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


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.

SUBMITTER: Prokopenko I 

PROVIDER: S-EPMC3974640 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Prokopenko Inga I   Poon Wenny W   Mägi Reedik R   Prasad B Rashmi R   Salehi S Albert SA   Almgren Peter P   Osmark Peter P   Bouatia-Naji Nabila N   Wierup Nils N   Fall Tove T   Stančáková Alena A   Barker Adam A   Lagou Vasiliki V   Osmond Clive C   Xie Weijia W   Lahti Jari J   Jackson Anne U AU   Cheng Yu-Ching YC   Liu Jie J   O'Connell Jeffrey R JR   Blomstedt Paul A PA   Fadista Joao J   Fadista Joao J   Alkayyali Sami S   Dayeh Tasnim T   Ahlqvist Emma E   Taneera Jalal J   Lecoeur Cecile C   Kumar Ashish A   Hansson Ola O   Hansson Karin K   Voight Benjamin F BF   Kang Hyun Min HM   Levy-Marchal Claire C   Vatin Vincent V   Palotie Aarno A   Syvänen Ann-Christine AC   Mari Andrea A   Weedon Michael N MN   Loos Ruth J F RJ   Ong Ken K KK   Nilsson Peter P   Isomaa Bo B   Tuomi Tiinamaija T   Wareham Nicholas J NJ   Stumvoll Michael M   Widen Elisabeth E   Lakka Timo A TA   Langenberg Claudia C   Tönjes Anke A   Rauramaa Rainer R   Kuusisto Johanna J   Frayling Timothy M TM   Froguel Philippe P   Walker Mark M   Eriksson Johan G JG   Ling Charlotte C   Kovacs Peter P   Ingelsson Erik E   McCarthy Mark I MI   Shuldiner Alan R AR   Silver Kristi D KD   Laakso Markku M   Groop Leif L   Lyssenko Valeriya V  

PLoS genetics 20140403 4


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 glucag  ...[more]

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