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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.

Aims/hypothesis: The cytokine interleukin 6 (IL-6) is an essential regulator of the acute phase response associated with insulin-resistant states including type 2 diabetes and obesity. Three polymorphisms at positions -597, -572, and -174 of the IL6 promoter have been reported to influence IL6 transcription. The aim of this study was to investigate whether the IL6 promoter polymorphisms were associated with features of the WHO-defined metabolic syndrome and related quantitative traits in 7,553 Caucasian Danes., Methods: Using analysis of PCR-generated primer extension products by mass spectrometry we examined -597 G/A, -572 G/C, and -174 G/C IL6 variants in the population-based Inter99 study cohort of middle-aged people (n=6,164) and in a group of type 2 diabetic patients (n=1,389)., Results: The -174 G/C and -597 G/A polymorphisms were in strong linkage disequilibrium (R(2)=0.95). In the Inter99 cohort the -174 G-allele was associated with insulin resistance (p<0.02) and dyslipidaemia (p<0.007) whereas the C-allele of the -572 polymorphism was associated with increased serum insulin release during an OGTT (p<0.0005). Composite genotype or haplotype analyses of all 3 IL6 promoter variants showed associations with type 2 diabetes (p<0.002), obesity (p<0.02), and the metabolic syndrome (p<0.01)., Conclusions: The present studies suggest that single-nucleotide polymorphisms and composite genotypes or haplotypes of the IL6 promoter may be associated with several features of the metabolic syndrome in Caucasians.

Aims: Recently, a novel human G protein-coupled receptor 40 (GPR40), which is predominantly expressed in pancreatic islets, was shown to mediate an amplifying effect of long-chain fatty acids on glucose-induced insulin secretion. The present aim was to examine the coding region of GPR40 for variation and to assess whether identified variants confer an increased risk of Type 2 diabetes or altered insulin release., Methods: Mutation analysis was performed in 43 patients with Type 2 diabetes, 18 normal glucose-tolerant subjects, and 3 maturity-onset of diabetes in the young (MODY) X patients using direct sequencing. Genotyping was performed using polymerase chain reaction (PCR)-generated primer extension products analysis by high throughput chip-based mass spectrometry (MALDI-TOF). The potential impact of GPR40 mutations on [(3)H]-myo-inositol turnover was estimated in COS-7 cells after stimulation with various concentrations of 5,8,11-eicosatriynoic acid., Results: Two nucleotide substitutions, an Arg211His polymorphism and a rare Asp175Asn mutation, were identified. Both variants showed EC(50) values similar to the wild type. However, the maximal efficacy of the rare Asp175Asn was 39% lower compared with the wild type (P = 0.01). The Arg211His polymorphism had a similar allele frequency among 1384 Type 2 diabetic patients [MAF%; 23.4 (95% CI: 21.8-25.0)] and 4424 middle-aged glucose-tolerant subjects [24.1% (23.2-25.0)]. A genotype-quantitative trait study of 5597 non-diabetic, middle-aged subjects from the Inter99 cohort showed no significant differences in oral glucose tolerance test (OGTT)-derived estimates of insulin release between carriers of various GPR40 genotypes., Conclusions: Variations in the coding region of GPR40 do not appear to be associated with Type 2 diabetes or insulin release alterations.

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.

