A central role for GRB10 in regulation of islet function in man.

PLoS Genet
Authors
Inga Prokopenko
Wenny Poon
Reedik Mägi
Rashmi 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 Jackson
Yu-Ching Cheng
Jie Liu
Jeffrey O'Connell
Paul Blomstedt
Joao Fadista
Sami Alkayyali
Tasnim Dayeh
Emma Ahlqvist
Jalal Taneera
Cecile Lecoeur
Ashish Kumar
Ola Hansson
Karin Hansson
Benjamin Voight
Hyun Kang
Claire Lévy-Marchal
Vincent Vatin
Aarno Palotie
Ann-Christine Syvänen
Andrea Mari
Michael Weedon
Ruth Loos
Ken Ong
Peter Nilsson
Bo Isomaa
Tiinamaija Tuomi
Nicholas Wareham
Michael Stumvoll
Elisabeth Widén
Timo Lakka
Claudia Langenberg
Anke Tönjes
Rainer Rauramaa
Johanna Kuusisto
Timothy Frayling
Philippe Froguel
Mark Walker
Johan Eriksson
Charlotte Ling
Peter Kovacs
Erik Ingelsson
Mark McCarthy
Alan Shuldiner
Kristi Silver
Markku Laakso
Leif Groop
Valeriya Lyssenko
Keywords
Humans
Male
Middle Aged
Alleles
Signal Transduction
Glucose
Insulin
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Diabetes Mellitus, Type 2
Fasting
Insulin Resistance
Receptor, Insulin
Islets of Langerhans
GRB10 Adaptor Protein
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.
Year of Publication
2014
Journal
PLoS Genet
Volume
10
Issue
4
Pages
e1004235
Date Published
2014 Apr
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004235
PubMed ID
24699409
PubMed Central ID
PMC3974640
Links
Grant list
R01 DK68495 / DK / NIDDK NIH HHS / United States
083270 / Wellcome Trust / United Kingdom
090532 / Wellcome Trust / United Kingdom
P60 DK79637 / DK / NIDDK NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
M01 RR02719 / RR / NCRR NIH HHS / United States
M01 RR16500 / RR / NCRR NIH HHS / United States
MC_UU_12015/1 / Medical Research Council / United Kingdom
MC_U106179471 / Medical Research Council / United Kingdom
MC_UU_12015/2 / Medical Research Council / United Kingdom
P30 DK072488 / DK / NIDDK NIH HHS / United States
MC_U106179472 / Medical Research Council / United Kingdom
G1002084 / Medical Research Council / United Kingdom
MC_UP_A620_1017 / Medical Research Council / United Kingdom
R01 DK54261 / DK / NIDDK NIH HHS / United States
090367 / Wellcome Trust / United Kingdom
U01 HL84756 / HL / NHLBI NIH HHS / United States
089062 / Wellcome Trust / United Kingdom
098381 / Wellcome Trust / United Kingdom
89061/Z/09/Z / Wellcome Trust / United Kingdom
G0601261 / Medical Research Council / United Kingdom
089062/Z/09/Z / Wellcome Trust / United Kingdom

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