Design and methodology of the PRIMETIME 1 cohort study: PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy.

Background: Clinical features of diabetic kidney disease alone cannot differentiate between the histopathology that defines diabetic nephropathy (DN) and non-diabetic nephropathy (NDN). A kidney biopsy is necessary to make the definitive diagnosis of DN. However, there is no consensus on when to perform a kidney biopsy in individuals with diabetes and kidney disease. Furthermore, the implications of NDN versus DN for management, morbidity and kidney prognosis are unclear. To address the gap in knowledge, we aimed to create a national retrospective cohort of people with diabetes and a performed kidney biopsy. Methods: Adults diagnosed with diabetes in Denmark between 1996 and 2020 who had a kidney biopsy performed were included. The cohort was established by linking a nationwide diabetes registry with the Danish Pathology Registry. Data from 11 national registries and databases were compiled. The type of kidney disease was classified using a three-step analysis of Systematized Nomenclature of Medicine codes reported in relation to the histopathological examinations of kidney tissue. The final cohort and classification of kidney disease was as follows: out of 485 989 individuals with diabetes 2586 were included, 2259 of whom had type 2 diabetes. We were able to classify 599 (26.5%) with DN, 703 (31.1%) with NDN and 165 (7.3%) with mixed disease in individuals with type 2 diabetes. In individuals with type 1 diabetes, 132 (40.4%) had DN, 73 (22.3%) NDN and 39 (11.9%) mixed disease. The remaining could not be classified or had normal histology. The overall median (Q1-Q3) follow-up time was 3.8 (1.6-7.2) years. Conclusions: This cohort is a novel platform based on high-quality registry data for important longitudinal studies of the impact of kidney disease diagnosis on prognosis. With regular updates of data from the Danish registries, the presented follow-up will increase over time and is only limited by emigration or death.

Childhood body mass index trajectories, adult-onset type 2 diabetes, and obesity-related cancers.

BACKGROUND: Elevated childhood body mass index (BMI), commonly examined as a "once-only" value, increases the risk of cancer and type 2 diabetes (T2D) in adulthood. Continuous exposure to adiposity during childhood may further increase cancer risk. We examined whether longitudinal childhood BMI trajectories were associated with adult obesity-related cancer and the role of adult-onset T2D in these associations. METHODS: Five sex-specific latent class BMI trajectories were generated for 301 927 children (149 325 girls) aged 6-15 years from the Copenhagen School Health Records Register. Information on obesity-related cancers and T2D was obtained from national health registers. Incidence rate ratios (IRR), cumulative incidences, and confidence intervals (CI) were estimated using Poisson regressions. RESULTS: Compared with the average childhood BMI trajectory (containing approximately 40% of individuals), the rate of obesity-related cancer (excluding breast cancer) increased with higher childhood BMI trajectories among women. The highest rates occurred in the overweight (IRR = 1.27, 95% CI = 1.17 to 1.38) and obesity (IRR = 1.79, 95% CI = 1.53 to 2.08) BMI trajectories. Similar patterns were observed among men. In contrast, women with the obesity childhood BMI trajectory had the lowest rate of pre- and postmenopausal breast cancer (IRR = 0.59, 95% CI = 0.43 to 0.80, and IRR = 0.41, 95% CI = 0.30 to 0.57, respectively). For all trajectories, the cumulative risk of obesity-related cancer increased with adult-onset T2D. CONCLUSION: Consistent childhood overweight or obesity may increase the rates of adult obesity-related cancer and decrease the rates of breast cancer. Adult-onset T2D conferred additional risk for obesity-related cancer, but the effect did not differ across childhood BMI trajectories.

Association of general health and lifestyle factors with the salivary microbiota - Lessons learned from the ADDITION-PRO cohort.

Introduction: Previous research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening. Materials & Methods: ADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05). Results: Glycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%). Conclusions: Glycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings.

