Discounts on fruit and vegetables combined with a space management intervention increased sales in supermarkets.

BACKGROUND/OBJECTIVES: To examine the effects of two interventions on consumer purchases of fruits and vegetables (F&V) on the Danish island of Bornholm: a 20% discount on F&V combined with improved shelf-space allocation, and improved shelf-space allocation alone. SUBJECTS/METHODS: A space management intervention to promote F&V sales was performed in two large discount supermarkets on Bornholm in Denmark for 3 months (September-November 2012). In addition, a 20% discount on F&V was introduced for 3 months in one of the supermarkets ('space + price'). The effect was evaluated using sales data from the two intervention supermarkets and three control supermarkets from the same supermarket chain but in Odsherred, Denmark (control area). Both the effect on sales of fresh F&V and potential unhealthy substitution effects were evaluated using multi-level regression analyses. RESULTS: During the price intervention period, the index number for sales of fresh vegetables increased by 22.2% (P=0.001) in the 'space + price' intervention supermarket compared with the control supermarkets. Furthermore, the index number for the sale of organic fresh fruit and vegetables increased by 12.1% (P=0.04) and the sale of the total amount of fruit and vegetables (fresh, frozen, dried and canned) increased by 15.3% (P=0.01) compared with the control supermarkets. In the 'space only' intervention supermarket no significant increase in the sale of fruit and vegetables was found. No unhealthy substitution effects were found. CONCLUSIONS: In conclusion, a 20% price reduction on F&V significantly increased sales of F&V. The effect was most pronounced on vegetables and no negative/unhealthy substitution effects were found.

The effects of adding group-based lifestyle counselling to individual counselling on changes in plasma glucose levels in a randomized controlled trial: the Inter99 study.

AIM: This study aimed to assess whether group-based lifestyle counselling offered to a high-risk population subgroup had any effect beyond individual multifactorial interventions on fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) changes. METHODS: In a population-based study of 6784 participants, 4053 were determined to be at high risk based on a risk estimate of ischaemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolaemia, obesity, impaired glucose tolerance). Of these subjects, 90% were randomized to high-intensity intervention (group A) and 10% to low-intensity intervention (group B). All participants went through health examinations, risk assessments and individual lifestyle counselling. Participants in group A were further offered group-based lifestyle counselling. The intervention was repeated after 1 and 3 years. A total of 2738 participants free of diabetes at baseline (1999-2001) and with at least one FPG and/or 2hPG measurement during 5 years of follow-up were included in the analyses. Differences in changes of plasma glucose between groups A and B were analyzed using multilevel linear regression. RESULTS: For FPG, crude 5-year changes were significantly different between the two groups (group A: -0.003 mmol/L vs group B: -0.079 mmol/L; P=0.0427). After adjusting for relevant confounders, no differences in FPG changes were observed (P=0.116). Also, no significant differences in the 5-year changes in 2hPG between the two groups were observed (group A: - 0.127 mmol/L vs group B: -0.201 mmol/L; P=0.546). CONCLUSION: Offering additional group-based intervention to a high-risk population subgroup had no clinical effects on changes in plasma glucose beyond those of individualized multifactorial interventions.

The Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) update of the Finnish diabetes risk score for prediction of incident type 2 diabetes.

