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

被引：133

作者：

Prokopenko, Inga ^{[1
,2
,3
]}

Poon, Wenny ^{[4
]}

Maegi, Reedik ^{[2
,5
]}

Prasad, Rashmi B. ^{[4
]}

Salehi, S. Albert ^{[4
]}

Almgren, Peter ^{[4
]}

Osmark, Peter ^{[4
]}

Bouatia-Naji, Nabila ^{[6
,7
,8
]}

Wierup, Nils ^{[9
]}

Fall, Tove ^{[10
]}

Stancakova, Alena ^{[11
,12
]}

Barker, Adam ^{[13
]}

Lagou, Vasiliki ^{[1
,2
]}

Osmond, Clive ^{[14
]}

Xie, Weijia ^{[15
]}

Lahti, Jari ^{[16
,17
]}

Jackson, Anne U. ^{[18
,19
]}

Cheng, Yu-Ching ^{[20
]}

Liu, Jie ^{[20
]}

O'Connell, Jeffrey R. ^{[20
]}

Blomstedt, Paul A. ^{[21
,22
]}

Fadista, Joao ^{[4
]}

Alkayyali, Sami ^{[4
]}

Dayeh, Tasnim ^{[23
]}

Ahlqvist, Emma ^{[4
]}

Taneera, Jalal ^{[4
]}

Lecoeur, Cecile ^{[6
,7
]}

Kumar, Ashish ^{[2
,24
]}

Hansson, Ola ^{[4
]}

Hansson, Karin ^{[4
]}

Voight, Benjamin F. ^{[25
,26
]}

Kang, Hyun Min ^{[18
,19
]}

Levy-Marchal, Claire ^{[27
,28
]}

Vatin, Vincent ^{[6
,7
]}

Palotie, Aarno ^{[29
,30
,31
,32
]}

Syvanen, Ann-Christine ^{[33
]}

Mari, Andrea ^{[34
]}

Weedon, Michael N. ^{[15
]}

Loos, Ruth J. F. ^{[13
]}

Ong, Ken K. ^{[13
]}

Nilsson, Peter ^{[35
]}

Isomaa, Bo ^{[17
,36
]}

Tuomi, Tiinamaija ^{[17
,31
]}

Wareham, Nicholas J. ^{[13
]}

Stumvoll, Michael ^{[37
,38
]}

Widen, Elisabeth ^{[29
]}

Lakka, Timo A. ^{[39
,40
]}

Langenberg, Claudia ^{[13
]}

Tonjes, Anke ^{[37
,38
]}

Rauramaa, Rainer ^{[40
,41
]}

机构：

[1] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, Hammersmith Hosp, London, England

[4] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden

[5] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[6] Univ Lille Nord France, Lille, France

[7] Inst Pasteur, CNRS, UMR8199, Lille, France

[8] INSERM, U970, Paris Cardiovasc Res Ctr PARCC, Paris, France

[9] Lund Univ, Dept Clin Sci, Ctr Diabet, Malmo, Sweden

[10] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden

[11] Univ Eastern Finland, Dept Med, Kuopio, Finland

[12] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[13] Univ Cambridge, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England

[14] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[15] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[16] Univ Helsinki, Inst Behav Sci, Helsinki, Finland

[17] Folkhalsan Res Ctr, Helsinki, Finland

[18] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[19] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[20] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[21] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[22] Abo Akad Univ, Dept Math, Turku, Finland

[23] Lund Univ, CRC, Scania Univ Hosp, Epigenet & Diabet Unit,Dept Clin Sci, Malmo, Sweden

[24] Univ Basel, Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[25] Univ Penn, Dept Pharmacol, Perelman Sch Med, Philadelphia, PA 19104 USA

[26] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[27] Inst Sante Publ, INSERM, Paris, France

[28] Hop Robert Debre, INSERM, CIC EC 05, F-75019 Paris, France

[29] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[30] Wellcome Trust Sanger Inst, Cambridge, England

[31] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland

[32] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA

[33] Uppsala Univ, Sci Life Lab, Dept Med Sci, Uppsala, Sweden

[34] CNR, Inst Biomed Engn, Padua, Italy

[35] Skane Univ Hosp Malmo, Dept Clin Sci, Malmo, Sweden

[36] Dept Social Serv & Hlth Care, Pietarsaari, Finland

[37] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany

[38] Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany

[39] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland

[40] Kuopio Res Inst Exercise Med, Kuopio, Finland

[41] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland

[42] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[43] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[44] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland

[45] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

[46] Baltimore Geriatr Res Educ & Clin Ctr, Baltimore, MD USA

[47] Steno Diabet Ctr AS, Gentofte, Denmark

来源：

PLOS GENETICS | 2014年 / 10卷 / 04期

基金：

英国惠康基金; 瑞典研究理事会; 英国医学研究理事会; 芬兰科学院;

关键词：

GENOME-WIDE ASSOCIATION; GLYCEMIC TRAITS; RISK-FACTORS; LOCI; GENES; POPULATION; GLUCOSE; METHYLATION; DISRUPTION; VARIANTS;

D O I：

10.1371/journal.pgen.1004235

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：13

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