Analysis of Genetic Variation in Akt2/PKB-β in Severe Insulin Resistance, Lipodystrophy, Type 2 Diabetes, and Related Metabolic Phenotypes

Abstract

We previously reported a family in which a heterozygous missense mutation in Akt2 led to a dominantly inherited syndrome of insulin-resistant diabetes and partial lipodystrophy. To determine whether genetic variation in AKT2 plays a broader role in human metabolic disease, we sequenced the entire coding region and splice junctions of AKT2 in 94 unrelated patients with severe insulin resistance, 35 of whom had partial lipodystrophy. Two rare missense mutations (R208K and R467W) were identified in single individuals. However, insulin-stimulated kinase activities of these variants were indistinguishable from wild type. In two large case-control studies (total number of participants 2,200), 0 of 11 common single nucleotide polymorphism (SNPs) in AKT2 showed significant association with type 2 diabetes. In a quantitative trait study of 1,721 extensively phenotyped individuals from the U.K., no association was found with any relevant intermediate metabolic trait. In summary, although heterozygous loss-offunction mutations in AKT2 can cause a syndrome of severe insulin resistance and lipodystrophy in humans, such mutations are uncommon causes of these syndromes. Furthermore, genetic variation in and around the AKT2 locus is unlikely to contribute significantly to the risk of type 2 diabetes or related intermediate metabolic traits in U.K. populations.

Insulin Receptor Signaling in Normal and Insulin-Resistant States

“…Two other missense mutations (R208 K and R467W) have also been identified in diabetic patients, but surprisingly, these mutant forms display unaltered insulin-stimulated kinase activities in vitro (Tan et al 2007). In type-2 diabetic patients, a gain-of-function mutation (Q84R) in Trb3 has been associated with insulin resistance and decreased insulin-stimulated Akt phosphorylation (Prudente et al 2005(Prudente et al , 2009.…”

Functional Variants of the <emph type="ital">HMGA1</emph> Gene and Type 2 Diabetes Mellitus

“…34 Also variants in this gene, especially one resulting in a K to Q substitution at codon 121, are associated with both insulin resistance and type 2 DM. 34 Rare abnormalities of other genes have been reported that cause insulin resistance and type 2 DM, including INSR, 13 PPARγ, 35 Akt, 36 and leptin and its receptor. 37 Genome-wide association studies have been performed to identify genes implicated in insulin resistance and type 2 DM susceptibility.…”

The Akt signaling pathway

“…142,143 In addition, Akt-2 null mice exhibited insulin resistance, hyperglycemia, hyperinsulinemia and glucose intolerance. 144 Another study has also demonstrated that inhibiting mTOR induced diabetes. Similarly, inhibiting Akt activity using the pan Akt inhibitor GSK690693 induced glucose dysregulation in the form of transient hyperglycemia as well as hyperinsulinemia in animals.…”