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

A central role for GRB10 in regulation of islet function in man
A central role for GRB10 in regulation of islet function in man
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.
1553-7390
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Prokopenko, I., Poon, W., Magi, R., Prasad, B.R., Salehi, S.A., Almgren, P., Osmark, P., Bouatia-Naji, N., Wierup, N., Fall, T., Stancakova, A., Barker, A., Lagou, V., Osmond, Clive, Xie, W., Lahti, J., Jackson, A.U., Cheng, Y.C., Liu, J., O'Connell, J.R., Blomstedt, P.A., Fadista, J., Alkayyali, S., Dayeh, T., Ahlqvist, E., Taneera, J., Lecoeur, C., Kumar, A., Hansson, O., Hansson, K., Voight, B.F., Kang, H.M., Levy-Marchal, C., Vatin, V., Palotie, A., Syvanen, A.C., Mari, A., Weedon, M.N., Loos, R.J., Ong, K.K., Nilsson, P., Isomaa, B., Tuomi, T., Wareham, N.J., Stumvoll, M., Widen, E., Lakka, T.A., Langenberg, C., Tonjes, A., Rauramaa, R., Kuusisto, J., Frayling, T.M., Froguel, P., Walker, M., Eriksson, J.G., Ling, C., Kovacs, P., Inglesson, E., McCarthy, M.I., Shuldiner, A.R., Silver, K.D., Laakso, M., Groop, L. and Lyssenko, V. (2014) A central role for GRB10 in regulation of islet function in man. PLoS Genetics, 10 (4), 1-13. (doi:10.1371/journal.pgen.1004235). (PMID:24699409)

Record type: Article

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.

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Published date: 3 April 2014
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 365990
URI: http://eprints.soton.ac.uk/id/eprint/365990
DOI: doi:10.1371/journal.pgen.1004235
ISSN: 1553-7390
PURE UUID: 8b26c87a-e263-4760-8eae-ec37d36672d9
ORCID for Clive Osmond: ORCID iD orcid.org/0000-0002-9054-4655

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Date deposited: 24 Jun 2014 09:54
Last modified: 15 Mar 2024 02:50

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Contributors

Author: I. Prokopenko
Author: W. Poon
Author: R. Magi
Author: B.R. Prasad
Author: S.A. Salehi
Author: P. Almgren
Author: P. Osmark
Author: N. Bouatia-Naji
Author: N. Wierup
Author: T. Fall
Author: A. Stancakova
Author: A. Barker
Author: V. Lagou
Author: Clive Osmond ORCID iD
Author: W. Xie
Author: J. Lahti
Author: A.U. Jackson
Author: Y.C. Cheng
Author: J. Liu
Author: J.R. O'Connell
Author: P.A. Blomstedt
Author: J. Fadista
Author: S. Alkayyali
Author: T. Dayeh
Author: E. Ahlqvist
Author: J. Taneera
Author: C. Lecoeur
Author: A. Kumar
Author: O. Hansson
Author: K. Hansson
Author: B.F. Voight
Author: H.M. Kang
Author: C. Levy-Marchal
Author: V. Vatin
Author: A. Palotie
Author: A.C. Syvanen
Author: A. Mari
Author: M.N. Weedon
Author: R.J. Loos
Author: K.K. Ong
Author: P. Nilsson
Author: B. Isomaa
Author: T. Tuomi
Author: N.J. Wareham
Author: M. Stumvoll
Author: E. Widen
Author: T.A. Lakka
Author: C. Langenberg
Author: A. Tonjes
Author: R. Rauramaa
Author: J. Kuusisto
Author: T.M. Frayling
Author: P. Froguel
Author: M. Walker
Author: J.G. Eriksson
Author: C. Ling
Author: P. Kovacs
Author: E. Inglesson
Author: M.I. McCarthy
Author: A.R. Shuldiner
Author: K.D. Silver
Author: M. Laakso
Author: L. Groop
Author: V. Lyssenko

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