| 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. |
- Parikh, Hemang, et al.
(författare)
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TXNIP regulates peripheral glucose metabolism in humans
- 2007
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 4:5, s. 868-879
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Tidskriftsartikel (refereegranskat)abstract
- Background Type 2 diabetes mellitus ( T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein ( TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions TXNIP regulates both insulin-dependent and insulin- independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
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| 3. |
- Stemann Larsen, Pernille, et al.
(författare)
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Pregnancy and Birth Cohort Resources in Europe: a Large Opportunity for Aetiological Child Health Research
- 2013
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Ingår i: Paediatric and Perinatal Epidemiology. - : Wiley-Blackwell. - 0269-5022 .- 1365-3016. ; 27:4, s. 393-414
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Forskningsöversikt (refereegranskat)abstract
- Background During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. Methods European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. Results In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. Conclusion This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.
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