Risk factors associated with mortality among individuals with type 2 diabetes and depression across two cohorts.

Objective: Depression has been linked to excess mortality in individuals with type 2 diabetes, but it remains unclear what drives this association. We examined if the association depends on unhealthy lifestyle and medical comorbidity. Methods: We followed a clinically recruited cohort of Danish people with type 2 diabetes (n = 8175) with fine-grained clinical information and a population-wide register-based cohort of Danish individuals with HbA1c-defined type 2 diabetes (n = 87 500) representing everyday clinical practice. Antidepressant drug use prior to the onset of type 2 diabetes was used as a proxy for preexisting depression. In both cohorts, we first estimated the association between depression and 5-year mortality following type 2 diabetes, using a Cox proportional hazards model, yielding sex- and age-adjusted mortality rate ratios (MRRs). We subsequently examined how further adjustment for markers of unhealthy lifestyle (smoking, physical inactivity, obesity, alcohol abuse, and marital status) and medical comorbidity affected the association. Results: Preexisting depression was associated with an approximately 50% increased age- and sex-adjusted all-cause mortality rate in both the clinically recruited- (5-year MRR: 1.46; 95% CI: 1.12-1.90) and the register-based type 2 diabetes cohort (5-year MRR: 1.51; 95% CI: 1.45-1.57). The excess mortality associated with depression almost disappeared when the analyses were adjusted for unhealthy lifestyle and medical comorbidity in both the clinically recruited- (MRR: 1.05; 95% CI: 0.72-1.52) and the register-based type 2 diabetes cohort (MRR: 1.14, 95% CI: 1.09-1.19). Conclusions: A large fraction of the excess mortality associated with preexisting depression in type 2 diabetes is attributable to the unhealthy lifestyle and medical comorbidity accompanying depression.

Accelerometer-derived physical activity and sedentary behaviors in individuals with newly diagnosed type 2 diabetes: A cross-sectional study from the Danish nationwide DD2 cohort.

Introduction: Habitual physical activity behaviors of individuals with new-onset type 2 diabetes are largely unknown. We aimed to investigate accelerometer-derived physical activity behaviors in individuals with newly diagnosed type 2 diabetes. We also examined sociodemographic and health-related correlates of a high-risk physical activity profile. Methods: This cross-sectional study used data from 768 participants enrolled in an intervention study nested within the Danish Centre for Strategic Research in Type 2 diabetes (DD2) cohort. Physical activity was assessed by 24-h dual monitor accelerometry. Prevalence ratios of having a high-risk physical activity profile were estimated using Poisson regression adjusted for age and sex. Results: Study participants spent on average 9.7 (25th and 75th percentiles, 8.3; 11.1) hours/day sitting, walked for 1.1 (0.8; 1.6) hours/day and accumulated 4,000 (2,521; 5,864) steps/day. Still, 62% met the recommendations for physical activity. Characteristics associated with a high-risk physical activity profile (observed in 24.5% of participants) included older age, higher body mass index (BMI), unemployment, retirement, comorbidities, and current smoking. Hence, participants aged 60-69, 70-79 and 80+ years had prevalence ratios of 2.12 (95% CI 1.31; 3.42), 1.99 (1.18; 3.34) and 3.09 (1.42; 6.75) for a high-risk activity profile, respectively, versus participants <50 years. BMI values of 30-39 and 40+ were associated with 1.83 (1.06; 3.15) and 3.38 (1.88; 6.05) higher prevalence ratios compared to normal-weight. Unemployment or retirement was associated with 1.62 (1.09; 2.41) and 2.15 (1.37; 3.39) times higher prevalence ratios, compared to individuals in the working force. Having a Charlson Comorbidity Index score of 1-2 or 3+ was associated with 1.36 (1.03-1.79) and 1.90 (1.27-1.84) higher prevalence ratios, while current smoking was associated with a prevalence ratio of 1.72 (1.25; 2.35) compared to never smokers. Conclusion: This study shows that 62% of individuals with newly diagnosed type 2 diabetes met the recommendations for physical activity. Still, the majority of participants were also highly sedentary and accumulated very few daily steps, emphasizing the need for focusing on both increasing physical activity and reducing sedentary behaviors in the prevention of diabetes-related complications. Individuals with a high-risk physical activity profile were characterized by more obesity, socioeconomic inequalities, advanced age and comorbidities.Trial registration number: NCT02015130.

Extent of arterial calcification by conventional vitamin K antagonist treatment.

BACKGROUND AND AIMS: Vitamin K antagonists (VKA) remain the most frequently prescribed oral anticoagulants worldwide despite the introduction of non-vitamin K antagonist oral anticoagulants (NOAC). VKA interfere with the regeneration of Vitamin K1 and K2, essential to the activation of coagulation factors and activation of matrix-Gla protein, a strong inhibitor of arterial calcifications. This study aimed to clarify whether VKA treatment was associated with the extent of coronary artery calcification (CAC) in a population with no prior cardiovascular disease (CVD). METHODS: We collected data on cardiovascular risk factors and CAC scores from cardiac CT scans performed as part of clinical examinations (n = 9,672) or research studies (n = 14,166) in the period 2007-2017. Data on use of anticoagulation were obtained from the Danish National Health Service Prescription Database. The association between duration of anticoagulation and categorized CAC score (0, 1-99, 100-399, ≥400) was investigated by ordered logistic regression adjusting for covariates. RESULTS: The final study population consisted of 17,254 participants with no prior CVD, of whom 1,748 and 1,144 had been treated with VKA or NOAC, respectively. A longer duration of VKA treatment was associated with higher CAC categories. For each year of VKA treatment, the odds of being in a higher CAC category increased (odds ratio (OR) = 1.032, 95%CI 1.009-1.057). In contrast, NOAC treatment duration was not associated with CAC category (OR = 1.002, 95%CI 0.935-1.074). There was no significant interaction between VKA treatment duration and age on CAC category. CONCLUSIONS: Adjusted for cardiovascular risk factors, VKA treatment-contrary to NOAC-was associated to higher CAC category.

Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes.

Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥4 on the MNSI questionnaire determined possible DPN, whereas pain presence in both feet together with a score ≥3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, body mass index, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (odds ratio 1.52 [95% confidence interval: 1.20-1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality of life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.

Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile.

PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long-term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80°C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications.

Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.

AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis. METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression. RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of ≥7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C-peptide≥800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00-1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti-hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy. CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications.

The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) study: Collection of baseline data from the first 580 patients.

This paper provides an overview of the baseline data collected in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. The paper presents descriptive data from the first 580 patients enrolled in the DD2. The DD2 database will contain detailed interview data, clinical examination data, and urine and blood samples from up to 10,000 patients newly diagnosed with type 2 diabetes each year, collected from general practitioners and hospital outpatient clinics in all of Denmark. Of the first DD2 patients enrolled, blood and urine samples have been obtained from 97%. The median age of the first 580 patients was 59 years and 322 (56%) were men. Median weight gain from age 20 to maximum lifetime weight was 29 kg for men and 31 kg for women, and 364 patients (63%) did not currently participate in regular sports activities. Two hundred and ninety two patients (50%) had a known family history of diabetes. Two hundred fifty (43%) of the 580 DD2 patients have also been enrolled in the Danish Diabetes Database for Adults from which additional clinical data can be obtained. Among these 250 patients (154 of whom were men, 96 women), 75 (49%) men were currently obese, and 63 (41%) were overweight, whereas 62 (65%) women were obese, and another 21 (22%) were overweight. Twenty-nine patients (12%) received insulin, 164 patients (66%) received oral antidiabetics only, and 57 (23%) received no antidiabetic treatment. Glycemic regulation was modest (the glycosylated hemoglobin A of 46% was ≥7.5%). Two thirds of the patients received antihypertensive and hypolipidemic treatment. Self-reported daily tobacco smoking (23%) and alcohol overuse (6%) seemed comparable to occurrence in the general Danish population. One quarter of the patients with newly diagnosed diabetes had a history of hospital-diagnosed comorbidity at baseline as included in the Charlson comorbidity index, in particular prior myocardial infarction (5%), cerebrovascular disease (5%), peripheral vascular disease (4%), chronic pulmonary disease (6%), and previous solid cancer (6%). In the future, the DD2 database represents a valuable source for outcome studies in type 2 diabetes.

Effect of the SK/IK channel modulator 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591) on contractile force in rat, pig and human detrusor smooth muscle.

OBJECTIVE: • To investigate the importance of small (SK)- and intermediate (IK)-conductance Ca2(+) -activated K(+) channels on bladder function, by studying the effects of 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591), a new modulator of SK/IK channels, on contractions induced by electrical field stimulation (EFS) and carbachol in rat, pig and human detrusor. PATIENTS AND METHODS: • Detrusor biopsies were obtained from rats, pigs and male patients undergoing cystectomy because of bladder cancer. • Force was recorded using myographs. • Intracellular free Ca(2+) was measured in myocytes using microfluorimetry. RESULTS: • In rat bladder rings subjected to EFS, cumulative addition of NS4591 (0.1-30 µM) decreased force by 82 ± 2.9% (n = 6).This effect was reduced by 64 ± 5.2% in the presence of 0.3 µM apamin, a specific inhibitor of SK channels. Apamin increased the force evoked by EFS significantly: force was increased by 14.2 ± 3.4% (n = 5) and 10.1 ± 2.6% (n = 7) in pig and human detrusor strips, respectively (P = 0.04 and P = 0.02). • The cumulative addition of NS4591 (0.3-30 µM) significantly reduced the amplitude of carbachol-induced rhythmic oscillations by 62.0 ± 12.0% (n = 12) and the minimum force between oscillations by 30 ± 5% (n = 9) in pig detrusor strips (P < 0.005). In the presence of 10 µM NS4591, carbachol (1 µM) induced rhythmic contractions with an amplitude and normalized mean power frequency (nmeanPF) of 8.4 ± 5.1% and 0.11 ± 0.06 mN root mean square (rms) Hz (n = 12), respectively, vs. 21 ± 3.4% and 0.17 ± 0.04 mN rms Hz in control strips (n = 13). Apamin induced 6- and 11-fold increases in amplitude and nmeanPF vs. 1.3- and 2-fold increases in control strips. • In human detrusor strips (n = 15), the cumulative addition of NS4591 (1-30 µM) significantly reduced the amplitude by 69 ± 11%, the nmeanPF by 78 ± 6% and the minimum force between carbachol-induced oscillations by 59 ± 5% (P < 0.008). The addition of apamin (0.3 µM) before application of 1 µM carbachol abolished the effects of NS4591 on amplitude and partially abolished its effect on nmeanPF by 41 ± 7%, vs. a 78 ± 6% reduction in the absence of apamin (n = 8). • In spontaneously active detrusor preparations, NS4591 reduced or abolished contractions. • Furthermore, NS4591 (10 µM) decreased the carbachol-induced increase in the fura-2 ratio by 43 ± 3% compared with control (n = 12) (P < 0.03). CONCLUSIONS: • The SK/IK channel modulator NS4591 inhibits EFS- and carbachol-induced contractions in rat, pig and human detrusor muscle. • NS4591 may have therapeutic potential for treatment of detrusor overactivity.