Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These variants have, in different ethnic groups, been linked to estimates of insulin resistance and obesity. The objective of the present study was to investigate whether these genetic variants of TNF-alpha were associated with features of the insulin resistance syndrome or alterations in birth weight in two Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. All study participants underwent an iv glucose tolerance test with the addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the polymorphisms by applying PCR restriction fragment length polymorphism. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome (body mass index, waist to hip ratio, fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth weight and the ponderal index were also not associated with the polymorphisms. In conclusion, although the study was carried out on sufficiently large study samples, the study does not support a major role of the -308 or -238 substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.
Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.
Associations between a 45 bp 3'untranslated insertion polymorphism in the uncoupling protein 2 (UCP2) gene and both body mass index (BMI) and sleeping metabolic rate have previously been reported. We investigated the impact of this polymorphism on BMI and long-term body weight changes.
The allelic frequency of the UCP2 insertion variant was determined in a cohort of 744 obese Danish Caucasian men who had a BMI of at least 31 kg/m2 at the draft-board examinations and a randomly selected control cohort consisting of 872 draftees. Follow-up measurements of BMI were done on average 26 years after the draft-board examinations.
The prevalence of the insertion allele was 30.4% (95% confidence interval: 28.0-32.8%) among the obese and 29.6% (27.4-31.8%) in the control group (p = 0.6). In a lean group selected as the 354 subjects with a BMI less than 25 kg/m2 at 46 years of age from the control group, the frequency of insertion allele was 29.0% (27.2-30.8%) (p = 0.5 compared with the obese cohort). The BMI at the ages of 20 and 46 years did not differ between genotypes either in the obese or the control group. Similarly, the changes in BMI/year between examinations at 20 and 46 years of age did not differ between genotypes in either group.
In a large group of Danish Caucasian men we found no association between a 3'untranslated insertion polymorphism in the UCP2 gene and obesity. Neither did we identify a relation between this variant and BMI changes during adult age.
Testing association of the Asn363Ser variant of the glucocorticoid gene with measures of obesity and weight gain.
741 obese subjects (BMI > or = 31 kg/m(2) at selection) and 854 random control subjects from the same population, examined at draft board examination and after on average 27.4+/- y. A lean control group (n=351) was further selected as the fraction from the cohort group having a BMI below 25.0 kg/m(2) at the latest examination.
Using PCR-RFLP subjects were genotyped for the Asn363Ser variant and grouped according to genotype.
The prevalence of the Ser363 allele was 4.7% (95% Cl: 3.3-6.2%) among the obese, 4.1% (2.7-5.5%) among the random cohort subjects and 4.3% (2.1-6.5%) among lean control subjects, respectively, showing no significant differences between the groups (P > 0.1). Furthermore, no differences in BMI, waist-hip ratio or weight gain were seen within any of the groups when defined according to the glucocorticoid receptor genotype.
In the examined population this marker is not a relevant predictor of obesity.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1, DIKU Building, Room 1.1.N121, DK-2100 Copenhagen, Denmark. Kristoffer.Burgdorf@sund.ku.dk
Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting.
By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n?=?6,039).
Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p?=?4.0?×?10?7) and increased disposition index of 5.6% (p?=?6.4?×?10?5). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p?=?0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p?=?0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p?=?0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p?=?0.00036) and 4.0% decrease in Matsuda index (p?=?2?×?10?4).
Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.
Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), but mortality may be as high as 10% to 15% after 1 year. Verapamil prevents cardiac events after an AMI in patients without CHF. We hypothesized that in postinfarct patients with CHF already prescribed diuretics and an ACE inhibitor, additional treatment with verapamil may reduce cardiac event rate. In this multicenter, double-blind study, patients with CHF receiving diuretic treatment were consecutively randomized to treatment with trandolapril 1 mg/day for 1 month and 2 mg/day the following 2 months (n = 49), or to trandolapril as mentioned plus verapamil 240 mg/day for 1 month and 360 mg/day for 2 months (n = 51). Trial medication started 3 to 10 days after AMI. All patients were followed for 3 months. End points in the trandolapril/trandolapril-verapamil groups were death 1/1, reinfarction 7/1, unstable angina 9/3, and readmission for CHF 6/2. The 3-month first cardiac event rate was 35% in trandolapril-treated patients and 14% in trandolapril-verapamil-treated patients (hazard ratio 0.35, 95% confidence interval 0.15 to 0.85, p = 0.015). These data suggest that verapamil reduces cardiac event rates in post-AMI patients with CHF when added to an ACE inhibitor and a diuretic.