Time trends of cardiovascular risk management in type 1 diabetes - nationwide analyses of real-life data.

BACKGROUND: Individuals diagnosed with and treated for type 1 diabetes (T1D) have increased risk of micro- and macrovascular disease and excess mortality. Improving cardiovascular (CV) risk factors in individuals with T1D is known to reduce diabetes- related CV complications. AIM: To examine time trends in CV risk factor levels and CV-protective treatment patterns. Additionally, examine incidence rates of diabetes-related CV complications in relation to exposure CV-protective treatment. METHODS: We analysed records from 41,630 individuals with T1D, registered anytime between 1996 and 2017 in a nationwide diabetes register. We obtained CV risk factor measurements (2010-2017), CV-protective drug profiles (1996-2017) and CV complication history (1977-2017) from additional nationwide health registers. RESULTS: From 2010 to 2017 there were decreasing levels of HbA1c, LDL-C, and blood pressure. Decreasing proportion of smokers, individuals with glycaemic dysregulation (HbA1c ≥ 58 mmol/mol), dyslipidaemia (LDL-C > 2.6 mmol/l), and hypertension (≥ 140/85 mmHg). Yet, one fifth of the T1D population by January 1st, 2017 was severely dysregulated (HbA1c > 75 mmol/mol). A slight increase in levels of BMI and urinary albumin creatinine ratio and a slight decrease in estimated glomerular filtration rate (eGFR) levels was observed. By January 1st, 2017, one fourth of the T1D population had an eGFR < 60 ml/min/1.73 m2. The proportion of the T1D population redeeming lipid-lowering drugs (LLDs) increased from 5% in 2000 to 30% in 2010 followed by a plateau and then a decline. The proportion of the T1D population redeeming antihypertensive drugs (AHDs) increased from 28% in 1996 to 42% in 2010 followed by a tendency to decline. Use of LLDs was associated with lower incidence of micro- and macrovascular complications, while use of AHDs had higher incidence of CVD and CKD, when compared to non-use and discontinued use, respectively. CONCLUSION: Improvements were seen in CV risk factor control among individuals with T1D in Denmark between 2010 and 2017. However, there is clearly a gap between current clinical guidelines and clinical practice for CV risk management in T1D. Action is needed to push further improvements in CV risk control to reduce CVD and the related excess mortality.

Health-related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: Cross-sectional analysis of the ADDITION-PRO study.

AIMS: We estimated and compared health-related quality of life for individuals with normal glucose tolerance, prediabetes and diabetes. METHODS: Participants in the ADDITION-PRO study, Denmark, who attended a health assessment between 2009 and 2011, and who completed the 3-level EuroQoL 5-dimensions (EQ-5D-3L) questionnaire were included. For the present study, they were classified as normal glucose tolerance, prediabetes and diabetes (screen-detected and known) using the 2019 American Diabetes Association criteria. Prediabetes was defined as impaired fasting glucose, impaired glucose tolerance or HbA1c between 5.7-6.4% (39-47 mmol/mol). EQ-5D-3L data were converted into utility scores using Danish and UK values, where '1' equals full health and '0' equals death. Regression models estimated the association between utility and the different glucose health states. RESULTS: The mean EQ-5D-3L score in the sample population was 0.86 ± 0.17 (median 0.85, interquartile range 0.76 to 1) using UK values. Almost half of the sample (48%) reported full health with an EQ-5D score of '1'. Individuals with known diabetes reported the lowest EQ-5D-3L utility scores (0.81 ± 0.20), followed by individuals with screen-detected diabetes (0.85 ± 0.19), prediabetes (0.86 ± 0.17) and normal glucose tolerance (0.90 ± 0.15). The differences were statistically significant for normal glucose and known diabetes relative to prediabetes, after adjusting for sex, age, smoking, BMI and physical activity. These findings also held using Danish values albeit the differences were of smaller magnitude. CONCLUSIONS: Having prediabetes and diabetes was significantly associated with lower health-related quality of life relative to normal glucose tolerance. Our estimates will be useful to inform the value of interventions to prevent diabetes or prediabetes.

