| 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. |
- Olsson, Anders H, et al.
(författare)
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The expression of myosin heavy chain (MHC) genes in human skeletal muscle is related to metabolic characteristics involved in the pathogenesis of type 2 diabetes.
- 2011
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 103, s. 275-281
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes patients exhibit a reduction in oxidative muscle fibres and an increase in glycolytic muscle fibres. In this study, we investigated whether both genetic and non-genetic factors influence the mRNA expression levels of three myosin heavy chain (MHC) genes represented in different fibre types. Specifically, we examined the MHC7 (slow-twitch oxidative fibre), MHCIIa (fast-twitch oxidative fibre) and MHCIIx/d (fast-twitch glycolytic fibre) genes in human skeletal muscle. We further investigated the use of MHC mRNA expression as a proxy to determine fibre-type composition, as measured by traditional ATP staining. Two cohorts of age-matched Swedish men were studied to determine the relationship of muscle mRNA expression of MHC7, MHCIIa, and MHCIIx/d with muscle fibre composition. A classical twin approach, including young and elderly Danish twin pairs, was utilised to examine if differences in expression levels were due to genetic or environmental factors. Although MHCIIx/d mRNA expression correlated positively with the level of type IIx/d muscle fibres in the two cohorts (P<0.05), a relatively low magnitude of correlation suggests that mRNA does not fully correlate with fibre-type composition. Heritability estimates and genetic analysis suggest that the levels of MHC7, MHCIIa and MHCIIx/d expression are primarily under non-genetic influence, and MHCIIa indicated an age-related decline. PGC-1α exhibited a positive relationship with the expression of all three MHC genes (P<0.05); meanwhile, PGC-1β related positively with MHCIIa expression and negatively with MHCIIx/d expression (P<0.05). While MHCIIa expression related positively with insulin-stimulated glucose uptake (P<0.01), MHCIIx/d expression related negatively with insulin-stimulated glucose uptake (P<0.05). Our findings suggest that the expression levels of the MHC genes are associated with age and both PGC-1α and PGC-1β and indicate that the MHC genes may to some extent be used to determine fibre-type composition in human skeletal muscle.
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