Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to analyze the frequency of K121Q polymorphism in the ENPP1 gene of Brazilian subjects according to ethnic origin and to determine its possible association with diabetes mellitus (DM) and/or diabetic complications. A cross-sectional study was conducted on 1027 type 2 DM patients and 240 anonymous blood donors (BD). Ethnicity was classified based on self-report of European and African descent. The Q allele frequency was increased in African descendant type 2 DM patients (KK = 25.9%, KQ = 48.2%, and QQ = 25.9%) and BD (KK = 22.0%, KQ = 53.8%, and QQ = 24.2%) compared to European descendant type 2 DM patients (KK = 62.7%, KQ = 33.3%, and QQ = 4.1%) and BD (KK = 61.0%, KQ = 35.6%, and QQ = 3.4%). However, there was no difference in genotype distribution or Q allele frequency between diabetic and non-diabetic subjects (European descendants: DM = 0.21 vs BD = 0.21, P = 0.966, and African descendants: DM = 0.50 vs BD = 0.51, P = 0.899). In addition, there were no differences in clinical, laboratory or insulin resistance indices among the three genotypes. The prevalence of DM complications was also similar. In conclusion, K121Q polymorphism is more common among Afro-Brazilian descendants regardless of glycemic status or insulin sensitivity indices. Likewise, insulin sensitivity and DM chronic complications appear not to be related to the polymorphism in this sample.
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PMID:The role of K121Q ENPP1 polymorphism in diabetes mellitus and its complications. 1817 22

Obesity results from the complex interaction of environmental factors that act on a genetic background that determines the susceptibility to obesity. The identification of such obesity susceptibility genes can provide important insights into the mechanism underlying this condition. While candidate gene approaches have not been tremendously successful in identifying relevant genetic contributors to obesity, except PPAR , the advent of genome-wide strategies has recently revealed novel and unexpected genetic factors with strong associations with obesity and/or diabetes, i.e. FTO, TCF7L2, INSIG2, ENPP1, or FASN (reviewed herein), although some of them are not undebated. Considering the function of the encoded proteins, it will now be of interest to investigate the cellular and molecular mechanisms, how these genetic variations affect body weight, energy metabolism and/or obesity-associated morbidity.
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PMID:Polygenic contribution to obesity: genome-wide strategies reveal new targets. 1823 Aug 92

Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.
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PMID:Association of genetic variation in ENPP1 with obesity-related phenotypes. 1846 50

Type 2 diabetes is characterized by insulin resistance, and ENPP1 plays an important role in insulin resistance. We investigated the association of the ENPP1 K121Q polymorphism with both diabetes and obesity (body mass index [BMI]) in Korean male workers. The study design was case-control. Subjects were 1,945 male workers (type 2 diabetes, 195; non-diabetes, 1,750) of nuclear power plants who received examinations from March to October in 2004. We collected venous blood samples under fasting (> or =8 hr) conditions, calculated BMI by height and weight, and assessed relevant biochemical factors. The results of this study demonstrated that the ENPP1 121Q genotype (KQ+QQ types) was not associated with type 2 diabetes (odds ratios [OR], 0.854; 95% confidence interval [CI], 0.571-1.278) or obesity (OR, 0.933; 95% CI, 0.731-1.190). In addition, the frequency of the Q allele was not related to type 2 diabetes (OR, 0.911; 95% CI, 0.630-1.319) or obesity (OR, 0.962; 95% CI, 0.767-1.205). We concluded that the ENPP1 121Q allele is not a critical determinant for either diabetes or obesity in Korean males. The discordance between the results of this study and those derived from studies of Dominican, South Asian, Caucasian, Finnish, and French populations might be due to differences in genetic backgrounds between these populations.
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PMID:The K121Q polymorphism in ENPP1 (PC-1) is not associated with type 2 diabetes or obesity in Korean male workers. 1858 83