Factors Associated With Nonattendance in a Nationwide Screening Program for Diabetic Retinopathy: A Register-Based Cohort Study.

OBJECTIVE: The aim of the study was to identify factors associated with nonattendance in a Danish nationwide screening program for diabetic retinopathy among people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A retrospective observational study linking individual-level register data was performed. First, we compared characteristics of 156,878 people with type 2 diabetes divided into attenders and never-attenders on the basis of their screening history over a 6-year period. Second, we assessed 230,173 screening intervals within the same 6-year period. Mixed-effects models were used to investigate the effect of sociodemographic and health-related factors on the likelihood of having a nonattender interval (i.e., failing to attend screening within the recommended interval). RESULTS: A total of 42,068 (26.8%) people were identified as never-attenders, having no registered eye screening over a 6-year period. Compared with attenders, never-attenders were more frequently divorced/widowed, lived in the Capital Region of Denmark, and had poorer health. A total of 62,381 (27.1%) screening intervals were identified as nonattender intervals. Both sociodemographic and health-related factors were significantly associated with the likelihood of having a nonattender interval. The largest odds ratios for nonattendance were seen for mental illness, nonwestern descent, divorce, comorbidity, and place of residence. CONCLUSIONS: Our findings suggest that never- and nonattendance of screening for diabetic retinopathy are more common among people who are divorced/widowed and of poorer health. Additionally, nonattendance is more frequent among people of nonwestern decent. These population subgroups may benefit from targeted interventions aimed at increasing participation in diabetic retinopathy screening.

Instrumental variable analysis using offspring BMI in childhood as an indicator of parental BMI in relation to mortality.

Childhood BMI shows associations with adult mortality, but these may be influenced by effects of ill health in childhood on BMI and later mortality. To avoid this, we used offspring childhood BMI as an instrumental variable (IV) for own BMI in relation to mortality and compared it with conventional associations of own childhood BMI and own mortality. We included 36,097 parent-offspring pairs with measured heights and weights from the Copenhagen School Health Records Register and register-based information on death. Hazard ratios (HR) were estimated using adjusted Cox regression models. For all-cause mortality, per zBMI at age 7 the conventional HR = 1.07 (95%CI: 1.04-1.09) in women and 1.02 (95%CI: 0.92-1.14) in men, whereas the IV HR = 1.23 (95%CI: 1.15-1.32) in women and 1.05 (95%CI: 0.94-1.17) in men. Per zBMI at age 13, the conventional HR = 1.11 (95%CI: 1.08-1.15) in women and 1.03 (95%CI: 0.99-1.06) in men, whereas the IV HR = 1.30 (95%CI: 1.19-1.42) in women and 1.15 (95%CI: 1.04-1.29) in men. Only conventional models showed indications of J-shaped associations. Our IV analyses suggest that there is a causal relationship between BMI and mortality that is positive at both high and low BMI values.

Normative data on cardiovascular autonomic function in Greenlandic Inuit.

INTRODUCTION: Diabetes is increasing among Greenlandic Inuit; however, the prevalence of cardiovascular autonomic neuropathy (CAN) is yet unknown. The assessment of CAN requires an ability to differentiate between normal and abnormal. The aim was to establish normative reference data of cardiovascular autonomic function in Greenlandic Inuit. RESEARCH DESIGN AND METHODS: In this cross-sectional study, cardiovascular autonomic function was evaluated in participants without diabetes during the Greenlandic Population Study 2018 and in the town Qasigiannguit in 2020. Assessment included cardiovascular autonomic reflex tests (CARTs) and power spectral analysis of heart rate variability (HRV). Normative reference limits were estimated by applying piecewise linear quantile regression models at the fifth percentile. Models were adjusted for age and sex. RESULTS: Based on examinations of 472 participants (61.7% females), normative reference data was established for all outcomes. Mean age was 54 years (SD 13.1). Higher age was inversely associated with all outcomes of CARTs and HRV. A linear fall in cardiovascular autonomic function tended to level off beyond age of 60 or 70 years for supine-to-upright position ratio and low frequency power. However, the number of observations in subjects older than 60 or 70 years was limited, which may have caused a flattening of the curve around that age. No other associations were found. CONCLUSIONS: The general level of the CARTs and HRV for all age groups is notably lower than in previous studies from other nationalities. We speculate that sociodemographic and cultural aspects of the Greenlandic Inuit population including body mass index, smoking, physical activity and alcohol consumption may have affected the cardiovascular autonomic function.

