Disease relevance of ENPP1

• Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia [1].
• Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis [2].
• The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction [3].
• To produce mice with overexpression of PC-1 in liver, a key glucose regulatory organ in this species, we injected them with a PC-1 adenovirus vector that expresses human PC-1 [4].
• Objective: Therefore, in this study, we aimed to explore the role of ENPP1 genetic variants in obesity and related traits in a representative population of Caucasian children and in cohorts of obese children with detailed metabolic characteristics including oral glucose tolerance test [5].

High impact information on ENPP1

• These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions [6].
• Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes [6].
• The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity [6].
• Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver [6].
• The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children [6].

Chemical compound and disease context of ENPP1

• Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus [7].
• A multiple linear regression analysis revealed that albuminuria, mean arterial blood pressure, haemoglobin A(1C) and serum cholesterol during follow-up predicted a steeper decline in GFR [R(2) (adjusted)=0.27], whereas the PC-1 genotype did not contribute [8].
• Membrane glycoprotein plasma cell 1 (PC-1) has been shown to be increased in type 2 diabetes and involved in insulin resistance through inhibiting the insulin receptor tyrosine kinase, which was demonstrated using cultured breast cancer cells [9].
• We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15) [10].
• The regulation of glutathione and various glutathione-dependent enzymes has been studied in two ovarian adenocarcinoma cell lines derived from a patient before (PE01) and after (PE04) the onset of drug resistance to cis-platinum, chlorambucil and 5-fluorouracil [11].

Biological context of ENPP1

• In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI [3].
• Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians [12].
• The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure [12].
• RESULTS: No difference was observed in the allele or genotype frequencies between patients and controls at either ENPP1 or TNAP [2].
• METHODS: Exons, untranslated regions (UTR) and exon-intron boundaries of ENPP1 and TNAP were sequenced using ABI Big Dye chemistry on automated sequencers [2].

Anatomical context of ENPP1

• The ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1), is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of insulin-resistant humans [4].
• Compared with controls, these mice had two- to threefold elevations of PC-1 content in liver but no changes in other tissues such as skeletal muscle [4].
• Because each PDNP-family isozyme was expressed by cells near calcifications, we transfected the isozymes in nonadherent knee meniscal cells cultured with ascorbic acid, beta-glycerophosphate, and dexamethasone supplementation to stimulate them to calcify the matrix [13].
• Immunohistochemically E-NPP1 was located on the apical cytoplasmic side of cancer cells, whereas E-NPP3 was located in the apical plasma membrane [14].
• We investigated the expression and localization of E-NPP1 and -3 in human inflammatory and neoplastic bile duct diseases [14].

Associations of ENPP1 with chemical compounds

• ENPP1 is an ectoenzyme that generates phosphate (Pi) and pyrophosphate (PPi) [15].
• The PC-1 animals had 30-40 mg/dl higher glucose levels and twofold higher insulin levels [4].
• PC-1 also increased matrix calcification (with hydroxyapatite crystals) by meniscal cells [13].
• Context: ENPP1 (nucleotide pyrophosphatase/phosphodiesterase-1) encodes a membrane-bound glycoprotein that inhibits the insulin-receptor tyrosine kinase activity, resulting in reduced insulin sensitivity [5].
• Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10, 11) [7].

Co-localisations of ENPP1

• We hypothesize that an E-NPP is co-localized with an ecto-nucleoside triphosphate diphosphohydrolase and an ecto-5'-nucleotidase on the platelet surface, as part of a multiple system for nucleotide hydrolysis, since they can act under distinct physiological conditions and can be differently regulated [16].

Regulatory relationships of ENPP1

• Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling [17].
• In some cell types, NPP1 expression is constitutive or can be induced by TGF-beta and glucocorticoids, but the signal transduction pathways that control expression are poorly documented [18].

Other interactions of ENPP1

• The frequency of carrying at least one copy of the PC-1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS-1 972A (6% and 7%) [19].
• These include ANKH, ectonucleotide pyrophosphatase (ENPP1) and TNAP [2].
• OBJECTIVE: To analyze whether polymorphisms of the nucleotide pyrophosphatase (NPPS) gene and the leptin receptor gene predispose to an increased frequency and severity of OPLL [20].
• Polymorphisms of the NPPS gene and the leptin receptor gene were analyzed using the PCR assay [20].
• The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR [3].

Analytical, diagnostic and therapeutic context of ENPP1

• However, the effects of PC-1 overexpression on insulin action have not been studied in animal models [4].
• A significantly higher insulin area under the curve during oral glucose tolerance testing (P < 0.0001) and lower insulin sensitivity during hyperinsulinemic-euglycemic clamps (P = 0.04) were found in Asian Indians with PC-1 121Q variant compared with Asian Indians with wild-type PC-1 and with Caucasians with or without the polymorphism [19].
• Constitutive low abundance PC-1 mRNA expression was detected in U20S cells and chondrocytes by a nested RNA-PCR assay and by Northern blotting [21].
• Moreover, at Western blot, insulin elicited the appearance, in both plasma membrane and cytosol, of a PC-1-related 146-kDa band (in addition to bands of 163, 117, 106, and 97 kDa observed also in absence of insulin) that was sensitive to endoglycosidase H [22].
• CONCLUSIONS/INTERPRETATION: In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes [23].

References