Diabetes mellitus is the most common chronic metabolic disease. The raising diabetes epidemic is unfolding as an interaction between several environmental factors and a genetic predisposition. The aim of the current study was to evaluate the role of the PPARgamma-Pro12Ala and ENPP1-K121Q polymorphisms on type 2 diabetes (T2D) risk in a case-control study in the Tunisian population. To assess for any association of ENPP1-K121Q and PPARgamma-Pro12Ala polymorphisms with T2D risk, we analysed the genotypic and allelic distributions of each variant in the studied cohort. Our results support that the genetic variation at ENPP1-K121Q predisposes to T2D in the Tunisian population after adjustment on gender, age and BMI status (OR=1.55, 95%CI [1.11-2.16], p=0.007). Conversely, the PPARgamma-Pro12Ala variant seems not to have a significant effect on T2D risk in our Tunisian cohort. However, the minor A-allele would convey protection against overweight in the Tunisian population. In fact, the over weighted subjects showed a significantly lower frequency of A-allele than lean controls (OR=0.49, 95%CI [0.25-0.97], p=0.02). In conclusion, our findings support the hypothesis that ENPP1-121Q is involved in the genetic susceptibility of T2D in the Tunisian population, while the PPARgamma-12Ala allele may confer protection against overweight.
Diabetes Res Clin Pract 2008 Sep
PMID:Effect of ENPP1/PC-1-K121Q and PPARgamma-Pro12Ala polymorphisms on the genetic susceptibility to T2D in the Tunisian population. 1865 35

Plasma cell membrane glycoprotein-1 or ectonucleotide pyrophosphatase/phosphodiesterase (PC-1/ENPP1) has been shown to inhibit insulin signaling, and its genetic polymorphism or increased expression is associated with type 2 diabetes in humans. Therefore, PC-1 inhibition represents a potential strategy in treating diabetes. Since patients with phosphodiesterase/pyrophosphatase deficient PC-1 manifest abnormal calcification, enhancing insulin signaling by inhibiting PC-1 for the treatment of diabetes will be feasible only if PC-1 phosphodiesterase/pyrophosphatase activity needs not be significantly diminished. However, whether inhibition of insulin receptor signaling by PC-1 is dependent upon its phosphodiesterase/pyrophosphatase activity remains controversial. In this study, the extracellular domain of the human PC-1 in its native form or with a T256A or T256S mutation was overexpressed and purified. Enzymatic assays showed that both mutants have less than 10% of the activity of the wild-type protein. In HEK293 cells stably expressing recombinant insulin receptor or insulin-like growth factor 1 (IGF1) receptor, transient expression of wild-type full length PC-1 (PC-1.FL.WT) but not the T256A or T256S mutants inhibits insulin signaling without affecting IGF1 signaling. Western blot and FACS analysis showed that the wild-type and mutant full length PC-1 proteins are expressed at similar levels in the cells, and were localized to the similar levels on the cell surface. Overexpression of PC-1.FL.WT did not affect insulin receptor mRNA level, total protein and cell surface levels. Together, these results suggest that the inhibition of insulin signaling by PC-1 is somewhat specific and is dependent upon the enzymatic activity of the phosphodiesterase/pyrophosphatase.
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PMID:Evidence that inhibition of insulin receptor signaling activity by PC-1/ENPP1 is dependent on its enzyme activity. 1937 58

Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells in vitro and in transgenic mice in vivo when overexpressed. Furthermore, both genetic polymorphism and increased expression of PC-1 have been reported to be associated with type 2 diabetes in humans. Thus it was proposed that PC-1 inhibition represents a potential strategy for the treatment of type 2 diabetes. However, it has not been proven that suppression of PC-1 expression or inhibition of its function will actually improve insulin sensitivity. We show in the current study that transient overexpression of PC-1 inhibits insulin-stimulated insulin receptor tyrosine phosphorylation in HEK293 cells, while knockdown of PC-1 with siRNA significantly increases insulin-stimulated Akt phosphorylation in HuH7 human hepatoma cells. Adenoviral vector expressing a short hairpin RNA against mouse PC-1 (PC-1shRNA) was utilized to efficiently knockdown PC-1 expression in the livers of db/db mice. In comparison with db/db mice treated with a control virus, db/db mice treated with the PC-1shRNA adenovirus had approximately 80% lower hepatic PC-1 mRNA levels, approximately 30% lower ambient fed plasma glucose, approximately 25% lower fasting plasma glucose, and significantly improved oral glucose tolerance. Taken together, these results demonstrate that suppression of PC-1 expression improves insulin sensitivity in vitro and in an animal model of diabetes, supporting the proposition that PC-1 inhibition is a potential therapeutic approach for the treatment of type 2 diabetes.
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PMID:Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo. 1957 57