A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes.

OBJECTIVE: End-stage kidney disease (ESKD) is a life-threatening complication of diabetes that can be prevented or delayed by intervention. Hence, early detection of people at increased risk is essential. RESEARCH DESIGN AND METHODS: From a population-based cohort of 5,460 clinically diagnosed Danish adults with type 1 diabetes followed from 2001 to 2016, we developed a prediction model for ESKD accounting for the competing risk of death. Poisson regression analysis was used to estimate the model on the basis of information routinely collected from clinical examinations. The effect of including an extended set of predictors (lipids, alcohol intake, etc.) was further evaluated, and potential interactions identified in a survival tree analysis were tested. The final model was externally validated in 9,175 adults from Denmark and Scotland. RESULTS: During a median follow-up of 10.4 years (interquartile limits 5.1; 14.7), 303 (5.5%) of the participants (mean [SD] age 42.3 [16.5] years) developed ESKD, and 764 (14.0%) died without having developed ESKD. The final ESKD prediction model included age, male sex, diabetes duration, estimated glomerular filtration rate, micro- and macroalbuminuria, systolic blood pressure, hemoglobin A1c, smoking, and previous cardiovascular disease. Discrimination was excellent for 5-year risk of an ESKD event, with a C-statistic of 0.888 (95% CI 0.849; 0.927) in the derivation cohort and confirmed at 0.865 (0.811; 0.919) and 0.961 (0.940; 0.981) in the external validation cohorts from Denmark and Scotland, respectively. CONCLUSIONS: We have derived and validated a novel, high-performing ESKD prediction model for risk stratification in the adult type 1 diabetes population. This model may improve clinical decision making and potentially guide early intervention.

The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial.

AIMS/HYPOTHESIS: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. METHODS: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30-70 years of age, and prediabetes (HbA1c 39-47 mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). RESULTS: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). CONCLUSIONS/INTERPRETATION: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. TRIAL REGISTRATION: ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

Quality assessment of a screening algorithm for diabetic retinopathy: prolongation of screening intervals with minimal effect of HbA1c and arterial hypertension on the length of intervals.

PURPOSE: At Steno Diabetes Center Copenhagen (SDCC), diabetic retinopathy (DR) screening intervals are based on quantification of retinal lesions. Screening intervals are, for the milder forms of DR, prolonged to 2-3 years. The purpose of the present study was to evaluate the effect of the prolongation on developing unexpected events and to evaluate the effect of HbA1c and arterial hypertension. METHODS: We assessed 18 972 screening intervals from 6000 patients from 1/1-2003 to 1/5-2017 for occurrence of unexpected events, defined as: (1) DR progression requiring treatment, at the following screening date, and (2) DR-related hospital contact within the planned interval. We modelled the effect of several risk factors for developing unexpected events in a Cox regression. Furthermore, we assessed the risk of unexpected events in a logistic regression analysis using cubic splines to model the effect of HbA1c , stratified by arterial hypertension status. RESULTS: 16 283 (86%) intervals followed the planned interval and among those, only 86 (0.5%) experienced unexpected events. Intervals of dysregulated patients (86% of all intervals) did not experience more unexpected events, compared with well-regulated patient intervals (Hazard Ratio: 1.12, 95% CI: 0.55-2.27). We found a nonlinear effect of HbA1c on the risk of unexpected events which peaked around HbA1c levels of 80 mmol/mol. Having arterial hypertension slightly increased the risk of unexpected events. CONCLUSIONS: The present study supports the validity of the current algorithm. We found no increased risk of unexpected events among dysregulated intervals but a nonlinear effect of HbA1c . Age, diabetes duration and diabetes type were significantly associated with unexpected events.

