The AKT (murine thymoma viral (v-akt) oncogene homologue), also termed protein kinase B (PKB) or RAC protein kinase, is a serine and threonine protein kinase homologous to protein kinases A and C [1] [2].Three mammalian isoforms (AKT1±3) have been cloned. For maximal enzymatic activation of AKT1, Thr-308 and Ser-473 are required to be phosphorylated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and 3-phosphoinositide-dependent protein kinase-2 (PDK2) respectively, while PDK2 has yet to be identified. AKTs are important for many cellular processes such as growth and differentiation and have anti-apoptotic effects through several target molecules. AKT also mediates a variety of peripheral metabolic actions of insulin.Recent experiments in transgenic mice, including tissue-specific disruptions of the islet beta cell insulin receptor (IR) and the insulin receptor substrates Diabetologia (2001) Abstract Aims/hypothesis. AKT1, a serine/threonine protein kinase, is an important downstream target of the insulin-signalling pathway, with both anti-apoptotic and peripheral metabolic effects. Because impaired insulin signalling is a major hallmark of Type II (non-insulin-dependent) diabetes mellitus, we considered whether the AKT1 gene could be a candidate gene involved in susceptibility of this condition. To test this possibility, we isolated and characterized the human AKT1 gene. We also looked for single nucleotide polymorphisms in the gene and examined their association with Type II diabetes mellitus in the Ashkenazi Jewish population. Methods. Human BAC/P1 genomic libraries were screened to isolate the AKT1 gene. To obtain structural information and the sequences of the exon-intron boundaries, BAC/P1 clones were directly sequenced. Identification of single nucleotide polymorphisms was done by polymerase chain reaction of each exon, followed by denaturing high performance liquid chromatography. Six single nucleotide polymorphisms were genotyped in Ashkenazi Jewish patients with Type II diabetes mellitus and in control subjects.Results. The human AKT1 gene was at least 24.6 kb in length and comprised 14 exons. Altogether 13 putative intragenic single nucleotide polymorphisms, with minor-allele frequencies ranging from 0.011 to 0.354, were identified. The allelic and the genotypic frequencies of 6 single nucleotide polymorphisms were the same in diabetic patients and in control subjects. Conclusion/interpretation. The results of our studies show that the AKT1 gene is not a major contributor to susceptibility to Type II diabetes mellitus in Ashkenazi Jews. [Diabetologia (2001) 44: 910±913]