| 1. |
- Koeck, Thomas, et al.
(författare)
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A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
- 2011
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 13:1, s. 80-91
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.
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| 2. |
- Reiling, Erwin, et al.
(författare)
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Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 20:6, s. 696-700
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Tidskriftsartikel (refereegranskat)abstract
- p53 is involved in stress response, metabolism and cardiovascular functioning. The C-allele of rs1042522 in the gene encoding for p53 is associated with longevity and cancer. In this study, we aimed to investigate the association of rs1042522 with changes in blood pressure, BMI and waist circumference using a longitudinal approach. Rs1042522 was analyzed in two longitudinal studies; the Doetinchem Cohort Study (DCS) and the Botnia Prospective Study (BPS). Changes in quantitative traits over time were investigated according to rs1042522 genotypes. An association between rs1042522 and changes in diastolic blood pressure (DBP) in the DCS over time was observed (P=0.004). Furthermore, a borderline significant association was detected with changes in waist circumference over time (P=0.03). These findings were also observed in the BPS (P=0.02 and P=0.05). The C/C-genotype (Pro/Pro) showed the most moderate time-related increase for the studied endpoints. Furthermore, data from the BPS suggested that the C/C-genotype protects against increases in glucose levels over time at 30 and 60 min during oral glucose tolerance test (P=0.01 and P=0.02). In conclusion, we found an association between the C/C-genotype of rs1042522 and changes in DBP and waist circumference over time. This might contribute to the longevity phenotype observed for the same genotype by others. European Journal of Human Genetics (2012) 20, 696-700; doi:10.1038/ejhg.2011.240; published online 21 December 2011
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| 3. |
- Reiling, Erwin, et al.
(författare)
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The Association of Mitochondrial Content with Prevalent and Incident Type 2 Diabetes.
- 2010
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 1909-1915
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Tidskriftsartikel (refereegranskat)abstract
- Context: It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive. Objective: In this study, we assessed the heritability of mtDNA content in buccal cells and analyzed the association of mtDNA content in blood with prevalent and incident T2D. Design and Setting: mtDNA content from cells from buccal and blood samples was assessed using a real-time PCR-based assay. Heritability of mtDNA content was estimated in 391 twins from the Netherlands Twin Register. The association with prevalent T2D was tested in a case control study from The Netherlands (n = 329). Incident T2D was analyzed using prospective samples from Finland (n = 444) and The Netherlands (n = 238). Main Outcome Measures: We measured the heritability of mtDNA content and the association of mtDNA content in blood with prevalent and incident T2D. Results: A heritability of mtDNA content of 35% (19-48%) was estimated in the twin families. We did not observe evidence of an association between mtDNA content and prevalent or incident T2D and related traits. Furthermore, we observed a decline in mtDNA content with increasing age that was male specific (P = 0.001). Conclusion: In this study, we show that mtDNA content has a heritability of 35% in Dutch twins. There is no association between mtDNA content in blood and prevalent or incident T2D and related traits in our study samples.
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