Diabetes mellitus is a major cause of morbidity and mortality among transplanted patients. This study evaluated the role of the ENPP1 K121Q polymorphism and other variables known to affect diabetes risk in 115 nondiabetic and unrelated patients who underwent kidney transplant at our institution and had consented for use of genetic material (30% whites, 48% blacks, and 22% Hispanics). Thirty-six of these patients (30%) developed posttransplant diabetes mellitus (PTDM) within 1 year of observation from transplant. Black race, ENPP1 K121Q polymorphism, age, body mass index (BMI), and immunosuppressive medications were found to have the strongest associations with PTDM in the logistic regression and receiver operator characteristic (ROC) analysis. However, because ENPP1 K121Q is more common in Hispanics and in blacks, who also have higher PTDM prevalence, the studied genetic polymorphism did not exert independent predictive effect, whereas ethnicity, specifically black versus non-black, was the most robust predictor of PTDM. The model with the largest ROC area under the curve (AUC) of 0.80 was comprised of black/non-black, age, BMI, and tacrolimus treatment as significant predictors. A reduced model containing only ethnicity (black/non-black) and age as predictors yielded similar results (ROC AUC 0.78). We conclude that black race and age are major and not modifiable risk factors for PTDM. The specific role of ENPP1 K121Q on ethnic susceptibility to PTDM deserves further investigation in larger cohorts of transplanted patients.
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PMID:ENPP1/PC-1 K121Q and other predictors of posttransplant diabetes. 2095 5

Type 2 diabetes (T2D) mellitus is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. It has been a worldwide public health problem, which is increasing rapidly, especially in developing countries such as China. The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, also known as plasma cell membrane glycoprotein 1, has been reported by genetic association studies as being associated with T2D and obesity in various populations, such as Caucasian and African American. However, there are also some controversial results in Asian populations. Our study tried to examine the associations between ENPP1 and T2D and obesity. Rs1044498 (K121Q) and rs7754561 were genotyped in 1912 patients and 2041 control subjects through TaqMan technology on the ABI7900 system. They showed no statistical association with T2D, obesity or any metabolic quantitative traits. Our meta-analysis result was consistent with it. Our study did not replicate the positive association found previously and suggested that K121Q of ENPP1 might not have a major role in the susceptibility to T2D or obesity in the Chinese Han population.
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PMID:The ENPP1 K121Q polymorphism is not associated with type 2 diabetes or obesity in the Chinese Han population. 2098 Oct 35

Artery calcification reflects an admixture of factors such as ectopic osteochondral differentiation with primary host pathological conditions. We review how genetic factors, as identified by human genome-wide association studies, and incomplete correlations with various mouse studies, including knockout and strain analyses, fit into "pieces of the puzzle" in intimal calcification in human atherosclerosis, and artery tunica media calcification in aging, diabetes mellitus, and chronic kidney disease. We also describe in sharp contrast how ENPP1, CD73, and ABCC6 serve as "cogs in a wheel" of arterial calcification. Specifically, each is a minor component in the function of a much larger network of factors that exert balanced effects to promote and suppress arterial calcification. For the network to normally suppress spontaneous arterial calcification, the "cogs" ENPP1, CD73, and ABCC6 must be present and in working order. Monogenic ENPP1, CD73, and ABCC6 deficiencies each drive a molecular pathophysiology of closely related but phenotypically different diseases (generalized arterial calcification of infancy (GACI), pseudoxanthoma elasticum (PXE) and arterial calcification caused by CD73 deficiency (ACDC)), in which premature onset arterial calcification is a prominent but not the sole feature.
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PMID:Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. 2185 56


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