Comment In: Am J Cardiol. 1997 Mar 15;79(6):788-99070561
The Arctic is warming more rapidly than other region on the planet, and the northern Barents Sea, including the Svalbard Archipelago, is experiencing the fastest temperature increases within the circumpolar Arctic, along with the highest rate of sea ice loss. These physical changes are affecting a broad array of resident Arctic organisms as well as some migrants that occupy the region seasonally. Herein, evidence of climate change impacts on terrestrial and marine wildlife in Svalbard is reviewed, with a focus on bird and mammal species. In the terrestrial ecosystem, increased winter air temperatures and concomitant increases in the frequency of "rain-on-snow" events are one of the most important facets of climate change with respect to impacts on flora and fauna. Winter rain creates ice that blocks access to food for herbivores and synchronizes the population dynamics of the herbivore-predator guild. In the marine ecosystem, increases in sea temperature and reductions in sea ice are influencing the entire food web. These changes are affecting the foraging and breeding ecology of most marine birds and mammals, and are associated with an increase in abundance of several temperate fish, seabird and marine mammal species. Our review indicates that, even though a few species are benefiting from a warming climate, most Arctic endemic species in Svalbard are experiencing negative consequences induced by the warming environment. Our review emphasizes the tight relationships between the marine and terrestrial ecosystems in this High Arctic archipelago. Detecting changes in trophic relationships within and between these ecosystems requires long-term (multi-decadal) demographic, population- and ecosystem-based monitoring, the results of which are necessary to set appropriate conservation priorities in relation to climate warming. This article is protected by copyright. All rights reserved.
AIMS/HYPOTHESIS: Associations between variations in the lymphotoxin-alpha gene (LTA) and myocardial infarction, cerebral infarction and type 1 diabetes have previously been reported. We hypothesised that, in its homozygous form, the functional T60N variant of LTA is associated with type 2 diabetes and other features of the metabolic syndrome among Danish Caucasian individuals. METHODS: The T60N polymorphism of LTA was genotyped in the population-based Inter99 study cohort (6,514 Caucasian subjects) and in a group of type 2 diabetic patients by analysis of PCR-generated primer extension products using high-throughput chip-based matrix-assisted laser desorption/ionisation time-of-flight mass spectronomy. RESULTS: Comparison of 1,401 diabetic patients with 1,470 matched glucose-tolerant control subjects from the Inter99 cohort revealed that the frequency of the mutant at codon 60 in its homozygous form (N/N genotype) was higher among the diabetic patients than among the control subjects (14.6% [95% CI 12.8-16.5] vs 12.0% [95% CI 10.3-13.7], p=0.048; odds ratio=1.24). This association was even stronger among the 131 patients with early-onset (diagnosis at 40 years or younger) diabetes (21.4% [95% CI 14.4-28.4] vs 12.0% [95% CI 10.3-13.7], p=0.004; odds ratio=1.99). Additionally, studies of the metabolic syndrome (as defined by the 1999 World Health Organization criteria) in the Inter99 study cohort revealed that the frequency of the N/N LTA genotype was higher among subjects presenting one or more features of the metabolic syndrome (n=4,425) than among subjects with no characteristics of this syndrome (n=1,752) (p=0.026). CONCLUSIONS/INTERPRETATION: The T60N LTA polymorphism is associated with type 2 diabetes and other features of the metabolic syndrome among Caucasian individuals.
Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure.
Obese young men (n = 753, BMI > or = 31.0 kg m(-2)) and a randomly selected group (n = 874) identified from a population of 174 800 men were re-examined in three surveys at mean ages 35, 46 and 49 years (S-35, S-46 and S-49). Measurements were available at upto eight times from birth to adulthood. Logistic regression analysis was used to assess odds ratio (OR) for the presence of the carrier allele for a given difference in phenotypic values.
Rs17782313 minor C-allele was associated with overall, abdominal and peripheral fatness (range of OR = 1.06-1.14 per z-score units) at all three surveys, although only consistently significant at S-35 and S-46. Rs17700633 minor A-allele was also associated with the fatness measures, but significantly so only at S-49 for overall and abdominal fatness (range of OR = 1.03-1.15 per z-score units), and peripheral fatness (OR = 1.15-1.20 per z-score units). There were only few significant associations with metabolic traits. The rs17782313 C-allele and the rs17700633 A-allele were both associated with lower high-density lipoprotein cholesterol (range of OR = 0.64-0.84 per mol l(-1)), significantly at S-46. The rs17700633 A-allele was significantly associated with insulin (OR = 1.25 per 50 pmol l(-1)), leptin (OR = 1.42 per 10 ng microl(-1)) and insulin sensitivity (OR = 0.81 per model unit). The rs17782313 C-allele and the rs17700633 A-allele were both associated with BMI in childhood and adolescence (range of OR = 1.04-1.17 per z-score units), significant for the rs17782313 C-allele at the age of 13-19 years and for rs17700633 A-allele at age 7, 10, 13 and 19 years. No significant associations were found for energy expenditure.
Near MC4R variants appear to contribute to body fat, body fat distribution, some metabolic traits, weight development during childhood, but not to energy expenditure.
There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits.
OxPhos gene variants (n = 10) that had been nominally associated (p