A Central Role for GRB10 in Regulation of Islet Function in Man
2014 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 4, e1004235Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 10, no 4, e1004235
IdentifiersURN: urn:nbn:se:uu:diva-222122DOI: 10.1371/journal.pgen.1004235ISI: 000335499600017PubMedID: 24699409OAI: oai:DiVA.org:uu-222122DiVA: diva2:710773
FunderSwedish Research Council, SFO EXODIAB: Dnr 2009-1039 Dnr 521-2010-3490 Dnr 521-2007-4037 Dnr 521-2008-2974 ANDIS Dnr 825-2010-5983Knut and Alice Wallenberg Foundation, KAW 2009.0243Torsten Söderbergs stiftelse, MT33/09Ragnar Söderbergs stiftelse, MT33/09Novo NordiskSwedish Heart Lung FoundationEU, European Research Council, QLG1-CT-2001-01252 HEALTH-F4-2007-201413AstraZenecaNIH (National Institute of Health), R01 DK54261 R01 DK68495 U01 HL84756The Royal Swedish Academy of SciencesSwedish Foundation for Strategic Research Swedish Diabetes AssociationSwedish Society of MedicineGerman Research Foundation (DFG), DFG - SFB 1052Wellcome trust, 89061/Z/09/Z 089062/Z/09/Z WT089062 083270 090367 090532 098381EU, FP7, Seventh Framework Programme, HEALTH-F4-2007-201413