Role of fasting duration and weekday in incretin and glucose regulation.

Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of 'weekend behavior' on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.

Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study.

BACKGROUND: Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. METHODS: Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. RESULTS: Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. CONCLUSIONS: Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes.

AIMS: Vitamin B12 deficiency could be associated with cardiovascular autonomic neuropathy (CAN) in diabetes patients. We aim to investigate the association between serum levels of vitamin B12 and CAN in type 2 diabetes patients. METHODS: 469 ambulatory type 2 diabetes patients (mean diabetes duration 10.0years (IQR 5.0;17.0), mean age 59.0years (SD 11.6), 63% men, mean B12 289.0pmol/l (IQR 217;390)) were screened for CAN using three cardiovascular reflex tests, five minute resting heart rate (5min RHR) and heart rate variability indices. RESULTS: Serum levels of vitamin B12 were significantly lower in patients treated with metformin and/or proton pump inhibitors (PPIs) compared with patients not treated (p<0.001). A 25pmol/l higher level of vitamin B12 was associated with an odds ratio of the CAN diagnosis of 0.94 (95% CI 0.88; 1.00, p=0.034), an increase in E/I-ratio of 0.21% (95% CI 0.01; 0.43, p=0.038), and a decrease in 5min RHR of 0.25 beats per minute (95% CI -0.47; -0.03, p=0.025). CONCLUSION: Vitamin B12 may be inversely associated with CAN in patients with type 2 diabetes. Confirmatory studies investigating a causal role of vitamin B12 for the development of diabetic CAN are warranted.

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study.

OBJECTIVE: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. DESIGN AND METHODS: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. RESULTS: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. CONCLUSIONS: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

Prediction of First Cardiovascular Disease Event in Type 1 Diabetes Mellitus: The Steno Type 1 Risk Engine.

BACKGROUND: Patients with type 1 diabetes mellitus are at increased risk of developing cardiovascular disease (CVD), but they are currently undertreated. There are no risk scores used on a regular basis in clinical practice for assessing the risk of CVD in type 1 diabetes mellitus. METHODS AND RESULTS: From 4306 clinically diagnosed adult patients with type 1 diabetes mellitus, we developed a prediction model for estimating the risk of first fatal or nonfatal CVD event (ischemic heart disease, ischemic stroke, heart failure, and peripheral artery disease). Detailed clinical data including lifestyle factors were linked to event data from validated national registers. The risk prediction model was developed by using a 2-stage approach. First, a nonparametric, data-driven approach was used to identify potentially informative risk factors and interactions (random forest and survival tree analysis). Second, based on results from the first step, Poisson regression analysis was used to derive the final model. The final CVD prediction model was externally validated in a different population of 2119 patients with type 1 diabetes mellitus. During a median follow-up of 6.8 years (interquartile range, 2.9-10.9) a total of 793 (18.4%) patients developed CVD. The final prediction model included age, sex, diabetes duration, systolic blood pressure, low-density lipoprotein cholesterol, hemoglobin A1c, albuminuria, glomerular filtration rate, smoking, and exercise. Discrimination was excellent for a 5-year CVD event with a C-statistic of 0.826 (95% confidence interval, 0.807-0.845) in the derivation data and a C-statistic of 0.803 (95% confidence interval, 0.767-0.839) in the validation data. The Hosmer-Lemeshow test showed good calibration (P>0.05) in both cohorts. CONCLUSIONS: This high-performing CVD risk model allows for the implementation of decision rules in a clinical setting.