AIMS/HYPOTHESIS: The Finnish diabetes risk questionnaire is a widely used, simple tool for identification of those at risk for drug-treated type 2 diabetes. We updated the risk questionnaire by using clinically diagnosed and screen-detected type 2 diabetes instead of drug-treated diabetes as an endpoint and by considering additional predictors. METHODS: Data from 18,301 participants in studies of the Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project with baseline and follow-up information on oral glucose tolerance status were included. Incidence of type 2 diabetes within 5 years was used as the outcome variable. Improvement in discrimination and classification of the logistic regression model was assessed by the area under the receiver-operating characteristic (ROC) curve and by the net reclassification improvement. Internal validation was by bootstrapping techniques. RESULTS: Of the 18,301 participants, 844 developed type 2 diabetes in a period of 5 years (4.6%). The Finnish risk score had an area under the ROC curve of 0.742 (95% CI 0.726-0.758). Re-estimation of the regression coefficients improved the area under the ROC curve to 0.766 (95% CI 0.750-0.783). Additional items such as male sex, smoking and family history of diabetes (parent, sibling or both) improved the area under the ROC curve and net reclassification. Bootstrapping showed good internal validity. CONCLUSIONS/INTERPRETATION: The predictive value of the original Finnish risk questionnaire could be improved by adding information on sex, smoking and family history of diabetes. The DETECT-2 update of the Finnish diabetes risk questionnaire is an adequate and robust predictor for future screen-detected and clinically diagnosed type 2 diabetes in Europid populations.

Cumulative glycaemia as measured by lens fluorometry: association with retinopathy in type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the association between lifelong cumulative glycaemia estimated by lens fluorometry and the presence of retinopathy in individuals with type 2 diabetes. METHODS: We carried out a cross-sectional population-based study of 970 participants aged between 30 and 60 years, of which 170 were diagnosed with diabetes on screening (WHO 1999 criteria) and 35 had known type 2 diabetes. Procedures included clinical and laboratory examinations, non-invasive assessment of the intrinsic fluorescence of the lens of the eye, and seven-field fundus photography. RESULTS: Retinopathy was found in 46 (22%) of 205 participants with type 2 diabetes. In a logistic regression analysis controlling for age, sex and diabetes status (screen-detected or known), a two-fold increase in lens fluorescence increased the odds for retinopathy by 3.46 (95% CI 1.25-9.55, p = 0.017). The association was marginally significant (OR 3.00 [95% CI 1.00-9.01], p = 0.050) when also adjusted for smoking, systolic blood pressure, body mass index and HbA(1c). CONCLUSIONS/INTERPRETATION: Diabetic retinopathy was related to cumulative lifelong glycaemia as estimated by lens fluorometry in participants with type 2 diabetes. This supports the hypothesis that retinopathy is a marker of lifelong elevated glycaemia as well as of the unknown, pre-diagnostic duration of type 2 diabetes. The powerful association between lens fluorescence and retinopathy underscores the importance of strict long-term glycaemic control in the prevention of retinopathy in people with diabetes.

Differential relationship between physical activity and progression to diabetes by glucose tolerance status: the Inter99 Study.

AIMS/HYPOTHESIS: The aim of the study was to analyse how strongly commuting and leisure-time physical activity affect progression to diabetes and to study whether this relationship is different in individuals with isolated impaired fasting glucose (i-IFG) and isolated impaired glucose tolerance (i-IGT). METHODS: We studied the incidence of diabetes in 4,031 individuals without diabetes at baseline who participated in the baseline and 5 year follow-up examinations of a population-based primary prevention study, the Inter99 Study. Glucose tolerance status at baseline and at follow-up were based on OGTTs. Commuting and leisure-time physical activity at baseline were assessed by questionnaire. We present rate ratios from Poisson regression analyses adjusted for relevant confounders. RESULTS: The progression rate to diabetes was lower among physically active individuals in the total study population and particularly among those with i-IGT. The associations were attenuated and lost statistical significance after further adjustment for BMI. We observed no impact of physical activity on the progression to diabetes in individuals with i-IFG. CONCLUSIONS/INTERPRETATION: Physical activity was associated with a lower progression to diabetes in the total study population and in individuals with i-IGT, a condition primarily characterised by muscle insulin resistance. Physical activity did not predict progression to diabetes in individuals with i-IFG, a condition primarily characterised by hepatic insulin resistance. Our results suggest that there is a differential relationship between physical activity and progression to diabetes among those with i-IFG and i-IGT. Therefore, clinical trials testing the effect of physical activity on progression from i-IFG to diabetes are needed. TRIAL REGISTRATION: ClinicalTrials.gov ID No.: NCT00289237 FUNDING: The Danish Medical Research Council, the Danish Center for Evaluation and Health Technology Assessment, Novo Nordisk, Copenhagen County, the Danish Heart Foundation, the Danish Diabetes Association, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation and the Becket Foundation.

