Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes.
BACKGROUND
The variant rs11085226 (G) within the gene encoding polypyrimidine tract binding protein 1 (PTBP1) was reported to associate with reduced insulin release determined by an oral glucose tolerance test (OGTT) as well as an intravenous glucose tolerance test (IVGTT). The aim of the present study was to validate the association of the rs11085226 G-allele of PTBP1 with previously investigated OGTT- and IVGTT-derived diabetes-related metabolic quantitative phenotypes, to conduct exploratory analyses of additional measures of beta-cell function, and to further investigate a potential association with type 2 diabetes.


METHODS
PTBP1 rs11085226 was genotyped in 20,911 individuals of Danish Caucasian ethnicity ascertained from 9 study samples. Case control analysis was performed on 5,634 type 2 diabetic patients and 11,319 individuals having a normal fasting glucose level as well as 4,641 glucose tolerant controls, respectively. Quantitative trait analyses were performed in up to 13,605 individuals subjected to an OGTT or blood samples obtained after an overnight fast, as well as in 596 individuals subjected to an IVGTT.


RESULTS
Analyses of fasting and OGTT-derived quantitative traits did not show any significant associations with the PTBP1 rs11085226 variant. Meta-analysis of IVGTT-derived quantitative traits showed a nominally significant association between the variant and reduced beta-cell responsiveness to glucose (β = -0.1 mmol · kg(-1) · min(-1); 95% CI: -0.200.20 - -0.024; P = 0.01) assuming a dominant model of inheritance, but failed to replicate a previously reported association with area under the curve (AUC) for insulin. Case control analysis did not show an association of the PTBP1 rs11085226 variant with type 2 diabetes.


CONCLUSIONS
Despite failure to replicate the previously reported associations of PTBP1 rs11085226 with OGTT- and IVGTT-derived measures of beta-cell function, we did find a nominally significant association with reduced beta-cell responsiveness to glucose during an IVGTT, a trait not previously investigated, leaving the potential influence of this variant in PTBP1 on glucose stimulated insulin release open for further investigation. However, the present study does not support the hypothesis that the variant confers risk of type 2 diabetes.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DK-2100, Copenhagen, Denmark. tuehhansen@sund.ku.dk.
Tue H
TH
Hansen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DK-2100, Copenhagen, Denmark. henrik.vestergaard@sund.ku.dk.
Henrik
H
Vestergaard
Research Centre for Prevention and Health, Glostrup University Hospital, Nordre Ringvej 57, Building 84-85, DK-2600, Glostrup, Denmark. torben.joergensen@regionh.dk.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. torben.joergensen@regionh.dk.
Torben
T
Jørgensen
Steno Diabetes Center, Niels Steensens Vej 2, DK-2820, Gentofte, Denmark. maej@steno.dk.
Marit Eika
ME
Jørgensen
Department of Public Health, Section of General Practice, Aarhus University, Bartholins Allé 2, DK-8000, Aarhus, Denmark. tl@ph.au.dk.
Torsten
T
Lauritzen
Department of Clinical Biochemistry, Vejle Hospital, Kabbeltoft 25, DK-7100, Vejle, Denmark. ivan.brandslund@rsyd.dk.|Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. ivan.brandslund@rsyd.dk.
Ivan
I
Brandslund
Department of Internal Medicine and Endocrinology, SLB, Vejle Hospital, Kabbeltoft 25, DK-7100, Vejle, Denmark. cramer.kjeldahl.christensen@rsyd.dk.
Cramer
C
Christensen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DK-2100, Copenhagen, Denmark. oluf@sund.ku.dk.
Oluf
O
Pedersen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DK-2100, Copenhagen, Denmark. hansen@sund.ku.dk.|Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. hansen@sund.ku.dk.
Torben
T
Hansen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, DK-2100, Copenhagen, Denmark. anette.gjesing@sund.ku.dk.
Anette P
AP
Gjesing
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics*
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007328:Insulin; C450006:PTBP1 protein, human; D038941:Polypyrimidine Tract-Binding Protein; D005947:Glucose