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PLoS Genet. 2014 Apr 3;10(4):e1004235. doi: 10.1371/journal.pgen.1004235. eCollection 2014 Apr.

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

Author information

1
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.
2
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Estonian Genome Center, University of Tartu, Tartu, Estonia.
4
University of Lille Nord de France, Lille, France; CNRS UMR8199, Institut Pasteur de Lille, Lille, France; INSERM U970, Paris Cardiovascular Research Center PARCC, Paris, France.
5
Department of Clinical Science, Neuroendocrine Cell Biology, Lund University Diabetes Centre, Malmö, Sweden.
6
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
7
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
8
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
9
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
10
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
11
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
12
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland.
13
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
14
Division of Endocrinology Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
15
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Department of Mathematics, Åbo Akademi University, Turku, Finland.
16
Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, CRC, Scania University Hospital, Malmö, Sweden.
17
University of Lille Nord de France, Lille, France; CNRS UMR8199, Institut Pasteur de Lille, Lille, France.
18
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
19
Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
20
INSERM - Institut de Santé Publique, Paris, France; INSERM CIC EC 05, Hôpital Robert Debré, Paris, France.
21
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Program in Medical and Population Genetics and Genetics Analysis Platform, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusettes, United States of America.
22
Molecular Medicine, Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
23
CNR Institute of Biomedical Engineering, Padova, Italy.
24
Department of Clinical Science, Internal Medicine, Skåne University Hospital Malmö, Malmö, Sweden.
25
Folkhälsan Research Centre, Helsinki, Finland; Department of Social Service and Health Care, Jakobstad, Finland.
26
Folkhälsan Research Centre, Helsinki, Finland; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
27
University of Leipzig, Department of Medicine, Leipzig, Germany; University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.
28
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
29
Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
30
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
31
Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom; University of Lille Nord de France, Lille, France; CNRS UMR8199, Institut Pasteur de Lille, Lille, France.
32
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
33
Folkhälsan Research Centre, Helsinki, Finland; Helsinki University, Department of General Practice and Primary Health Care, Helsinki, Finland; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
34
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
35
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kindom.
36
Division of Endocrinology Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Baltimore Geriatric Research, Education and Clinical Center, Baltimore, Maryland, United States of America.
37
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
38
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Steno Diabetes Center A/S, Gentofte, Denmark.

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.

PMID:
24699409
PMCID:
PMC3974640
DOI:
10.1371/journal.pgen.1004235
[Indexed for MEDLINE]
Free PMC Article

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