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Mechanisms of Disease: ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 694–701 (2006)Cite this article

Abstract

Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its β-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described.The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease.

Key Points

  • Specific inhibitors of insulin receptor signaling have a pathogenic role in insulin resistance, type 2 diabetes and cardiovascular disease

  • Ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing the receptor's β-subunit autophosphorylation

  • The primary, intrinsic role of E-NPP1 in the pathogenesis of in vivo insulin resistance is suggested by its overexpression in skeletal muscle, adipose tissue and cultured skin fibroblasts of nonobese, nondiabetic insulin-resistant individuals

  • Genetic studies have shown that, compared with the common E-NPP1 variant Lys121, the Gln121 variant is a stronger inhibitor of insulin receptor function and is associated with insulin resistance, type 2 diabetes and related cardiovascular and nephrovascular complications

  • Overall, the data published to date on the effect of all known E-NPP1 genetic mutations and risk for type 2 diabetes in more than 19,000 people show quite consistently that E-NPP1 gene variants are associated with type 2 diabetes in several different populations

  • Understanding the mechanisms that regulate E-NPP1 expression and/or function promises to yield important information and new targets to treat or prevent type 2 diabetes and cardiovascular disease

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Figure 1: Schematic representation of inhibitors of insulin signaling pathway with established roles in in vivo human insulin resistance
Figure 2: Effect of known ENPP1 genetic variations on the risk of type 2 diabetes in 19,826 individuals (with type 2 diabetes or controls) from 13 different published studies

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Acknowledgements

V Trischitta is supported by Telethon grant E1239, and R Di Paola is supported by Telethon grant GGP02423, and Ministry of University and Scientific Research grant FIRB RBNE01N4Z9_009, N Abate is supported by NIH grants K23-RR16075 and RO1 DK072158-01, and M Chandalia is supported by CDC grants H75/CCH523202 and AHA 0465017Y.

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Authors and Affiliations

  1. Associate Professors of Internal Medicine at the University of Texas (UT) Southwestern Medical Center, Dallas

    Nicola Abate & Manisha Chandalia

  2. Professors of Internal Medicine at UT Southwestern Medical Center, Texas, USA

    Daniel W Foster & Scott M Grundy

  3. Diabetes Research Unit at Scientific Institute Casa Sollievo della Sofferenza (CSS) in San Giovanni Rotondo,

    Rosa Di Paola & Vincenzo Trischitta

  4. Department of Clinical Sciences at the University 'La Sapienza' in Rome,

    Rosa Di Paola & Vincenzo Trischitta

  5. Diabetes Research Unit at CSS in San Giovanni Rotondo, Italy

    Rosa Di Paola & Vincenzo Trischitta

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  1. Nicola Abate
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Correspondence to Nicola Abate or Vincenzo Trischitta.

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Abate, N., Chandalia, M., Di Paola, R. et al. Mechanisms of Disease: ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors. Nat Rev Endocrinol 2, 694–701 (2006). https://doi.org/10.1038/ncpendmet0367

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