterozygous carriers, K-G was reduced by 40% ( P = 0.004) and S-G by 23% (P = 0.03) in homozygous carriers of the p85 alpha variant. Moreover, in homozygous carriers, a 32% reduction was found in S-I (P = 0.08). In conclusion, a codon 326(Met-->Ile) variant in the gene encoding the PI3-K p85 alpha regulatory subunit is found in 31% of a random sample of young healthy Caucasians. About 2% of the subjects in this population carry the gene variant in its homozygous form, and these carriers are characterized by significant reductions i n whole-body glucose effectiveness and intravenous glucose disappearan ce constant. In itself, the gene variant does not confer an increased risk of diabetes.