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

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.

Publication metadata

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

Year: 2014

Volume: 10

Issue: 4

Pages: 1-13

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


DOI: 10.1371/journal.pgen.1004235


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Funder referenceFunder name
Boehringer Ingelheim Foundation
City of Kuopio
E. Lundstrom Foundation
ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium
European Commission
European Science Foundation (EUROSTRESS)
Finnish Diabetes Research Society
Finnish Heart Association
Juho Vainio Foundation
Kuopio University Hospital
Ministry of Education
Paivikki and Sakari Sohlberg Foundation
Region Skane County Council funds
Samfundet Folkhalsan
Science for Life Laboratory and the Swedish Research Council for Infrastructures (RFI)
Swedish Cultural Foundation in Finland
Swedish Diabetes Foundation
Swedish Heart and Lung Foundation
Swedish Heart-Lung Foundation
Swedish Research Council
Sydvastra Skanes Diabetesforening
Ahokas Foundation
Baltimore Veterans Administration Geriatric Research and Education Clinical Center
DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland)
Diabetes Research Foundation
Diabetes Research Wellness
EFSD New Horizons grant
Emil Aaltonen Foundation
European Community
Finnish Diabetes Association
Finska Lakaresallskapet
Folkhalsan Research Foundation
Foundation for Life and Health in Finland
German Diabetes Association
Heart and Lung Foundation
Jakobstad Hospital
Liv och Halsa
Medical Society of Finland
Narpes Research Foundation
Novo Nordisk foundation
Ollqvist Foundation
Royal Swedish Academy of Sciences
Signe and Ane Gyllenberg Foundation
Sigrid Juselius Foundation
Swedish Foundation for Strategic Research
Swedish Society of Medicine
Univeristy of Helsinki
Vasa and Narpes Health centers
083270Wellcome Trust
089062/Z/09/ZWellcome Trust
090367Wellcome Trust
090532Wellcome Trust
098381Wellcome Trust
123885Academy of Finland
102318Academy of Finland
141226Academy of Finland
2007-35205-17883USDA NIFA NRI Competitive Grant
120386Academy of Finland
125876Academy of Finland
141069Academy of Finland
627Ministry of Education and Culture of Finland
359Inga Britt och Arne Lundberg's Research Foundation
4/26/2010Social Insurance Institution of Finland
89061/Z/09/ZWellcome Trust
ANDIS Dnr 825-2010-5983Swedish Research Council
DFG - SFB 1052German Research Council
Dnr 521-2008-2974Swedish Research Council
Dnr 521-2007-4037Swedish Research Council
Dnr 521-2010-3490Swedish Research Council
FKZ: 01EO1001Federal Ministry of Education and Research (BMBF), Germany
G0601261Medical Research Council
KAW 2009.0243Knut & Alice Wallenberg foundation
LUDC Dnr 349-2008-6589Linnaeus grant
M01 RR02719Hopkins Bayview General Clinical Research Center
M01 RR16500University of Maryland General Clinical Research Center
MT33/09Torsten och Ragnar Soderbergs Stiftelser
HEALTH-F4-2007-201413ENGAGE project
HEALTH-F4-2007-201413EU Framework 7: ENGAGE Consortium
HEALTH-F4-2007-201413European Community
QLG1-CT-2001-01252European Union
R01 DK54261NIH
R01 DK68495NIH
RD08/0003704Diabetes UK
P30 DK072488Mid-Atlantic Nutrition Obesity Research Center
P60 DK79637Baltimore Diabetes Research and Training Center grant
SF0180142s08Estonian Government
SFO EXODIAB: Dnr 2009-1039Swedish Research Council
SP1GVARENGDevelopment Fund of the University of Tartu, in the frame of the Centre of Transitional Genomics
U01 HL84756NIH
WT089062Wellcome Trust