Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes

BMC Medical Genetics, Mar 2015

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.

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Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes

Hansen et al. BMC Medical Genetics Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes Tue H Hansen 0 Henrik Vestergaard 0 Torben Jrgensen Marit Eika Jrgensen Torsten Lauritzen Ivan Brandslund Cramer Christensen Oluf Pedersen 0 Torben Hansen 0 Anette P Gjesing 0 0 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 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 ( = 0.1 mmol kg1 min1; 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. Polypyrimidine tract binding protein 1; Type 2 diabetes; Beta-cell function; Genetics; Insulin release - Background The global prevalence of type 2 diabetes (T2D) is reaching pandemic proportions with an alarming estimate of 439 million affected individuals world-wide (equal to 7.7% of the worlds population) by the year 2030 [1]. It is well established, that the hyperglycemia observed in T2D arises due to a combination of peripheral insulin resistance and impaired pancreatic beta-cell function and consequently reduced insulin secretion [2,3]. T2D is a heritable [4-6], complex metabolic disorder involving several molecular pathways with currently 90 known genetic susceptibility loci, most of which have been identified in recent years by large-scale genome-wide association studies (GWAS) [7]. However, despite recent advances in the understanding of the genetic mechanisms underlying T2D, a substantial part of the heritability (~80-90%) remains unexplained [8]. A candidate-gene study by Heni and colleagues [9] reported a nominal association between reduced glucose stimulated insulin release and the rs11085226 G-allele of the gene encoding polypyrimidine tract binding protein 1 (PTBP1). PTBP1 is a 57 kDa protein consisting of four RNA recognition motifs [10]. It is involved in pre-mRNA and mRNA metabolism as a regulator of alternative splicing, polyadenylation, mRNA stability and initiation of translation [11-13]. It facilitates the biosynthesis and secretion of insulin by binding the pyrimidine rich tract of the 3-untranslated region of insulin mRNA [14] and other mRNA molecules encoding secretory proteins present in insulin granules of the pancreatic beta-cell [15-17], thus increasing mRNA stability and translation [12,18-20]. Disruption of PTBP1 function, either by siRNA mediated inhibition or mutation of the PTB binding site, results in insulin mRNA destabilization and lower insulin contents [14,15]. Similarly, depletion of PTB levels by microRNA mediated inhibition of PTBmRNA translation, lowers insulin biosynthesis rates [21]. Also, nuclear retention of PTBP1 has been proposed as a contributing factor in the impairment of rapid glucosestimulated (...truncated)


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Tue H Hansen, Henrik Vestergaard, Torben Jørgensen, Marit Jørgensen, Torsten Lauritzen, Ivan Brandslund, Cramer Christensen, Oluf Pedersen, Torben Hansen, Anette P Gjesing. Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes, BMC Medical Genetics, 2015, pp. 17, 16, DOI: 10.1186/s12881-015-0160-7