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Lookup NU author(s): Professor Mark Walker
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
Author(s): Prokopenko I, Poon W, Magi R, Prasad BR, Salehi SA, Almgren P, Osmark P, Bouatia-Naji N, Wierup N, Fall T, Stancakova A, Barker A, Lagou V, Osmond C, Xie WJ, Lahti J, Jackson AU, Cheng YC, Liu J, O'Connell JR, Blomstedt PA, Fadista J, Alkayyali S, Dayeh T, Ahlqvist E, Taneera J, Lecoeur C, Kumar A, Hansson O, Hansson K, Voight BF, Kang HM, Levy-Marchal C, Vatin V, Palotie A, Syvanen AC, Mari A, Weedon MN, Loos RJF, Ong KK, Nilsson P, Isomaa B, Tuomi T, Wareham NJ, Stumvoll M, Widen E, Lakka TA, Langenberg C, Tonjes A, Rauramaa R, Kuusisto J, Frayling TM, Froguel P, Walker M, Eriksson JG, Ling C, Kovacs P, Ingelsson E, McCarthy MI, Shuldiner AR, Silver KD, Laakso M, Groop L, Lyssenko V
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Print publication date: 03/04/2014
Online publication date: 03/04/2014
Acceptance date: 20/01/2014
Date deposited: 22/08/2014
ISSN (print): 1553-7390
ISSN (electronic): 1553-7404
Publisher: Public Library of Science
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