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- Olsson, Anders H, et al.
(författare)
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Two common genetic variants near nuclear encoded OXPHOS genes are associated with insulin secretion in vivo.
- 2011
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 164:5, s. 765-771
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Tidskriftsartikel (refereegranskat)abstract
- Context Mitochondrial ATP production is important in the regulation of glucose-stimulated insulin secretion. Genetic factors may modulate the capacity of the β-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes. OBJECTIVE: The aim of this study was to identify genetic loci in or adjacent to nuclear encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo. DESIGN AND METHODS: To find polymorphisms associated with glucose-stimulated insulin secretion, data from a genome-wide association study (GWAS) of 1467 non-diabetic individuals, the Diabetes Genetic Initiative (DGI), was examined. 413 single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) ≥0.05 located in or adjacent to 76 OXPHOS genes were included in the DGI GWAS. A more extensive population based study of 4323 non-diabetics, the PPP-Botnia, was used as a replication cohort. Insulinogenic index during an oral glucose tolerance test (OGTT) was used as a surrogate marker of glucose-stimulated insulin secretion. Multivariate linear regression analyses were used to test genotype-phenotype associations. RESULTS: Two common variants were indentified in the DGI, where the major C-allele of rs606164, adjacent to NDUFC2 (NADH dehyrogenase (ubiqinone) 1 subunit C2), and the minor G-allele of rs1323070, adjacent to COX7A2 (cythochrome c oxidase subunit VIIa polypeptide 2), showed nominal associations with decreased glucose-stimulated insulin secretion (p=0.0009 respective p=0.003). These associations were replicated in PPP-Botnia (p=0.002 and p=0.05). CONCLUSION: Our study shows that genetic variation near genes involved in oxidative phosphorylation may influence glucose-stimulated insulin secretion in vivo.
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| 2. |
- Rönn, Tina, et al.
(författare)
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Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Impaired oxidative capacity of skeletal muscle mitochondria contribute to insulin resistance and type 2 diabetes (T2D). Furthermore, mRNA expression of genes involved in oxidative phosphorylation, including ATP5O, is reduced in skeletal muscle from T2D patients. Our aims were to investigate mechanisms regulating ATP5O expression in skeletal muscle and association with glucose metabolism, and the relationship between ATP5O single nucleotide polymorphisms (SNPs) and risk of T2D. METHODOLOGY/PRINCIPAL FINDINGS: ATP5O mRNA expression was analyzed in skeletal muscle from young (n = 86) and elderly (n = 68) non-diabetic twins before and after a hyperinsulinemic euglycemic clamp. 11 SNPs from the ATP5O locus were genotyped in the twins and a T2D case-control cohort (n = 1466). DNA methylation of the ATP5O promoter was analyzed in twins (n = 22) using bisulfite sequencing. The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005). The degree of DNA methylation around the transcription start of ATP5O was <1% in both young and elderly twins and not associated with mRNA expression (p = 0.32). The mRNA level of ATP5O in skeletal muscle was positively related to insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02). Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins. However, we could not detect any genetic association with T2D. CONCLUSIONS/SIGNIFICANCE: Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle. These findings propose a role for ATP5O, in cooperation with other OXPHOS genes, in the regulation of in vivo glucose metabolism.
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