Aims: In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide responses during an oral glucose tolerance test (OGTT) in glucose-tolerant subjects. The aims of the present study were to evaluate the influence of the polymorphism on the serum insulin and C-peptide responses to an OGTT in glucose-tolerant women with and without previous GDM and to investigate if this polymorphism is associated with GDM., Methods: The Ala/Val98 polymorphism was measured in 376 women of Danish origin with previous GDM, and in 724 age-matched and 310 middle-aged glucose tolerant women using polymerase chain reaction-restriction fragment length polymorphism., Results: The allelic frequency of the Ala/Val98 polymorphism was 0.043 [95% confidence interval (CI) 0.028, 0.057] in women with previous GDM vs. 0.037 (95% CI 0.028, 0.047) in age-matched and 0.039 (95% CI 0.024, 0.054) in middle-age women. Among 117 glucose-tolerant women with previous GDM, 10 carriers of the Ala/Val98 polymorphism had a non-significant 27% and 22% reduction in serum C-peptide and insulin levels, respectively, at 30 min during an OGTT. Seventy-eight control subjects carrying the Ala/Val98 polymorphism had a 10% (P = 0.001) and 16% (P = 0.004) reduction in serum C-peptide and insulin levels, respectively, compared with 956 Ala/Ala control subjects., Conclusions: The Ala/Val polymorphism at codon98 of HNF-1alpha is not associated with GDM in Danish women. However, the codon 98 variant is associated with a significant impairment of serum insulin and C-peptide responses during an OGTT in glucose-tolerant women without previous GDM.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 alpha-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other pre-diabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P = 0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5-40.1] in diabetic subjects vs. 41.2% [40.2-42.2] in control subjects; P = 0.007). The odds ratio for the Asp/Asp carriers versus Ala/Ala carriers was 1.38 (1.09-1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with estimates of obesity, post-oral glucose tolerance test serum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites.

Aims/hypothesis: Polymorphisms of the butyrylcholinesterase gene (BCHE) are reported to associate with Alzheimer's disease and a recent study found a significant association of the BCHE K variant (G1615A/Ala539Thr) with Type 2 diabetes. The objectives of our study were to examine whether the BCHE K variant is associated with Type 2 diabetes or estimates of pancreatic beta cell function in large-scale populations of glucose-tolerant Caucasians., Methods: The variant was genotyped in association studies comprising a total of 1408 Type 2 diabetic patients and 4935 glucose-tolerant control subjects. Genotype-phenotype studies were carried out in the 4935 glucose-tolerant control subjects., Results: There was no difference in allele frequency between Type 2 diabetic patients and control subjects (20.3% [95% confidence interval: 18.8-21.8] vs 20.4% [19.6-21.2], non-significant). In the genotype-phenotype studies we found no consistent association with BMI, fasting or post-OGTT plasma glucose, serum insulin or serum C-peptide levels., Conclusions/interpretation: The present study does not support the suggestion that the BCHE K polymorphism is associated with Type 2 diabetes or with estimates of pancreatic beta cell function in large-scale Danish Caucasian populations.

Aims: To determine the cost and performance of a Danish risk score, fasting plasma glucose (FPG), and HbA1c as single screening tests and in combination with targeted screening., Subjects and Methods: In the Inter99 study, 12 934 inhabitants of Copenhagen County were invited to participate. All participants underwent anthropometric measurements, blood samples, and a 75-g standardized oral glucose tolerance test [N = 6784 (52.5%)]., Results: Of the 6117 individuals included in the analysis, 252 (4.1%) had previously undiagnosed diabetes. As a stand-alone test, the FPG had the highest performance expressed by a significantly higher area under the receiver-operating curve [0.89; 95% confidence interval (CI) 0.86, 0.99] compared with the Danish risk score (0.78; 95% CI 0.76, 0.81) and HbA1c (0.76; 95% CI 0.72, 0.80). Targeted screening where the initial test was a risk score reduced the FPG measurements by 72% (100% vs. 27.8%). Using FPG in population-based screening, the cost per newly diagnosed diabetic individual was 583 euro compared with 270 euro if screened by questionnaire followed by FPG. The sensitivity and specificity were 78.6% and 87.7% for FPG, and 61.5% and 89.2% for the combination of the questionnaire and FPG, respectively., Conclusions: The performance of FPG was superior to a questionnaire and HbA1c used as single tests. However taking into account workload, the burden on the population and the cost per identified person with undiagnosed diabetes, targeted screening using a questionnaire followed by FPG appears to be the strategy of choice., (Copyright 2004 Diabetes UK)

