A Central Role for GRB10 in Regulation of Islet Function in Man

Inga Prokopenko(Centre for Human Genetics), Wenny Poon(Lund University), Reedik Mägi(Centre for Human Genetics), Rashmi B. Prasad(Lund University), Albert Salehi(Lund University), Peter Almgren(Lund University), Peter Osmark(Lund University), Nabila Bouatia‐Naji(Centre National de la Recherche Scientifique), Nils Wierup(Lund University), Tove Fall(Uppsala University), Alena Stančáková(University of Eastern Finland), Adam Barker(University of Cambridge), Vasiliki Lagou(Centre for Human Genetics), Clive Osmond(MRC Lifecourse Epidemiology Unit), Weijia Xie(University of Exeter), Jari Lahti(University of Helsinki), Anne Jackson(University of Michigan), Yu-Ching Cheng(University of Maryland, Baltimore), Jie Liu(University of Maryland, Baltimore), Jeffrey R. O’Connell(University of Maryland, Baltimore), Paul Blomstedt(Åbo Akademi University), João Fadista(Lund University), Sami Alkayyali(Lund University), Tasnim Dayeh(Scania (Sweden)), Emma Ahlqvist(Lund University), Jalal Taneera(Lund University), Cécile Lecœur(Centre National de la Recherche Scientifique), Ashish Kumar(Centre for Human Genetics), Ola Hansson(Lund University), Karin Hansson(Lund University), Benjamin F. Voight(University of Pennsylvania), Hyun Min Kang(University of Michigan), Claire Lévy‐Marchal(Inserm), Vincent Vatin(Centre National de la Recherche Scientifique), Aarno Palotie(Broad Institute), Ann-Christine Syvänen(Uppsala University), Andrea Mari, Michael N. Weedon(University of Exeter), Ruth J. F. Loos(University of Cambridge), Ken K. Ong(University of Cambridge), Peter M. Nilsson(Skåne University Hospital), Bo Isomaa(Folkhälsans Forskningscentrum), Tiinamaija Tuomi(Helsinki University Hospital), Nicholas J. Wareham(University of Cambridge), Michael Stümvoll(IFB Adiposity Diseases), Elisabeth Widén(University of Helsinki), Timo A. Lakka(University of Eastern Finland), Claudia Langenberg(University of Cambridge), Anke Tönjes(IFB Adiposity Diseases), Rainer Rauramaa(University of Eastern Finland), Johanna Kuusisto(University of Eastern Finland), Timothy M. Frayling(University of Exeter), Philippe Froguel(Centre National de la Recherche Scientifique), Mark Walker(Newcastle University), Johan G. Eriksson(University of Helsinki), Charlotte Ling(Scania (Sweden)), Péter Kovács(IFB Adiposity Diseases), Erik Ingelsson(Uppsala University), Mark I. McCarthy(Centre for Human Genetics), Alan R. Shuldiner(University of Maryland, Baltimore), Kristi D. Silver(University of Maryland, Baltimore), Markku Laakso(University of Eastern Finland), Leif Groop(University of Helsinki), Valeriya Lyssenko(Steno Diabetes Centers)
PLoS Genetics
April 3, 2014
10.1371/journal.pgen.1004235
Cited by 199Open Access
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Abstract

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.

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