 A Central Role for GRB10 in Regulation of Islet Function in ManInga Prokopenko, Wenny Poon, Reedik Mägi, Rashmi Prasad B, S Albert Salehi, Peter Almgren, Peter Osmark, Nabila Bouatia-Naji, Nils Wierup, Tove Fall, Alena Stančáková, Adam Barker, Vasiliki Lagou, Clive Osmond, Weijia Xie, Jari Lahti, Anne U Jackson, Yu-Ching Cheng, Jie Liu, Jeffrey R O'Connell, Paul A Blomstedt, Joao Fadista, Sami Alkayyali, Tasnim Dayeh, Emma Ahlqvist, Jalal Taneera, Cecile Lecoeur, Ashish Kumar, Ola Hansson, Karin Hansson, Benjamin F Voight, Hyun Min Kang, Claire Levy-Marchal, Vincent Vatin, Aarno Palotie, Ann-Christine Syvänen, Andrea Mari, Michael N Weedon, Ruth J F Loos, Ken K Ong, Peter Nilsson, Bo Isomaa, Tiinamaija Tuomi, Nicholas J Wareham, Michael Stumvoll, Elisabeth Widen, Timo A Lakka, Claudia Langenberg, Anke Tönjes, Rainer Rauramaa, Johanna Kuusisto, Timothy M Frayling, Philippe Froguel, Mark Walker, Johan G Eriksson, Charlotte Ling, Peter Kovacs, Erik Ingelsson, Mark I McCarthy, Alan R Shuldiner, Kristi D Silver, Markku Laakso, Leif Groop and Valeriya Lyssenko PLOS Genetics, 2014, vol. 10, issue 4, 1-13 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.Author Summary: In this paper, we report the first large genome-wide association study in man for glucose-stimulated insulin secretion (GSIS) indices during an oral glucose tolerance test. We identify seven genetic loci and provide effects on GSIS for all previously reported glycemic traits and obesity genetic loci in a large-scale sample. We observe paradoxical effects of genetic variants in the growth factor receptor-bound protein 10 (GRB10) gene yielding both reduced GSIS and reduced fasting plasma glucose concentrations, specifically showing a parent-of-origin effect of GRB10 on lower fasting plasma glucose and enhanced insulin sensitivity for maternal and elevated glucose and decreased insulin sensitivity for paternal transmissions of the risk allele. We also observe tissue-specific differences in DNA methylation and allelic imbalance in expression of GRB10 in human pancreatic islets. We further disrupt GRB10 by shRNA in human islets, showing reduction of both insulin and glucagon expression and secretion. In conclusion, we provide evidence for complex regulation of GRB10 in human islets. Our data suggest that tissue-specific methylation and 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. Date: 2014 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1004235 DOI: 10.1371/journal.pgen.1004235 Access Statistics for this article More articles in PLOS Genetics from Public Library of Science |
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