Aims/hypothesis: In November 2003 the American Diabetes Association expert committee on the diagnosis and classification of diabetes mellitus suggested a revision of the diagnostic criteria for IFG, lowering the diagnostic threshold from 6.1 to 5.6 mmol/l. The aim of the present study was to evaluate the consequences of this change with respect to: (i) the prevalence of IFG in five different countries; (ii) the concordance between IFG and IGT (classification of individuals); and (iii) the cardiovascular risk profile of these groups. Finally we discuss the likelihood that intervention for cardiovascular risk and prevention strategies developed for individuals with IGT are applicable to subjects with IFG., Methods: The first part of the study is based on the population-based Danish Inter99 study, where 6265 individuals, aged 30 to 60 years and without previously diagnosed diabetes, underwent an oral glucose tolerance test. The second part is based on the DETECT-2 project, in which studies from China, India, France and USA were used to analyse the impact of the proposed revision of the diagnostic criteria in different ethnic groups., Results: The proposed change in diagnostic criteria would increase the prevalence of IFG in Denmark from 11.8 to 37.6%. The proposed IFG category would identify 60.0% of all subjects with IGT compared to 29.2% with the old criteria, but among individuals with the new IFG category only 18.5% would also have IGT. Individuals with isolated IFG had lower insulin levels and a lower cardiovascular risk profile with the proposed criteria compared with the current WHO criteria. Data from the DETECT-2 study confirmed the marked increase in the prevalence of IFG, and the estimated number of individuals in the age range 40 to 64 years with IFG in urban India, urban China and the USA would increase by 78%, 135% and 193% respectively., Conclusions/interpretation: The proposed revised diagnostic criteria will lead to a dramatic increase in the prevalence of IFG, but the concordance rate between IFG and IGT remains low. This new IFG group will have a more favourable cardiovascular risk profile than the current IFG group as defined by the WHO. This seriously questions whether the existing intervention strategies are applicable to the new category of individuals with IFG.

Aims/hypothesis: The class III allele of the variable-number-of-tandem-repeats polymorphism located 5' of the insulin gene (INS-VNTR) has been associated with Type 2 diabetes and altered birthweight. It has also been suggested, although inconsistently, that the class III allele plays a role in glucose-induced insulin response among NGT individuals., Methods: We investigated the impact of the class III allele on Type 2 diabetes susceptibility in a case-control study involving 1462 Type 2 diabetic patients and 4931 NGT subjects. We also examined the potential impact of the class III allele in genotype-quantitative trait studies in three Danish study populations containing (i) 358 young healthy subjects; (ii) 4444 middle-aged NGT subjects, 490 subjects with IFG and 678 subjects with IGT; and (iii) 221 NGT subjects, of whom one parent had Type 2 diabetes., Results: There was no difference in frequency of the class III allele or in genotype distribution between the 1462 Type 2 diabetic patients and the 4931 NGT subjects. Among the 358 young subjects the class III/III carriers had significantly reduced post-IVGTT acute serum insulin and C-peptide responses (p=0.04 and 0.03 respectively). However, among the 4444 middle-aged subjects we failed to demonstrate any association between the class III allele and post-OGTT serum insulin and C-peptide levels., Conclusions/interpretation: The class III allele of the INS-VNTR does not confer susceptibility to Type 2 diabetes or consistent alterations in glucose-induced insulin release in the examined populations, which consisted of Danish Caucasians.

Objective: To investigate whether the obesity observed among the Inuit of Greenland and in a general Danish population was associated with the same degree of metabolic disturbances., Design: Comparison of data from two population-based cross-sectional surveys conducted in 1999-2001., Subjects: A total of 7892 individuals aged 30-60 y, 1108 Inuit participants from the Greenland Population study, and 6784 Danish participants in the Danish Inter99 study., Measurements: Height, weight, waist and hip circumference were measured, and BMI and waist-to-hip ratio were calculated. The participants received a standard 75 g OGTT. s-Triglyceride, s-HDL cholesterol, fasting and 2 h p-glucose and s-insulin were analysed. Blood pressure was measured. Information on lifestyle factors was obtained by a questionnaire and interview., Results: The Inuit had lower levels of 2-h glucose and insulin, blood pressure, triglyceride, and higher levels of HDL cholesterol than the Danish participants at any given level of obesity. Fasting glucose and fasting insulin levels within obesity categories were not different in the two populations. Adjustment for physical activity, smoking, school education, and alcohol consumption did not change these findings., Conclusion: The trends in the association between obesity and metabolic effects among the Inuit and a Northern European population were the same, but the levels of the risk factors were significantly different. This may be due to genetic factors and differences in body composition.