Five-year change in physical activity is associated with changes in cardiovascular disease risk factors: the Inter99 study.

OBJECTIVE: To evaluate whether five-year changes in self-reported physical activity level were associated with changes in waist circumference, weight, serum lipids and blood pressure. METHODS: In the Inter99 study (1999-2006) in Copenhagen, Denmark, 4039 men and women (30-60 years) answered questions on lifestyle and provided blood samples and anthropometric measures at baseline and after five years. Multiple regression analyses were performed with five-year value of each cardiovascular biomarker as outcome and change in physical activity level as explanatory variable. RESULTS: Approximately 50% of the study population were men (n=2023). Change in physical activity level was inversely associated with change in weight (p<0.0001), waist (p<0.0001), diastolic blood pressure (p=0.04), total cholesterol (p=0.006), LDL (p=0.007), triglycerides (p=0.02) and with a composite risk score "the Copenhagen risk score" (p<0.0001), and positively associated with HDL in men (p=0.01). CONCLUSION: Five-year changes in physical activity level were significantly associated with relevant changes in weight, waist circumference, diastolic BP and serum lipids in a population-based cohort of adult men and women. Change in physical activity level induced a significant change in HDL concentration in men only. Women's use of hormone replacement therapy may partly explain this gender difference.

Association of obesity and insulin resistance with asthma and aeroallergen sensitization.

BACKGROUND: It has been hypothesized that obesity and insulin resistance may play a role in the development of asthma and allergy. The aim of the study was to examine the association of obesity and insulin resistance with asthma and aeroallergen sensitization. METHODS: Cross-sectional population-based study of 3609 Danish men and women aged 30-60 years. Aeroallergen sensitization was defined as positive levels of specific IgE against a panel of inhalant allergens. Asthma was defined as self-reported physician diagnosed asthma. Allergic asthma was defined as the presence of both asthma and aeroallergen sensitization. The homeostasis model assessment of insulin resistance was used to estimate the degree of insulin resistance. Body mass index, waist-to-hip ratio, and waist circumference were used as measures of obesity. Data were analyzed by multiple logistic regression analyses. RESULTS: Obesity was associated with increased risk of aeroallergen sensitization as well as allergic and nonallergic asthma. Insulin resistance was asssociated with aeroallergen sensitization and allergic asthma, but not nonallergic asthma. The associations of obesity with aeroallegen sensitization and allergic asthma became nonsignificant after adjustment for insulin resistance, whereas the association of obesity with nonallergic asthma was unaffected. No sex-differences were observed. CONCLUSION: Obesity may be related to an increased risk of aeroallergen sensitization and allergic asthma through mechanisms also involved in the development of insulin resistance.

Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action.

