The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

ENPP1  -  ectonucleotide pyrophosphatase/phosphodies...

Homo sapiens

Synonyms: ARHR2, COLED, E-NPP 1, Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, M6S1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of ENPP1


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


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].


  1. Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia. Maddux, B.A., Chang, Y.N., Accili, D., McGuinness, O.P., Youngren, J.F., Goldfine, I.D. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  2. Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis. Zhang, Y., Brown, M.A., Peach, C., Russell, G., Wordsworth, B.P. Rheumatology (Oxford, England) (2007) [Pubmed]
  3. 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. Bacci, S., Ludovico, O., Prudente, S., Zhang, Y.Y., Di Paola, R., Mangiacotti, D., Rauseo, A., Nolan, D., Duffy, J., Fini, G., Salvemini, L., Amico, C., Vigna, C., Pellegrini, F., Menzaghi, C., Doria, A., Trischitta, V. Diabetes (2005) [Pubmed]
  4. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Dong, H., Maddux, B.A., Altomonte, J., Meseck, M., Accili, D., Terkeltaub, R., Johnson, K., Youngren, J.F., Goldfine, I.D. Diabetes (2005) [Pubmed]
  5. ENPP1 Variants and Haplotypes Predispose to Early Onset Obesity and Impaired Glucose and Insulin Metabolism in German Obese Children. B??ttcher, Y., K??rner, A., Reinehr, T., Enigk, B., Kiess, W., Stumvoll, M., Kovacs, P. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  6. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Meyre, D., Bouatia-Naji, N., Tounian, A., Samson, C., Lecoeur, C., Vatin, V., Ghoussaini, M., Wachter, C., Hercberg, S., Charpentier, G., Patsch, W., Pattou, F., Charles, M.A., Tounian, P., Clément, K., Jouret, B., Weill, J., Maddux, B.A., Goldfine, I.D., Walley, A., Boutin, P., Dina, C., Froguel, P. Nat. Genet. (2005) [Pubmed]
  7. Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Maddux, B.A., Sbraccia, P., Kumakura, S., Sasson, S., Youngren, J., Fisher, A., Spencer, S., Grupe, A., Henzel, W., Stewart, T.A. Nature (1995) [Pubmed]
  8. PC-1 amino acid variant (K121Q) has no impact on progression of diabetic nephropathy in type 1 diabetic patients. Jacobsen, P., Grarup, N., Tarnow, L., Parving, H.H., Pedersen, O. Nephrol. Dial. Transplant. (2002) [Pubmed]
  9. No correlation of plasma cell 1 overexpression with insulin resistance in diabetic rats and 3T3-L1 adipocytes. Sakoda, H., Ogihara, T., Anai, M., Funaki, M., Inukai, K., Katagiri, H., Fukushima, Y., Onishi, Y., Ono, H., Yazaki, Y., Kikuchi, M., Oka, Y., Asano, T. Diabetes (1999) [Pubmed]
  10. A PC-1 amino acid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria. De Cosmo, S., Argiolas, A., Miscio, G., Thomas, S., Piras, G.P., Trevisan, R., Perin, P.C., Bacci, S., Zucaro, L., Margaglione, M., Frittitta, L., Pizzuti, A., Tassi, V., Viberti, G.C., Trischitta, V. Diabetes (2000) [Pubmed]
  11. Glutathione and glutathione-dependent enzymes in ovarian adenocarcinoma cell lines derived from a patient before and after the onset of drug resistance: intrinsic differences and cell cycle effects. Lewis, A.D., Hayes, J.D., Wolf, C.R. Carcinogenesis (1988) [Pubmed]
  12. ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes. Abate, N., Chandalia, M., Satija, P., Adams-Huet, B., Grundy, S.M., Sandeep, S., Radha, V., Deepa, R., Mohan, V. Diabetes (2005) [Pubmed]
  13. Up-regulated expression of the phosphodiesterase nucleotide pyrophosphatase family member PC-1 is a marker and pathogenic factor for knee meniscal cartilage matrix calcification. Johnson, K., Hashimoto, S., Lotz, M., Pritzker, K., Goding, J., Terkeltaub, R. Arthritis Rheum. (2001) [Pubmed]
  14. Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E-NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile duct diseases. Yano, Y., Hayashi, Y., Sano, K., Nagano, H., Nakaji, M., Seo, Y., Ninomiya, T., Yoon, S., Yokozaki, H., Kasuga, M. Cancer Lett. (2004) [Pubmed]
  15. Isolation of novel mouse genes associated with ectopic ossification by differential display method using ttw, a mouse model for ectopic ossification. Koshizuka, Y., Ikegawa, S., Sano, M., Nakamura, K., Nakamura, Y. Cytogenet. Cell Genet. (2001) [Pubmed]
  16. Ecto-nucleotide pyrophosphatase/phosphodiesterase as part of a multiple system for nucleotide hydrolysis by platelets from rats: kinetic characterization and biochemical properties. Fürstenau, C.R., Trentin, D.d.a. .S., Barreto-Chaves, M.L., Sarkis, J.J. Platelets (2006) [Pubmed]
  17. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Maddux, B.A., Goldfine, I.D. Diabetes (2000) [Pubmed]
  18. Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Goding, J.W., Grobben, B., Slegers, H. Biochim. Biophys. Acta (2003) [Pubmed]
  19. Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. Abate, N., Carulli, L., Cabo-Chan, A., Chandalia, M., Snell, P.G., Grundy, S.M. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  20. The extent of ossification of posterior longitudinal ligament of the spine associated with nucleotide pyrophosphatase gene and leptin receptor gene polymorphisms. Tahara, M., Aiba, A., Yamazaki, M., Ikeda, Y., Goto, S., Moriya, H., Okawa, A. Spine. (2005) [Pubmed]
  21. Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells. Regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta. Huang, R., Rosenbach, M., Vaughn, R., Provvedini, D., Rebbe, N., Hickman, S., Goding, J., Terkeltaub, R. J. Clin. Invest. (1994) [Pubmed]
  22. Insulin modulates PC-1 processing and recruitment in cultured human cells. Menzaghi, C., Di Paola, R., Baj, G., Funaro, A., Arnulfo, A., Ercolino, T., Surico, N., Malavasi, F., Trischitta, V. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  23. Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects. Grarup, N., Urhammer, S.A., Ek, J., Albrechtsen, A., Glümer, C., Borch-Johnsen, K., Jørgensen, T., Hansen, T., Pedersen, O. Diabetologia (2006) [Pubmed]
WikiGenes - Universities