ABSTRACT: CONTEXT:Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in β-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus.OBJECTIVE:To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes.DESIGN:We genotyped UCP2 rs659366 in a total of 17 636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations.RESULTS:We found no consistent associations between the UCP2 -866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12 984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15 107 individuals showed no association. The -866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05).CONCLUSIONS:The UCP2 -866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.International Journal of Obesity advance online publication, 21 February 2012; doi:10.1038/ijo.2012.22.
International journal of obesity (2005) 02/2012; · 4.34 Impact Factor
ABSTRACT: Lamins are essential for nuclear shape and function. Polymorphisms in LMNA may associate with fat and muscle development and aging.
Our aim was to determine the influence of LMNA rs4641 on lean body mass (LBM) and fat mass (FM), in vivo metabolism, and expression of LMNA transcripts in human skeletal muscle.
We genotyped LMNA rs4641 in 196 Danish twins who were extensively phenotypically characterized. We measured mRNA levels of LMNA transcripts, lamin A and C, in basal and insulin-stimulated skeletal muscle biopsies.
The rs4641 T-allele was associated with increased weight and body mass index (P=0.02), including increased FM (P=0.03) and LBM (P=0.004). Impact of rs4641 on FM was seen primarily among elderly twins. The T-allele was associated with elevated fasting plasma insulin levels (P=0.01) and homeostasis model of insulin resistance (P=0.02) in young twins. T-allele carriers did not exhibit consistent changes of first phase insulin secretion, nor did they exhibit significant peripheral or hepatic insulin resistance, and rs4641 did not influence muscle lamin A or C mRNA levels. The lamin A-to-C mRNA ratio was increased with acute insulin stimulation (P<0.0005), and the lamin A and C mRNA levels were diminished in young compared to elderly twins (P<0.001).
The LMNA rs4641 T-allele is associated with increased LBM and FM with more fat relative to muscle in elderly twins, which may impact risk of type 2 diabetes. Increased mRNA levels of lamins with age may counteract muscle wasting, and influence of insulin on lamin A-to-C ratio suggests a role in cytoskeletal muscle protein regulation.
The Journal of clinical endocrinology and metabolism 08/2010; 95(8):3884-92. · 6.50 Impact Factor
ABSTRACT: A genome-wide association study recently identified an association between common variants, rs1535435 and rs9494266, in the AHI1 gene and type 2 diabetes. The aim of the present study was to investigate the putative association between these polymorphisms and type 2 diabetes or type 2 diabetes-related metabolic traits in Danish individuals.
The previously associated polymorphisms were genotyped in the population-based Inter99 cohort (n=6162), the Danish ADDITION study (n=8428), a population-based sample of young healthy participants (n=377) and in additional type 2 diabetes (n=2107) and glucose-tolerant participants (n=483) using Taqman allelic discrimination. The case-control study involved 4,104 type 2 diabetic patients and 5,050 glucose-tolerant control participants. Type 2 diabetes-related traits were investigated in 17,521 individuals.
rs1535435 and rs9494266 were not associated with type 2 diabetes. Odds ratios (OR) were OR(add) 1.0 (95% C.I. 0.9-1.2; p(add)=0.7) and OR(add) 1.1 (0.9-1.2; p(add)=0.4), respectively, a finding supported by meta-analyses: OR(add) 1.0 (0.9-1.1; p(add)=0.6) and OR(add) 1.0 (0.9-1.1; p(add)=0.6), respectively. Neither rs1535435 nor rs9494266 were consistently associated with any of the tested type 2 diabetes-related metabolic traits.
Data from large samples of Danish individuals do not support a role for AHI1 rs1535435 nor rs9494266 as major type 2 diabetes variants. This study highlights the importance of independent and well-powered replication studies of the recent genome-wide association scans before a locus is robustly validated as being associated with type 2 diabetes.
Diabetologia 05/2008; 51(4):609-14. · 6.81 Impact Factor