AIMS/HYPOTHESIS: The impact of strategies for prevention of type 2 diabetes in isolated impaired fasting glycaemia (i-IFG) vs isolated impaired glucose tolerance (i-IGT) may differ depending on the underlying pathophysiology. We examined insulin secretion during OGTTs and IVGTTs, hepatic and peripheral insulin action, and glucagon and incretin hormone secretion in individuals with i-IFG (n = 18), i-IGT (n = 28) and normal glucose tolerance (NGT, n = 20). METHODS: Glucose tolerance status was confirmed by a repeated OGTT, during which circulating insulin, glucagon, glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels were measured. A euglycaemic-hyperinsulinaemic clamp with [3-3H]glucose preceded by an IVGTT was performed. RESULTS: Absolute first-phase insulin secretion during IVGTT was decreased in i-IFG (p = 0.026), but not in i-IGT (p = 0.892) compared with NGT. Hepatic insulin sensitivity was normal in i-IFG and i-IGT individuals (p > or = 0.179). Individuals with i-IGT had peripheral insulin resistance (p = 0.003 vs NGT), and consequently the disposition index (DI; insulin secretion x insulin sensitivity) during IVGTT (DI(IVGTT))) was reduced in both i-IFG and i-IGT (p < 0.005 vs NGT). In contrast, the DI during OGTT (DI(OGTT)) was decreased only in i-IGT (p < 0.001), but not in i-IFG (p = 0.143) compared with NGT. Decreased levels of GIP in i-IGT (p = 0.045 vs NGT) vs increased levels of GLP-1 in i-IFG (p = 0.013 vs NGT) during the OGTT may partially explain these discrepancies. Basal and post-load glucagon levels were significantly increased in both i-IFG and i-IGT individuals (p < or = 0.001 vs NGT). CONCLUSIONS/INTERPRETATION: We propose that differentiated preventive initiatives in prediabetic individuals should be tested, targeting the specific underlying metabolic defects.

Short-term reproducibility of impaired fasting glycaemia, impaired glucose tolerance and diabetes The ADDITION study, DK.

We evaluated variations in glucose measurements and the reproducibility of glucose tolerance classification in a high-risk screening setting in general practice. Screening for diabetes was performed in persons aged 40-69 years. Based on capillary fasting (FBG) and 2-h blood glucose (2 hBG) individuals with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT) and diabetes had a second test done after 14 days. Intra-individual coefficients of variation (CV) were estimated in each glucose tolerance class using the approximation CV(2)(x)=var(ln(x)). Bland-Altman plots with limits of agreement were made. In the total population, the CV(intra) was 7.9% and 13.8% for FBG and 2 hBG, respectively. Limits of agreement ranged from -1.15 to 1.67 mmol/l for FBG and from - 2.62 to 3.27 mmol/l for 2 hBG. One individual with IFG and 22.5% with IGT had diabetes at the second test, 76.1% with diabetes had this diagnosis confirmed, and about 30% with IFG and IGT had normal glucose tolerance at the second test. The expected values of repeated capillary blood glucose measurements were about+/-1 and+/-3 mmol/l for FBG and 2 hBG, respectively. Yet, 70% of high-risk prediabetic individuals were persistently classified with abnormal glucose regulation; diabetes was confirmed in 76% of the cases.

Determinants of progression from impaired fasting glucose and impaired glucose tolerance to diabetes in a high-risk screened population: 3 year follow-up in the ADDITION study, Denmark.

AIMS/HYPOTHESIS: We sought to identify determinants of progression from impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) to diabetes in high-risk screened individuals. METHODS: In general practices in Denmark, stepwise screening for type 2 diabetes mellitus in persons aged 40 to 69 years included a risk questionnaire, random blood glucose, HbA1c, fasting blood glucose and an OGTT. The 1,821 individuals with IGT or isolated IFG (WHO 1999) were re-invited after 1 and 3 years. Follow-up data on glucose measurements were available in 1,510 individuals and additional clinical data in 1,002 collected at the 3-year visits. Regression models using interval censoring were used. RESULTS: Progression rates from IFG and IGT to diabetes over 3.5 years were 11.8 and 17.0 per 100 person-years, respectively and were particularly high in the first year. Baseline determinants of progression were: IFG: glucose measures, BMI [per kg/m2, rate ratio (RR) 1.04 (95% CI, 1.01-1.08)] and triacylglycerol [per twofold increase, RR 2.19 (1.49-3.22)]; and IGT: glucose measures and known hypertension [RR 1.46 (1.11-1.93)]. Weight reduction and decreased triacylglycerol were inversely associated with development of diabetes in IFG individuals [per 1 kg/year, RR 0.81 (0.66-0.98) and per 1 mmol l(-1) year(-1), RR 0.08 (0.01-0.51), respectively], whereas in IGT participants only weight reduction was inversely associated [per 1 kg/year, RR 0.80 (0.67-0.96)]. CONCLUSIONS/INTERPRETATION: Higher levels of glucose measures, larger BMI, known hypertension and hypertriacylglycerolaemia are significant determinants of progression in high-risk screened individuals. Weight loss of 1 kg/year or reduction of hypertriacylglycerolaemia markedly reduced the risk of diabetes.

