| 21. |
- Ribel-Madsen, Rasmus, et al.
(författare)
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Impact of rs361072 in the Phosphoinositide 3-Kinase p110 beta Gene on Whole-Body Glucose Metabolism and Subunit Protein Expression in Skeletal Muscle
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:4, s. 1108-1112
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110 beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects. The aim was to investigate the influence of rs361072 on in vivo glucose metabolism, skeletal muscle PI3K subunit protein levels, and type 2 diabetes. RESEARCH DESIGN AND METHODS-The functional role of rs361072 was studied in 196 Danish healthy adult twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp. Basal and insulin-stimulated biopsies were taken from the vastus lateralis muscle, and tissue p110 beta and p85 alpha proteins were measured by Western blotting. The genetic association with type 2 diabetes and quantitative metabolic traits was investigated in 9,316 Danes with glucose tolerance ranging from normal to overt type 2 diabetes. RESULTS-While hepatic insulin resistance was similar in the fasting state, carriers of the minor G allele had lower hepatic glucose output (per-allele effect: 16%, P-add = 0.004) during high physiological insulin infusion. rs361072 did not associate with insulin-stimulated peripheral glucose disposal despite a decreased muscle p85 alpha:p110 beta protein ratio (P-add = 0.03) in G allele carriers. No association with HOMA-IR or type 2 diabetes (odds ratio 1.07, P = 0.5) was identified, and obesity did not interact with rs361072 on these traits. CONCLUSIONS-Our study suggests that the minor G allele of PIK3CB rs361072 associates with decreased muscle p85 alpha:p110 beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found. Diabetes 59:1108-1112, 2010
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| 22. |
- Ribel-Madsen, Rasmus, et al.
(författare)
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Retinol-Binding Protein 4 in Twins Regulatory Mechanisms and Impact of Circulating and Tissue Expression Levels on Insulin Secretion and Action
- 2009
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:1, s. 54-60
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Retinol-binding protein (RBP) 4 is an adipokine of which plasma levels are elevated in obesity and type 2 diabetes. The aims of the study were to identify determinants of plasma RBP4 and RBP4 mRNA expression in subcutaneous adipose tissue (SAT) and skeletal muscle and to investigate the association between RBP4 and in vivo measures of glucose metabolism. RESEARCH DESIGN AND METHODS-The study population included 298 elderly twins (aged 62-83 years), with glucose tolerance ranging from normal to overt type 2 diabetes, and 178 young (aged 25-32 years) and elderly (aged 58-66 years) nondiabetic twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp, and beta-cell function was estimated from an intravenous glucose tolerance test. RESULTS-The influence of environmental versus genetic factors in the regulation of plasma RBP4 increased with age. Plasma RBP4 was elevated in type 2 diabetes and increased with duration of disease. Plasma RBP4 correlated inversely with peripheral, but not hepatic, insulin sensitivity. However, the association disappeared after correction for covariates, including plasma. adiponectin. Plasma retinol, and not RBP4, was inversely associated with insulin secretion. SAT RBP4 expression correlated positively with GLUT4 expression and inversely with glucose tolerance. Skeletal muscle RBP4 expression reflected intramuscular fat, and although it was suppressed by insulin, no association with insulin sensitivity was evident. RBP4 expression was not associated with circulatory RBP4. CONCLUSIONS-In conclusion, our data indicate that, RBP4 levels in plasma, skeletal muscle, and fat may be linked to insulin resistance and type 2 diabetes in a secondary and noncausal manner. Diabetes 58:54-60, 2009
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| 23. |
- Ribel-Madsen, Rasmus, et al.
(författare)
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Retinol-Binding Protein 4 in Young Men With Low Versus Normal Birth Weight: Physiological Response to Short-Term Overfeeding
- 2011
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Ingår i: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 19:6, s. 1304-1306
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Tidskriftsartikel (refereegranskat)abstract
- Retinol-binding protein 4 (RBP4) is a plasma protein which is elevated in obesity and type 2 diabetes. We aimed to investigate whether RBP4 represents a mechanism underlying the associations between low birth weight (LBW), high-fat diet, and insulin resistance. Forty-six young, lean men with low (n = 20) or normal (n = 26) birth weight underwent a 5-day high-fat high-calorie (HFHC) dietary intervention. In vivo glucose metabolism was assessed by euglycemic-hyperinsulinemic clamp, glucose tracer and intravenous glucose tolerance test techniques. Body composition was measured by a dual-energy x-ray absorptiometry scan, and plasma RBP4 by an enzyme-linked immunosorbent assay. RBP4 was not associated with birth weight, but with BMI (beta = 0.9 mu g/ml (0.08;1.8) (95% confidence interval), P = 0.03) and plasma levels of low-density lipoprotein cholesterol (beta = 5.3 mu g/ml (1.9;8.7), P = 0.03) and triglycerides (beta = 15.4 mu g/ml (9.5;21.3), P < 0.001). Under baseline diet conditions, RBP4 was associated with decreased disposition index (D-i) (beta = -2.4% (-4.5%;-0.2%), P = 0.04) and increased basal hepatic glucose production rate (HGP) (beta = 0.02 mg kg(-1) min(-1) (0.002;0.04), P = 0.03), but not associated with peripheral glucose disposal rate or hepatic insulin resistance index. RBP4 levels were not influenced by overfeeding or related to peripheral and hepatic insulin resistance provoked by the dietary intervention. In conclusion, plasma RBP4 in young men associates with components of the metabolic syndrome, but is not determined by birth weight and seems not to be involved in short-term high-fat diet-induced insulin resistance.
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| 24. |
- Rung, Johan, et al.
(författare)
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Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 89-1110
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.
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| 25. |
- 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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| 26. |
- 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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| 27. |
- Storgaard, Heidi, et al.
(författare)
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Relationships of plasma adiponectin level and adiponectin receptors 1 and 2 gene expression to insulin sensitivity and glucose and fat metabolism in monozygotic and dizygotic twins.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:7, s. 2835-2839
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Tidskriftsartikel (refereegranskat)abstract
- Context: Adiponectin is a key insulin-sensitizing adipokine acting on muscle metabolism via two specific receptors [adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2, respectively)]. Objectives: The aim of the study was to investigate the genetic and nongenetic control of plasma adiponectin and muscle AdipoR1/R2 gene expression and the impact of these components on in vivo glucose and fat metabolism. Design and Participants: Plasma adiponectin and muscle gene expression of AdipoR1/R2 were measured before and during insulin infusion in 89 young and 69 elderly monozygotic and dizygotic twins. Insulin action, and glucose and fat oxidation rates were determined using hyperinsulinemic euglycemic clamps and indirect calorimetry. Results: We demonstrated a genetic component in the control of plasma adiponectin and AdipoR1/R2 gene expression. Furthermore, levels of adiponectin and AdipoR1/R2 were influenced by age, sex, abdominal obesity, and aerobic capacity. Intrapair correlations in monozygotic twins indicated a nongenetic influence of birth weight on plasma adiponectin and AdipoR2 expression. Nonoxidative glucose metabolism was associated with AdipoR1 and plasma adiponectin, in young and elderly twins, respectively. In addition, plasma adiponectin was related to glucose and fat oxidation in younger subjects. Conclusions: Plasma adiponectin and muscle gene expression of its specific receptors are controlled by genetic and several specific nongenetic factors. The data suggest that the "adiponectin axis" plays a role in in vivo insulin action and nonoxidative glucose metabolism.
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