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.
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.
Inga
I
Prokopenko
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Wenny
W
Poon
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Estonian Genome Center, University of Tartu, Tartu, Estonia.
Reedik
R
Mägi
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Rashmi
R
Prasad B
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
S Albert
SA
Salehi
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Peter
P
Almgren
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Peter
P
Osmark
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.
Nabila
N
Bouatia-Naji
Department of Clinical Science, Neuroendocrine Cell Biology, Lund University Diabetes Centre, Malmö, Sweden.
Nils
N
Wierup
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Tove
T
Fall
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Alena
A
Stančáková
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Adam
A
Barker
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.
Vasiliki
V
Lagou
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
Clive
C
Osmond
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
Weijia
W
Xie
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland.
Jari
J
Lahti
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Anne U
AU
Jackson
Division of Endocrinology Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Yu-Ching
YC
Cheng
Division of Endocrinology Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Jie
J
Liu
Division of Endocrinology Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Jeffrey R
JR
O'Connell
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Department of Mathematics, Åbo Akademi University, Turku, Finland.
Paul A
PA
Blomstedt
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Joao
J
Fadista
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Sami
S
Alkayyali
Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, CRC, Scania University Hospital, Malmö, Sweden.
Tasnim
T
Dayeh
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Emma
E
Ahlqvist
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Jalal
J
Taneera
University of Lille Nord de France, Lille, France; CNRS UMR8199, Institut Pasteur de Lille, Lille, France.
Cecile
C
Lecoeur
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
Ashish
A
Kumar
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Ola
O
Hansson
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Karin
K
Hansson
Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
Benjamin F
BF
Voight
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Hyun Min
HM
Kang
INSERM - Institut de Santé Publique, Paris, France; INSERM CIC EC 05, Hôpital Robert Debré, Paris, France.
Claire
C
Levy-Marchal
University of Lille Nord de France, Lille, France; CNRS UMR8199, Institut Pasteur de Lille, Lille, France.
Vincent
V
Vatin
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.
Aarno
A
Palotie
Molecular Medicine, Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Ann-Christine
AC
Syvänen
CNR Institute of Biomedical Engineering, Padova, Italy.
Andrea
A
Mari
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
Michael N
MN
Weedon
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Ruth J F
RJ
Loos
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Ken K
KK
Ong
Department of Clinical Science, Internal Medicine, Skåne University Hospital Malmö, Malmö, Sweden.
Peter
P
Nilsson
Folkhälsan Research Centre, Helsinki, Finland; Department of Social Service and Health Care, Jakobstad, Finland.
Bo
B
Isomaa
Folkhälsan Research Centre, Helsinki, Finland; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
Tiinamaija
T
Tuomi
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Nicholas J
NJ
Wareham
University of Leipzig, Department of Medicine, Leipzig, Germany; University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.
Michael
M
Stumvoll
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Elisabeth
E
Widen
Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
Timo A
TA
Lakka
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Claudia
C
Langenberg
University of Leipzig, Department of Medicine, Leipzig, Germany; University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.
Anke
A
Tönjes
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
Rainer
R
Rauramaa
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Johanna
J
Kuusisto
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
Timothy M
TM
Frayling
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.
Philippe
P
Froguel
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Mark
M
Walker
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.
Johan G
JG
Eriksson
Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University, CRC, Scania University Hospital, Malmö, Sweden.
Charlotte
C
Ling
University of Leipzig, Department of Medicine, Leipzig, Germany; University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.
Peter
P
Kovacs
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.
Erik
E
Ingelsson
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.
Mark I
MI
McCarthy
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.
Alan R
AR
Shuldiner
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.
Kristi D
KD
Silver
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Markku
M
Laakso
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Leif
L
Groop
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden; Steno Diabetes Center A/S, Gentofte, Denmark.
Valeriya
V
Lyssenko
D000483:Alleles; D003924:Diabetes Mellitus, Type 2; D005215:Fasting / Q000378:metabolism; D051383:GRB10 Adaptor Protein / Q000235:genetics* / Q000378:metabolism*; D055106:Genome-Wide Association Study / Q000379:methods; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C096358:GRB10 protein, human; D007328:Insulin; D051383:GRB10 Adaptor Protein; D011972:Receptor, Insulin; D005947:Glucose