The pro-inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with incident type 2 diabetes among overweight but not obese individuals with impaired glucose regulation: effect modification by smoking and body weight status.

AIMS/HYPOTHESIS: Recent evidence links the soluble urokinase plasminogen activator receptor (suPAR), a stable biomarker of systemic immune activation, to several chronic diseases, including type 2 diabetes. suPAR is also associated with adiposity and smoking. We hypothesised that this biomarker would be linked to incident type 2 diabetes in individuals with impaired glucose regulation and that this association would be modified by smoking and body weight status. METHODS: The study included 1,933 participants with impaired glucose regulation, who were drawn from the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) and for whom data on suPAR, BMI and smoking were available. Logistic regression analysis was used to estimate the odds for incident type 2 diabetes per twofold increase in suPAR levels. Interactions between both smoking and body weight status and suPAR were tested. RESULTS: During a 3-year follow-up (599 incident diabetes cases), there was a 48% overall increase in the odds of developing type 2 diabetes per twofold increase in suPAR (p = 0.006). This association was modified by body weight status in overweight, but not in obese individuals (OR 2.36, 95% CI 1.48, 3.76 in overweight group), and by smoking status (OR 2.05, 95% CI 1.20, 3.51 in non-smokers). After adjustment for other diabetes risk factors, the association between suPAR and type 2 diabetes was attenuated in the whole sample and among non-smokers, but remained robust among overweight participants. CONCLUSIONS/INTERPRETATION: suPAR may be a good novel biomarker for systemic sub-clinical inflammation and immune activation linked to incident type 2 diabetes risk in overweight individuals and non-smokers. The observed interactions with adiposity and smoking should be investigated further.

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.

The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes.

AIMS/HYPOTHESIS: Recent genome-wide association studies have suggested that a polymorphism in GCKR, the gene encoding the glucokinase regulatory protein, is involved in triacylglycerol regulation. Our aim was to examine in large-scale studies the common GCKR rs780094 polymorphism in relation to metabolic traits (mainly fasting hypertriacylglycerolaemia) and traits related to pancreatic beta cell function. METHODS: The polymorphism was genotyped in 16,853 Danes using Taqman allelic discrimination. Association was analysed in case-control studies and quantitative trait analyses. We also analysed the possible interactive effect between the GCK -30G>A polymorphism and the GCKR rs780094 variant on metabolic traits. RESULTS: The minor GCKR A-allele of rs780094 is associated with an increased level of fasting serum triacylglycerol (p = 6 x 10(-14)), impaired fasting (p = 0.001) and OGTT-related insulin release (p = 3 x 10(-6)), reduced homeostasis model assessment of insulin resistance (p = 0.0004), WHO-defined dyslipidaemia (p = 6 x 10(-9)) and a modestly decreased risk of type 2 diabetes (p = 0.01). Significantly increased fasting serum insulin concentrations were demonstrated when analysing the GCK -30A and GCKR rs780094 G-alleles in an additive model. CONCLUSIONS/INTERPRETATION: The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes. We also suggest an additive effect of GCK and GCKR risk alleles on [corrected] serum insulin release.

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.