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PLoS Genet DOI:10.1371/journal.pgen.1004235

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

Publication TypeJournal Article
Year of Publication2014
AuthorsProkopenko, I, Poon, W, Mägi, R, B, RPrasad, S Salehi, A, Almgren, P, Osmark, P, Bouatia-Naji, N, Wierup, N, Fall, T, Stančáková, A, Barker, A, Lagou, V, Osmond, C, Xie, W, Lahti, J, Jackson, AU, Cheng, Y-C, 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, HMin, Lévy-Marchal, C, Vatin, V, Palotie, A, Syvänen, A-C, Mari, A, Weedon, MN, Loos, RJF, Ong, KK, Nilsson, P, Isomaa, B, Tuomi, T, Wareham, NJ, Stumvoll, M, Widén, E, Lakka, TA, Langenberg, C, Tönjes, 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
JournalPLoS Genet
Date Published2014 Apr
KeywordsAlleles, Diabetes Mellitus, Type 2, Fasting, Genome-Wide Association Study, Glucose, GRB10 Adaptor Protein, Humans, Insulin, Insulin Resistance, Islets of Langerhans, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Insulin, Signal Transduction

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.


Alternate JournalPLoS Genet.
PubMed ID24699409
PubMed Central IDPMC3974640
Grant ListR01 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