Studies of associations between the Arg389Gly polymorphism of the beta1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects.

AIMS: Activation of the beta(1)-adrenergic receptor (ADRB1) causes increased lipolysis in adipose tissue and enhances cardiac output. Analysis of the association of the functional ADRB1 Arg389Gly variant with obesity and hypertension has given ambiguous results. To clarify the potential impact of this variant on obesity and hypertension in the general population, we examined the Arg389Gly variant in a relatively large-scale population-based study. METHODS: Case-control studies and quantitative trait analyses were carried out in 7677 Danish Caucasians who were genotyped for the Arg389Gly variant (dbSNP rs1801253) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: A weak association between the Gly allele of the Arg389Gly variant and obesity was observed when comparing cases (n = 1540) defined as body mass index (BMI) > 30 kg/m(2) with control subjects (n = 6108) defined as BMI < or = 30 kg/m(2) for both allele frequencies (P = 0.05) and genotype distribution (P = 0.05). Case-control studies (cases n = 2518; control n = 3981) examining the effect on hypertension showed no association with allele frequencies (P = 0.3) or genotype distribution (P = 0.5); however, in the quantitative trait analyses, individuals carrying the Gly allele had slightly but significantly lower diastolic (Arg/Arg = 81.9 mmHg vs. Gly-allele carriers = 81.5 mmHg) and systolic (Arg/Arg = 129.4 mmHg vs. Gly-allele carriers = 128.8 mmHg) blood pressure as well as a lower mean arterial blood pressure. CONCLUSION: Our results suggest that the Arg389Gly polymorphism does not have any clinically important impact on the pathogenesis of obesity in Danish white subjects. Furthermore, despite the observed minor influence on blood pressure, this variant is most likely not to be a major contributor to the development of hypertension.

Genetic analysis of the estrogen-related receptor alpha and studies of association with obesity and type 2 diabetes.

BACKGROUND: The estrogen-related receptor alpha (ERRalpha or NR3B1) is a transcription factor from the nuclear receptor super-family, group III. The gene encoding ERRalpha (ESRRA) is located on chromosome 11q13, a region showing genetic linkage to body mass index and fat percentage. Through interaction with the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), ERRalpha regulates key enzymes involved in the beta-oxidation of fatty acids. RESULTS: By screening 48 overweight or obese subjects for variants in the exons, exon-intron boundaries and 1000 base pairs (bp) of the promoter region of ESRRA using bi-directional nucleotide sequencing, we identified seven variants. Four rare variants had minor allele frequencies (MAF) below 1%: Pro369Pro, Gly406Asp, 3'UTR+418G>A, 3'UTR+505C>A. Two single-nucleotide polymorphisms, Pro116Pro and IVS6+65C>T (MAF 15%), were in complete linkage disequilibrium (LD) (r (2)=1). We also confirmed the presence of a reported 23 bp microsatellite repeat (ESRRA23). The Pro116Pro and ESRRA23 variants were not associated with obesity, type 2 diabetes or related phenotypes in a large population-based study of 6365 Danish whites. The two variants were examined for interactions with variants in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta; however, no evidence of epistatic effects between the variants was demonstrated. CONCLUSION: The ESRRA23 and Pro116Pro variants of the gene encoding ERRalpha are not associated with obesity, type 2 diabetes or related quantitative traits in the examined Danish whites.

