Quantitative Trait Loci Near the Insulin-Degrading Enzyme (<i>IDE</i>) Gene Contribute to Variation in Plasma Insulin Levels

Gu, Harvest F.; Efendić, Suad; Nordman, Sofia; Östenson, Claes‐Göran; Brismar, Kerstin; Brookes, Anthony J.; Prince, Jonathan A.

doi:10.2337/diabetes.53.8.2137

Cited by 57 publications

(50 citation statements)

References 32 publications

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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: 84%

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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Section: Introductionmentioning

confidence: 84%

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

et al. 2009

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“…Thus, we have recently shown that polymorphisms in the insulin-degrading enzyme gene are linked to increased BMI and insulin resistance in men but not in women [36]. Similarly, a Leu7Pro polymorphism in the gene for neuropeptide Y, related to regulation of satiety and body weight, was demonstrated to be associated with IGT and type 2 diabetes in men but not in women [37].…”

Section: Discussionmentioning

confidence: 99%

The impact of family history of diabetes and lifestyle factors on abnormal glucose regulation in middle-aged Swedish men and women

et al. 2006

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Aims/hypothesis We investigated associations between abnormal glucose regulation and family history of diabetes, separately and in combination with lifestyle risk factors. Subjects and methods This cross-sectional study comprised 3,128 men and 4,821 women, aged 35-56 years, half with a family history of diabetes. Oral glucose tolerance testing identified subjects with previously undiagnosed prediabetes (IFG, IGT) and type 2 diabetes. Information on lifestyle factors was obtained by questionnaire. Biological interaction was measured with the synergy index. Results A family history of diabetes conferred a higher odds ratio (OR) for type 2 diabetes in men (OR=3.1, 95% CI 1.7-5.6) than in women (OR=1.7, 95% CI 1.0-3.0), and the synergy index was 2.8 (95% CI 0.9-9.0), suggesting interaction between a family history of diabetes and sex. For prediabetes and diabetes combined, the synergy index was 1.7 (1.0-2.8). Exposure to only one lifestyle risk factor (obesity, physical inactivity, smoking or low sense of coherence [a psychosocial index]) increased the risk to a similar extent in men and women. Combined exposure to a family history of diabetes and lifestyle-related risk factors had a greater effect on type 2 diabetes than any of these factors alone, especially in men. However, analysis of interaction between a family history of diabetes and the lifestyle factors did not indicate any interaction for diabetes, but did indicate interaction for a family history of diabetes and obesity in women with prediabetes. Conclusions/interpretation Our data suggest a more pronounced effect of a family history of diabetes on the risk of type 2 diabetes in men than in women. While both a family history of diabetes and lifestyle risk factors had effects on type 2 diabetes, irrespective of sex, these effects did not appear to interact.

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“…None of the markers were significantly associated with APOB levels in non-smokers. Having provided evidence of their potential independent effects, we used a diplotype strategy (Gu et al 2004) to test for interactions between the R219K and R1587K variants, focussing on the smoking population. This strategy allows testing of haplotype effects, and can expose hybrids (individuals with two unlike haplotypes) that may contribute to trait variance.…”

Section: Resultsmentioning

confidence: 99%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of b-amyloid (Ab) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab 1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Ab 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDLcholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus nonsmokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Ab and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

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Quantitative Trait Loci Near the Insulin-Degrading Enzyme (IDE) Gene Contribute to Variation in Plasma Insulin Levels

Cited by 57 publications

References 32 publications

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

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

The impact of family history of diabetes and lifestyle factors on abnormal glucose regulation in middle-aged Swedish men and women

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

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