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GCKR: How Genetic Variation Across the Allelic Spectrum Influences Protein Function and Metabolic Traits in Humans

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The Genetics of Type 2 Diabetes and Related Traits

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Abstract

Genome-wide association studies (GWAS) have generated considerable interest in glucokinase regulatory protein (GKRP; gene name GCKR) which is an inhibitor of hepatic glucokinase (GCK), an enzyme that plays a critical role in glucose update and disposal in liver. From the initial discovery of GCKR variants associated with triglyceride and glucose levels through the identification of pleiotropic associations with a wide variety of metabolic phenotypes, we have learned a great deal about the importance of GKRP as a critical node in hepatic metabolism. GKRP remains one of the few well-studied GWAS loci where attempts have been made to understand the functional as well as the phenotypic impact of genetic variants across the allelic spectrum. Given the interest in developing liver-specific glucokinase activators and small molecules which disrupt the GKRP:GCK interaction for the treatment of type 2 diabetes, these genetic insights provide a wealth of information regarding efficacy and potential adverse on-target effects in humans.

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  1. Department of Clinical Sciences in Malmö, Lund University Diabetes Center, Lund University, Malmö, Sweden

    Marju Orho-Melander

  2. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LE, UK

    Anna L. Gloyn

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  1. Marju Orho-Melander
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  1. Ctr Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Jose C. Florez

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Orho-Melander, M., Gloyn, A.L. (2016). GCKR: How Genetic Variation Across the Allelic Spectrum Influences Protein Function and Metabolic Traits in Humans. In: Florez, J. (eds) The Genetics of Type 2 Diabetes and Related Traits. Springer, Cham. https://doi.org/10.1007/978-3-319-01574-3_15

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