Progression from impaired fasting glucose and impaired glucose tolerance to diabetes in a high-risk screening programme in general practice: the ADDITION Study, Denmark.

AIMS/HYPOTHESIS: To estimate the 1-year progression rates from both IFG and IGT to diabetes in individuals identified in a pragmatic diabetes screening programme in general practice (the ADDITION Study, Denmark [Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care]). METHODS: Persons aged 40-69 years were screened for type 2 diabetes based on a high-risk, stepwise strategy. At baseline, anthropometric measurements, blood samples and questionnaire data were collected. A total of 1,160 persons had IFG or IGT at baseline: 811 (70%) accepted re-examination after 1 year. Glucose tolerance classification was based on the 1999 WHO definition. At follow-up, diabetes was based on one diabetic glucose value of fasting blood glucose or 2-h blood glucose. RESULTS: At baseline, 308 persons had IFG and 503 had IGT. The incidence of diabetes was 17.6 and 18.8 per 100 person-years in the two groups, respectively. CONCLUSIONS/INTERPRETATION: IFG and IGT identified in general practice during a stepwise, high-risk screening programme for type 2 diabetes have high 1-year progression rates to diabetes. Consequently, intensive follow-up and intervention strategies are recommended for these high-risk individuals.

Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects.

AIMS/HYPOTHESIS: The gene encoding neuropeptide Y receptor Y2 (NPY2R) is widely expressed in the central nervous system, with particularly high abundance in the hypothalamus, which is known to be important for appetite regulation. We tested whether variations in NPY2R are associated with obesity. METHODS: The coding region of NPY2R was analysed for mutations in 48 obese Danish white subjects and two silent substitutions were identified: SNPs 1 and 2 (rs1047214 and rs2880415). SNP1 and additional reported variants (SNPs 3-6 [rs11099992, rs12649641, rs2342676 and rs6857530]) located in the 5' region were examined in 5,971 Danish white subjects. Since SNPs 1-2 and 4-6, respectively, were in tight linkage disequilibrium large-scale analyses of genetic epidemiology were restricted to SNPs 1, 3 and 4. RESULTS: Homozygous carriers of the minor A allele of SNP4 were more common among obese subjects; the AA frequency was 15.9 (95% CI 15.2-16.6) among 4,837 non-obese subjects (BMI <30 kg/m(2)) vs 19.0 (95% CI 17.2-20.8) among 960 obese subjects (BMI > or =30 kg/m(2)), odds ratio 1.24 (95% CI 1.04-1.48), p=0.02. SNPs 1-3 were not associated with obesity. CONCLUSIONS/INTERPRETATION: Common variants rs12649641, rs2342676 and rs6857530 in the 5' region of NPY2R are associated with obesity in Danish white subjects.

Large-scale study of the -232C > G polymorphism of PCK1 in Type 2 diabetes.

AIMS: Phosphoenolpyruvate carboxykinase (PEPCK) is a catalyst of the rate-limiting step in the gluconeogenic pathway and is regulated at the transcriptional level predominantly by insulin, glucocorticoids, glucagon, and cAMP. The -232C > G polymorphism in the gene encoding PEPCK (PCK1) is reported to associate with Type 2 diabetes in Canadian Caucasians and Oji-Cree populations. We have estimated the impact of the PCK1-232C > G polymorphism in a relatively large-scale case-control study of Type 2 diabetes and in association studies of common metabolic phenotypes. Interaction studies of the PCK1-232C > G polymorphism with variants in the genes encoding peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1alpha and hepatic nuclear factor (HNF)-4alpha were also performed. METHODS: PCK1-232C > G was genotyped in a total of 7467 Danish white subjects using TaqMan allelic discrimination. A case-control study of Type 2 diabetes was performed using 6057 of the participants, and quantitative trait studies of metabolic variables were carried out in a subgroup of 5718 non-diabetic subjects. Additionally, variants in PGC-1alpha (Gly482Ser) and HNF-4alpha (Thr130Ile, Val255Met, and rs1884614) were investigated for epistatic interaction with the PCK1-232C > G polymorphism. RESULTS: In the case-control study of Type 2 diabetes of 1377 Type 2 diabetic patients and 4680 normoglycaemic and normal glucose-tolerant subjects we found no association of the PCK1-232C > G polymorphism with diabetes. In addition, the variant was not associated with age of clinical onset of Type 2 diabetes. In the study of 5718 non-diabetic subjects, we found no relationships of quantitative metabolic traits with the PCK1-232C > G polymorphism. We failed to demonstrate any convincing epistatic effects of the variants in the genes encoding PGC-1alpha and HNF-4alpha with the PCK1-232C > G polymorphism. CONCLUSIONS: The PCK1-232C > G polymorphism is not a major contributor to the pathogenesis of Type 2 diabetes in the Danish population.

