Dataset Information

Analysis of genetic variation in Akt2/PKB-beta 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-of- function 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.

SUBMITTER: Tan K

PROVIDER: S-EPMC2672155 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes.

Tan Karen K Kimber Wendy A WA Luan Jian'an J Soos Maria A MA Semple Robert K RK Wareham Nicholas J NJ O'Rahilly Stephen S Barroso Inês I

Diabetes 20070301 3

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 ...[more]

PMID: 17327441

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Project description:Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied.Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence.We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.

Project description:BackgroundIn the metabolic syndrome with hyperinsulinemia, mitochondrial inhibition facilitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochondrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to CO(2) and H(2)O or to drive glucose storage to glycogen.Methodology/principal findingsWe illustrate here that NO produced by translocated nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization. We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mitochondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4-8 fold, P<.05), high NO, and a lowering of mitochondrial oxygen uptake and resting metabolic rate (-25 to -60%, P<.05). Comparing in vivo insulin metabolic effects on gastrocnemius muscles by direct electroporation of siRNA nNOS or empty vector in the two legs of the same animal, confirmed that in the silenced muscles disrupted mtNOS allows higher oxygen uptake and complete (U-(14)C)-glucose utilization respect to normal mtNOS in the vector-treated ones (respectively 37+/-3 vs 10+/-1 micromolO(2)/h.g tissue and 13+/-1 vs 7.2+/-1 micromol (3)H(2)O/h.g tissue, P<.05), which reciprocally restricted glycogen-synthesis by a half.Conclusions/significanceThese evidences show that after energy replenishment, insulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromolecules; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunction with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome.

Dataset Information

Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes.

Publications

Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes.

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