Background: Various strategies have been used to induce lifestyle changes to reduce ischaemic heart disease (IHD) with various successes. The aim of Inter99 is to assess the effect on IHD incidence of individually tailored non-pharmacological intervention on lifestyle using a newly developed computer-based health educational tool. The article describes the study and baseline results., Methods: From a population of 61,301 individuals two random samples (high intensity intervention group (A), n = 11,708; low intensity intervention group (B), n = 1308) are screened to assess their absolute risk of IHD. Those at high risk receive individual lifestyle counselling. Individuals in group A are furthermore offered lifestyle counselling in groups on smoking cessation or physical activity/diet over a 6-month period. Individuals in group B are referred to their GP. High-risk persons are re-counselled after 1 and 3 years and the whole group is re-invited after 5 years. The remaining 48,285 (group C) are followed by questionnaire. The total population is followed through central registers. Intermediate end-points are changes in lifestyle, cholesterol, blood pressure and body mass index. Final end-point is reduction in incidence of IHD., Results: The randomization leads to comparable groups. Participation rate was 52.5%. A total of 60% fulfilled the predetermined criteria for being at high risk for developing IHD. After an individual lifestyle counselling 41% accepted group-based counselling., Conclusion: This large randomized population based trial discloses a noticeable need for and acceptance of lifestyle intervention in the general population.

Aims: Screening for Type 2 diabetes has been recommended in several countries due to the increasing prevalence of diabetes. This review evaluates whether Type 2 diabetes is a disease that fulfils the criteria for screening set by the World Health Organization., Methods: Literature search was performed on the literature bases MedLine, Pub Medical, NIDDK, Cochrane Library and CINAHL using the MeSH terms 'non-insulin-dependent-diabetes-mellitus' and mass screening. Using this strategy we identified studies specifically evaluating screening strategies and diagnostic tests for Type 2 diabetes. The evaluation of psychosocial consequences included studies related to other chronic diseases. This literature was used to evaluate whether the WHO criteria for screening were fulfilled., Results: The papers were reviewed but a meta-analysis was not possible, as no randomized controlled clinical trials were performed in the area of screening., Conclusion: Type 2 diabetes does not fulfil the criteria for population-based mass screening. No screening and intervention studies have been performed, systematically evaluating the positive and negative effects of screening. Furthermore, intervention studies up until now have been restricted to clinically diagnosed patients with diabetes, and most of these have recruited patients with long diabetes duration and early complications. These groups will have a worse prognosis and thus probably show greater benefits of such intervention. Finally, the psychosocial and health economic consequences of screening and intervention for Type 2 diabetes are largely unknown. Thus, systematic screening and intervention trials should be encouraged, and meanwhile intensified case finding and opportunistic screening in high-risk groups should be performed.

The E23K polymorphism of the pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucose-tolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P = 0.022) and serum insulin levels under the response curve during an OGTT (0-120 min) (P = 0.014) as well as with an increase in BMI (P = 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P = 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n = 2,824, odds ratio [OR] 1.49, P = 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.

Before the introduction of screening for type 2 diabetes, it is necessary to evaluate not only the technology, but also the patient perspective, the economical consequences, and the organising aspects. A review of the relevant literature shows that type 2 diabetes is a rapidly increasing, serious disease. However, there is no documentation that systematic screening will have a positive effect on morbidity and mortality, owing to the lack of randomised clinical trials. The methods for screening could be optimised, and there is a lack of literature on patient perspective. Economical models indicate that opportunistic screening is more cost-effective than is systematic screening, but the lack of randomised trials makes the conclusion dubious. A decision to introduce systematic screening for type 2 diabetes should await the results of ongoing randomised clinical trials. In the meantime, efforts should be spent on improving the level of care for those already diagnosed with diabetes.