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  • Review Article
  • Published:

Insulin signaling regulating genes: effect on T2DM and cardiovascular risk

Nature Reviews Endocrinology volume 5, pages 682–693 (2009)Cite this article

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disorder that has a heterogeneous genetic and environmental background. In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. The biological relevance of these three polymorphisms has been very thoroughly characterized both in vitro and in vivo and the available data indicate that they all affect insulin signaling and action as well as insulin secretion. They also affect insulin-mediated regulation of endothelial cell function. In addition, several reports indicate that the effects of all three polymorphisms on the risk of T2DM and cardiovascular diseases related to insulin resistance depend on the clinical features of the individual, including their body weight and age at disease onset. Thus, these polymorphisms might be used to demonstrate how difficult it is to ascertain the contribution of relatively infrequent genetic variants with heterogeneous effects on disease susceptibility. Unraveling the role of such variants might be facilitated by improving disease definition and focusing on specific subsets of patients.

Key Points

  • Insulin resistance in some individuals is probably the result of abnormalities that occur in the complex insulin signaling pathway; this pathway is modulated by both signaling and inhibitory molecules

  • T2DM is a complex disorder with a background that is likely to be extremely heterogeneous. Not taking this fact into account might exacerbate the difficulties of unraveling T2DM genetic architecture

  • Data obtained on the ENPP1 K121Q, the IRS1 G972R and the TRIB3 Q84R missense, functional variants suggest that they all affect insulin signaling and action as well as insulin secretion

  • These variants also affect insulin-dependent nitric oxide production by endothelial cells, thus supporting a direct deleterious role of insulin resistance on the endothelium

  • Despite such strong biological candidacies, the association of these variants with T2DM and cardiovascular risk does not reach genome-wide statistical significance (maybe due to their heterogeneous effects)

  • Overall, ENPP1 Q121, IRS1 R972 and TRIB3 R84 variants represent a paradigm of how genetic heterogeneity may become an obstacle for unraveling the genetic architecture of complex traits

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Figure 1: Association between the K121Q polymorphism of ENPP1 and T2DM.
Figure 2: Interactions between ENPP1 and obesity in modulating the risk of T2DM and cardiovascular events.
Figure 3: The effect of polymorphisms on upstream insulin signaling and insulin action a | (left side) individuals who carry all three wild-type variants (K121 variant of ENPP1, G972 variant of IRS1 and Q84 variant of TRIB3), are characterized by adequate insulin response in both 'classical' target tissues (that is, adipose tissue, liver, skeletal muscle and the endothelium) and pancreatic β-cells.

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Acknowledgements

This work was partly supported by the Italian Ministry of Health (“Ricerca Corrente 2007, 2008 and 2009” to S. P. and V. T.) and by Fondazione Roma (“Sostegno alla ricerca scientifica biomedica 2008” to V. T.).

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Authors and Affiliations

  1. IRCCS Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy

    Sabrina Prudente

  2. Department of Experimental Medicine, “Sapienza” University, Rome, Italy

    Eleonora Morini

  3. IRCCS Casa Sollievo della Sofferenza, Research Unit of Diabetes and Endocrine Diseases, San Giovanni Rotondo, Italy

    Vincenzo Trischitta

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  1. Sabrina Prudente
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Correspondence to Vincenzo Trischitta.

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Prudente, S., Morini, E. & Trischitta, V. Insulin signaling regulating genes: effect on T2DM and cardiovascular risk. Nat Rev Endocrinol 5, 682–693 (2009). https://doi.org/10.1038/nrendo.2009.215

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