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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Inga Prokopenko
  • Wenny Poon
  • Reedik Mägi
  • Peter Almgren
  • Peter Osmark
  • Nabila Bouatia-Naji
  • Tove Fall
  • Alena Stančáková
  • Adam Barker
  • Vasiliki Lagou
  • Clive Osmond
  • Weijia Xie
  • Jari Lahti
  • Anne U Jackson
  • Yu-Ching Cheng
  • Jie Liu
  • Jeffrey R O'Connell
  • Paul A Blomstedt
  • Joao Fadista
  • Sami Alkayyali
  • Tasnim Dayeh
  • Jalal Taneera
  • Cecile Lecoeur
  • Ashish Kumar
  • Benjamin F Voight
  • Hyun Min Kang
  • Claire Levy-Marchal
  • Vincent Vatin
  • Aarno Palotie
  • Ann-Christine Syvänen
  • Andrea Mari
  • Michael N Weedon
  • Ruth J F Loos
  • Ken K Ong
  • Bo Isomaa
  • Tiinamaija Tuomi
  • Nicholas J Wareham
  • Michael Stumvoll
  • Elisabeth Widen
  • Timo A Lakka
  • Claudia Langenberg
  • Anke Tönjes
  • Rainer Rauramaa
  • Johanna Kuusisto
  • Timothy M Frayling
  • Philippe Froguel
  • Mark Walker
  • Johan G Eriksson
  • Peter Kovacs
  • Erik Ingelsson
  • Mark I McCarthy
  • Alan R Shuldiner
  • Kristi D Silver
  • Markku Laakso
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Article numbere1004235
JournalPLoS Genetics
Volume10
Issue number4
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes

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