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects.

AIMS/HYPOTHESIS: Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor alpha subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes. SUBJECTS AND METHODS: The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites. RESULTS: No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10-1.25], p=1x10(-6)). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m(2); odds ratio 1.63 [95% CI 1.09-2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait. CONCLUSIONS/INTERPRETATION: In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.

What determines the cost-effectiveness of diabetes screening?

AIMS/HYPOTHESIS: The cost-effectiveness of screening for diabetes is unknown but has been modelled previously. None of these models has taken account of uncertainty. We aimed to describe these uncertainties in a model where the outcome was CHD risk. SUBJECTS AND METHODS: Our model used population data from the Danish Inter99 study, and simulations were run in a theoretical population of 1,000,000 individuals. CHD risk was estimated using the UK Prospective Diabetes Study (UKPDS) risk engine, and risk reduction from published randomised clinical trials. Probabilistic sensitivity analysis was used to provide confidence intervals for modelled outputs. Uncertain parameter values were independently simulated from distributions derived from existing literature and deterministic sensitivity analysis performed using multiple model runs under different strategy choices and using extreme parameter estimates. RESULTS: In the least conservative model (low costs and multiplicative risk reduction for combined treatments), the 95% confidence interval of the incremental cost-effectiveness ratio varied from pound23,300-82,000. The major contributors to this uncertainty were treatment risk reduction model parameters: the risk reduction for hypertension treatment and UKPDS risk model intercept. Overall cost-effectiveness ratio was not sensitive to decisions about which groups to screen, nor the costs of screening or treatment. It was strongly affected by assumptions about how treatments combine to reduce risk. CONCLUSIONS/INTERPRETATION: Our model suggests that there is considerable uncertainty about whether or not screening for diabetes would be cost-effective. The most important but uncertain parameter is the effect of treatment. In addition to directly influencing current policy decisions, health care modelling can identify important unknown or uncertain parameters that may be the target of future research.

The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group.

The category of IFG was introduced in the late 1990s to denote a state of non-diabetic hyperglycaemia defined by a fasting plasma glucose (FPG) concentration between 6.1 and 6.9 mmol/l. In 2003 the American Diabetes Association recommended that this diagnostic threshold be lowered to 5.6 mmol/l. The justification for lowering the threshold has been questioned. This simple change in cut-off value creates a pandemic of IFG, with a two- to five-fold increase in the prevalence of IFG across the world. Such a change in threshold has far-reaching public health implications. The European Diabetes Epidemiology Group (EDEG) has reviewed the evidence for this lower cut-off point for the definition of IFG and concludes that the previous definition should not be altered. EDEG further recommends that the value of all categorical definitions of non-diabetic hyperglycaemia should be reconsidered.

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes.

AIMS/HYPOTHESIS: The 825C>T polymorphism in the gene encoding the G protein beta3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. MATERIALS AND METHODS: The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case-control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. RESULTS: We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels-a finding in contrast with most previous studies-but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. CONCLUSIONS/INTERPRETATION: The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.