Polymorphisms in the Insulin-Degrading Enzyme Gene Are Associated With Type 2 Diabetes in Men From the NHLBI Framingham Heart Study

Karamohamed, Samer; Demissie, Serkalem; Volcjak, J S; Liu, Chunyu; Heard‐Costa, Nancy L.; Li, Jun; Shoemaker, Christina M.; Panhuysen, Carolien; Meigs, James B.; Wilson, Peter W.F.; Atwood, Larry D.; Cupples, L. Adrienne; Herbert, Alan

doi:10.2337/diabetes.52.6.1562

Cited by 106 publications

(83 citation statements)

References 26 publications

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“…30 Here, we found a novel association of rs11187007 with type 2 diabetes and triglycerides, in line with the findings that variants and haplotypes in IDE were associated with FPG, HbA1c and type 2 diabetes. 22,23,30,31 On the other hand, the association study and meta-analysis further confirmed the effect of HHEX rs1111875 on type 2 diabetes in Chinese population, consistent with previous genome-wide association studies and replication studies in other ethnic populations. [15][16][17][18][19]25,26,[32][33][34] The HHEX gene encodes a transcription factor that is also involved in the Wnt signaling pathway and that has been shown to be essential for pancreas development.…”

Section: Discussionsupporting

confidence: 73%

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

et al. 2010

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Several genetic loci (JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, ADAMTS9, VEGFA and HHEX-IDE) were identified to be significantly related to the risk of type 2 diabetes and quantitative metabolic traits in European populations. Here, we aimed to evaluate the impacts of these novel loci on type 2 diabetes risk in a population-based case-control study of Han Chinese (1912 cases and 2041 controls). We genotyped 13 single-nucleotide polymorphisms (SNPs) in/near these genes and examined the differences in allele/genotype frequency between cases and controls. We found that both IDE rs11187007 and HHEX rs1111875 were associated with type 2 diabetes risk (for both variants: odds ratio (OR)¼1.15, 95% confidence interval (CI) 1.04-1.28, P¼0.009). In a meta-analysis where we pooled our data with the three previous studies conducted in East Asians, we found that the variants of JAZF1 rs864745 (1.09 (1.03-1.16); P¼3.49Â10 À3 ) and TSPAN8/LGR5 rs7961581 (1.11 (1.05-1.17); P¼1.89Â10 À4 ) were significantly associated with type 2 diabetes risk. In addition, the meta-analysis (7207 cases and 8260 controls) also showed that HHEX rs1111875 did have effects on type 2 diabetes in Chinese population (OR¼1.15(1.10-1.21); P¼1.93Â10 À8 ). This large population-based study and meta-analysis further confirmed the modest effects of the JAZF1, TSPAN8/LGR5 and HHEX-IDE loci on type 2 diabetes in Chinese and other East Asians.

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Section: Discussionsupporting

confidence: 73%

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

et al. 2010

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“…Evidence for a putative influence of IDE on the pathogenesis of type 2 diabetes was confirmed in association studies in several independent human populations [15][16][17] and in a recently published meta-analysis [18].…”

Section: Introductionmentioning

confidence: 81%

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

et al. 2009

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Aims/hypothesis Hepatic insulin degradation decreases in type 2 diabetes. Insulin-degrading enzyme (IDE) plays a key role in insulin degradation and its gene is located in a diabetes-associated chromosomal region. We hypothesised that IDE may be regulated by insulin and/or glucose in a liver cell model. To validate the observed regulation of IDE in vivo, we analysed biopsies of human adipose tissue during different clamp experiments in men. Methods Human hepatoma HepG2 cells were incubated in normal (1 g/l) or high (4.5 g/l) glucose medium and treated with insulin for 24 h. Catalytic activity, mRNA and protein levels of IDE were assessed. IDE mRNA levels were measured in biopsies of human subcutaneous adipose tissue before and at 240 min of hyperinsulinaemic, euglycaemic and hyperglycaemic clamps. Results In HepG2 cells, insulin increased IDE activity under normal glucose conditions with no change in IDE mRNA or protein levels. Under conditions of high glucose, insulin increased mRNA levels of IDE without changes in IDE activity. Both in normal and high glucose medium, insulin increased levels of the catalytically more active 15a IDE isoform compared with the 15b isoform. In subcutaneous adipose tissue, IDE mRNA levels were not significantly upregulated after euglycaemic or hyperglycaemic clamps. Conclusions/interpretation Insulin increases IDE activity in HepG2 cells in normal but not in high glucose conditions. This disturbance cannot be explained by corresponding alterations in IDE protein levels or IDE splicing. The loss of insulin-induced regulation of IDE activity under hyperglycaemia may contribute to the reduced insulin extraction and peripheral hyperinsulinaemia in type 2 diabetes.

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“…Nevertheless, the preexisting strong biological candidature of IDE is certainly reason enough to prioritize it for further studies. Another reason to target IDE for detailed analysis is the recent demonstration that polymorphisms in this gene also contribute to the risk of type 2 diabetes, which itself appears to be a risk factor for AD [Karamohamed et al, 2003]. Given all available evidence, we consider it highly likely that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in a haplotype block spanningIDE influences Alzheimer disease

Prince

Feuk

et al. 2003

Hum. Mutat.

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Communicated by Richard G. H. CottonLinkage studies have identified a large (460-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid b-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by c-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early-and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to o1 Â 10 À9 ) were generally stronger when examining haplotypes rather than individual SNPs, and quantitative trait tests most uniformly revealed the detected associations. Consistent risk alleles and haplotypes were apparent across the study, with effects in some cases as large as that of the e4 allele of APOE. A subsequent mutation screen of exons in all three suspect genes provided no evidence for common causative mutations. These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD.

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Polymorphisms in the Insulin-Degrading Enzyme Gene Are Associated With Type 2 Diabetes in Men From the NHLBI Framingham Heart Study

Cited by 106 publications

References 26 publications

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells

Genetic variation in a haplotype block spanningIDE influences Alzheimer disease

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