Glucose-Dependent Insulinotropic Polypeptide Is Associated With Lower Low-Density Lipoprotein But Unhealthy Fat Distribution, Independent of Insulin: The ADDITION-PRO Study.

CONTEXT: Glucose-dependent insulinotropic polypeptide (GIP) may increase lipid clearance by stimulating lipid uptake. However, given that GIP promotes release of insulin by the pancreas and insulin is anti-lipolytic, the effect may be indirect. OBJECTIVE: In this study we examined the association between GIP and lipid metabolism in individuals with low to high risk of type 2 diabetes and assessed whether the associations were modified by or mediated through insulin. DESIGN, SETTING, AND PARTICIPANTS: Analyses were based on the Danish cross-sectional ADDITION-PRO study (n = 1405). Lipid metabolism was measured by fasting plasma lipids and obesity including abdominal fat distribution assessed by ultrasonography. GIP and insulin were measured during an oral glucose tolerance test (0, 30 and 120 min). Linear regression analysis was used to study the associations between GIP, plasma lipids, and obesity measures. RESULTS: A doubling in fasting GIP levels was associated with lower low-density lipoprotein in both men (mean [95% CI] -0.10 mmol/l [-0.18--0.03]) and women (-0.14 mmol/l [-0.23--0.04]) and with higher high-density lipoprotein in women (0.06 mmol/l [-0.02-0.10]). In men, a doubling in stimulated GIP was associated with 0.13 cm less 0.01-0.25 sc fat but with more visceral abdominal fat (0.45 cm [0.12-0.78]) and higher waist-hip ratio (0.011 [0.004-0.019]). CONCLUSIONS: Contrary to what was previously thought, GIP may be associated with improved low-density lipoprotein clearance but with an unhealthy fat distribution independent of insulin. The effect of GIP on obesity measures was substantially different between men and women. The potential effect of GIP on visceral and sc adipose tissue physiology warrants further examination.

Impact of intensive treatment on serum methylglyoxal levels among individuals with screen-detected type 2 diabetes: the ADDITION-Denmark study.

AIMS: Methylglyoxal (MG) has been implicated in the development of micro- and macrovascular diabetic complications, but it remains unclear how current treatments of type 2 diabetes affect its circulating levels. METHODS: In the Danish arm of the ADDITION trial, we (a) described serum MG levels at baseline and at 6-year follow-up among individuals with screen-detected type 2 diabetes, (b) examined the effect of intensive multifactorial treatment compared with routine care on MG, (c) examined the associations between MG and risk factors at baseline and at follow-up and (d) examined the associations between changes in MG and changes in risk factors. RESULTS: Patients in both treatment arms experienced a significant decline in MG from baseline to follow-up, with no effect of allocation to intensive treatment. In cohort analyses, MG was associated with smoking and fasting glucose at baseline and smoking and LDL cholesterol at follow-up. Compared with patients receiving no lipid-lowering treatment, patients receiving lipid-lowering treatment had higher MG at follow-up, and those initiating lipid-lowering treatment experienced a less pronounced decline in MG. CONCLUSIONS: Further studies are required to explore any possible effects of the observed decrease in MG in type 2 diabetes patients as well as the potential interplay between MG, lipids, lipid-lowering treatment and smoking.

Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985-2009.

BACKGROUND: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort. METHODS: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57-61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends. RESULTS: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57-61 age group along the entire distribution rather than in higher extremes only. CONCLUSION: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses.

HbA1c, fasting and 2 h plasma glucose in current, ex- and never-smokers: a meta-analysis.

AIMS/HYPOTHESIS: The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. METHODS: This meta-analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I (2) statistic was used to evaluate heterogeneity among studies. RESULTS: HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (-0.004 mmol/l [-0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower (-0.44 mmol/l [-0.52, -0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [-0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I (2) always above 50%; I (2) was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. CONCLUSION/INTERPRETATION: Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes.