Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria.

SIGNIFICANCE STATEMENT: Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added. Amiloride inhibits uPA and attenuates complement activation in vitro and in vivo . In conditional podocin knockout (KO) mice with severe proteinuria, blocking of uPA with monoclonal antibodies significantly reduces the urine excretion of C3a and C5a and lowers tissue NLRP3-inflammasome protein without major changes in early fibrosis markers. This mechanism provides a link to proinflammatory signaling in proteinuria with possible long-term consequences for kidney function. BACKGROUND: Persistent proteinuria is associated with tubular interstitial inflammation and predicts progressive kidney injury. In proteinuria, plasminogen is aberrantly filtered and activated by urokinase-type plasminogen activator (uPA), which promotes kidney fibrosis. We hypothesized that plasmin activates filtered complement factors C3 and C5 directly in tubular fluid, generating anaphylatoxins, and that this is attenuated by amiloride, an off-target uPA inhibitor. METHODS: Purified C3, C5, plasminogen, urokinase, and urine from healthy humans were used for in vitro / ex vivo studies. Complement activation was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout [KO]) treated with amiloride or inhibitory anti-uPA antibodies were analyzed. RESULTS: The combination of uPA and plasminogen generated anaphylatoxins C3a and C5a from intact C3 and C5 and was inhibited by amiloride. Addition of exogenous plasminogen was sufficient for urine from healthy humans to activate complement. Conditional podocin KO in mice led to severe proteinuria and C3a and C5a urine excretion, which was attenuated reversibly by amiloride treatment for 4 days and reduced by >50% by inhibitory anti-uPA antibodies without altering proteinuria. NOD-, LRR- and pyrin domain-containing protein 3-inflammasome protein was reduced with no concomitant effect on fibrosis. In patients with diabetic nephropathy, amiloride reduced urinary excretion of C3dg and sC5b-9 significantly. CONCLUSIONS: In conditions with proteinuria, uPA-plasmin generates anaphylatoxins in tubular fluid and promotes downstream complement activation sensitive to amiloride. This mechanism links proteinuria to intratubular proinflammatory signaling. In perspective, amiloride could exert reno-protective effects beyond natriuresis and BP reduction. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Increased Activity of a Renal Salt Transporter (ENaC) in Diabetic Kidney Disease, NCT01918488 and Increased Activity of ENaC in Proteinuric Kidney Transplant Recipients, NCT03036748 .

Retinal main vessel calibers and systemic markers for long-term development of proliferative diabetic retinopathy.

PURPOSE: To evaluate if retinal vascular calibers and systemic risk factors in patients with no or minimal diabetic retinopathy (DR) can predict risk of long-term progression to proliferative diabetic retinopathy (PDR). METHODS: This was a matched case-control study of patients with diabetes having no or minimal DR at baseline with (cases) or without (controls) subsequent development of PDR. We collected six-field, 45-degree retinal images, demographic and clinical data from the Funen Diabetes Database. RESULTS: We included 52 eyes from 39 cases and 107 eyes from 89 controls matched on sex, age, type of diabetes, time from first to last screening episode and baseline DR level. Cases had higher HbA1c (73 vs. 55 mmoL/moL; p < 0.001), triglycerides (1.32 vs. 1.16 mmoL/L; p = 0.02) and longer duration of diabetes (19 vs. 14 years; p = 0.01), but the groups did not differ in calibers of retinal arterioles (229 vs. 227 µm; p = 0.49), venules (289 vs. 290 µm; p = 0.83) or the arterio-to-venule ratio (0.78 vs. 0.77; p = 0.86).In a multivariable logistic regression model with cluster robust standard error, HbA1c (OR 1.54 per 10 mmoL/moL; 95%-CI: 1.15-2.07; p = 0.004), triglyceride (OR 1.39 per 1 mmoL/L; 95%-CI: 1.03-1.86; p = 0.03) and duration of diabetes (OR 1.09 per year; 95%-CI: 1.03-1.16; p = 0.003) were independent risk factors for PDR. CONCLUSION: Retinal vascular calibers did not predict long-term development of PDR in contrast to well-established risk factors like HbA1c, triglyceride and duration of diabetes.

Elevated risk of developing type 2 diabetes in people with a psychiatric disorder: What is the role of health behaviors and psychotropic medication?

AIMS: Several psychiatric disorders are linked with an increased risk of developing type 2 diabetes (T2D), but the mediating mechanisms are unclear. We aimed to investigate health behaviors, obesity, psychotropic medication use, and comorbidity as potential mediating mechanisms explaining these associations. METHODS: We combined data from a large population-based survey with register-based data and followed a sample of 250,013 Danes (≥16 years) for up to 8.9 years. We conducted mediation analyses investigating 10 potential mediators of the associations between psychiatric disorders and incident T2D. RESULTS: Individuals with a substance use disorder, schizophrenia, mood disorder, neurotic disorder, eating disorder, or a personality disorder had a significantly higher risk of developing T2D. Organic disorders, intellectual disabilities, developmental and behavioral disorders were not associated with T2D-risk. For all psychiatric disorders significantly associated with T2D, the use of antidepressant medication had the largest proportional mediating effect on the association (13-32 %). CONCLUSIONS: Use of antidepressant medication had the largest contribution to the associations between psychiatric disorders and incident T2D. Future epidemiological studies and prevention studies should focus on optimizing the use of antidepressant medication with minimal side effects, and the promotion of health behaviors in individuals with a psychiatric disorder to prevent T2D.

Retinal microvascular markers in type 2 diabetes subphenotypes and latent autoimmune diabetes of adults.

PURPOSE: To estimate if newly diagnosed patients with different subphenotypes of type 2 diabetes (T2DM) or latent autoimmune diabetes of adults (LADA) differ with respect to subclinical retinal microvascular structure or diabetic retinopathy (DR). METHODS: This population-based, cross-sectional study of 340 patients (675 eyes) classified patients with recently diagnosed T2DM in different subphenotypes according to beta cell function and insulin sensitivity in to; classical (n = 218), hyperinsulinaemic (n = 86), insulinopenic (n = 20), or LADA (n = 16). Retinal 6-field images were graded according to the International Clinical DR Severity Scale by a retinal expert. Retinal microvascular structures were analysed in eyes by a semiautomatic software. RESULTS: Median age and duration of diabetes were 58.1 (49.9; 65.5) and 0.9 (0.5; 2.4) years, respectively, and 56.8% were male. In a multivariate linear mixed model regression analysis of eyes without DR (n = 570), there was no statistically significant difference in retinal venular or arteriolar width between subtypes and patients with classical T2DM. In addition, eyes from different subphenotypes did not differ according to vessel density, tortuosity or fractal dimension. In a multivariate logistic regression model adjusted for age, sex, HbA1c, diabetes duration, body mass index, mean arterial blood pressure and history of cardiovascular disease, there was a tendency towards persons with hyperinsulinaemic T2DM to be more likely to have DR (OR 1.97, 95% CI 0.95; 4.09) compared to classical T2DM. CONCLUSION: We found no difference in retinal microvascular structure in patients with newly diagnosed subtypes of T2DM. However, DR may be more prevalent in newly diagnosed patients with hyperinsulinaemic T2DM compared to individuals with classical T2DM.

Risk of cardiovascular events associated with pathophysiological phenotypes of type 2 diabetes.

Objective: Hyperglycaemia in type 2 diabetes is caused by varying degrees of two defects: low insulin sensitivity and beta-cell dysfunction. We assessed if subgrouping of patients into three pathophysiological phenotypes according to these defects could identify individuals with high or low risk of future cardiovascular events. Design: This is a prospective cohort study. Methods: We assessed estimates of insulin sensitivity and beta-cell function from the homeostasis model assessment-2 in 4209 individuals with recently diagnosed type 2 diabetes enrolled from general practitioners and outpatient clinics in Denmark. Individuals were followed for a composite cardiovascular endpoint (either atherosclerotic outcomes (myocardial infarction, unstable angina pectoris, stroke, coronary or peripheral revascularization), heart failure, or cardiovascular death) and all-cause mortality. Results: Totally 417 individuals with the insulinopenic phenotype (high insulin sensitivity and low beta-cell function) had substantially lower risk of cardiovascular events (5-year cumulative incidence: 4.6% vs 10.1%; age-/sex-adjusted hazard ratio (aHR): 0.49; 95% CI: 0.30-0.82) compared with 2685 individuals with the classical phenotype (low insulin sensitivity and low beta-cell function), driven by atherosclerotic events. Conversely, 1107 individuals with the hyperinsulinaemic phenotype (low insulin sensitivity and high beta-cell function) had more cardiovascular events (5-year cumulative incidence: 12.6%; aHR: 1.33; 95% CI: 1.05-1.69), primarily driven by increased heart failure and cardiovascular death and increased all-cause mortality. Conclusions: Simple phenotyping based on insulin sensitivity and beta-cell function predicts distinct future risks of cardiovascular events and death in patients with type 2 diabetes. These results suggest that precision medicine according to underlying type 2 pathophysiology potentially can reduce diabetes complications.

Risk of Developing Type 2 Diabetes in Individuals With a Psychiatric Disorder: A Nationwide Register-Based Cohort Study.

OBJECTIVE: Previous studies have investigated the incidence of type 2 diabetes in individuals with psychiatric disorders, but most studies have focused on a specific psychiatric disorder or a selected sample. More population-based studies are needed to determine these associations in representative samples. We therefore aimed to determine these associations in a nationwide, register-based dynamic cohort study. RESEARCH DESIGN AND METHODS: We analyzed data from 5,005,612 adults living in Denmark between 1995 and 2018, without prior diabetes. We investigated 10 different categories of psychiatric disorders and a composite group with any psychiatric disorder. Individuals with a psychiatric disorder were compared with individuals without using multivariable-adjusted Poisson regression to estimate incidence rate ratios (IRR) of type 2 diabetes. We modeled age-specific incidence rates (IR) for individuals with and without the specific psychiatric disorder. All models were stratified by sex. RESULTS: In total, 334,739 individuals developed type 2 diabetes during follow-up. For all investigated categories of psychiatric disorders, we found increased IR of type 2 diabetes for individuals with versus those without a psychiatric disorder (IRR: men, 1.47 [95% CI 1.45-1.50]; women, 1.65 [95% CI 1.62-1.68]). When we examined age-specific IR, the largest differences were found in the younger population (<50 years). CONCLUSIONS: We found that the IR of type 2 diabetes was higher in individuals with a psychiatric disorder compared with individuals without a psychiatric disorder and particularly high in the younger people with a psychiatric disorder. New studies into the prevention and early detection of type 2 diabetes in these groups are warranted.

Prevalence of type 2 diabetes in psychiatric disorders: an umbrella review with meta-analysis of 245 observational studies from 32 systematic reviews.

AIMS/HYPOTHESIS: Estimates of the global prevalence of type 2 diabetes vary between 6% and 9%. The prevalence of type 2 diabetes has been investigated in psychiatric populations but a critical appraisal of the existing evidence is lacking, and an overview is needed. This umbrella review summarises existing systematic reviews of observational studies investigating the prevalence of type 2 diabetes in people with a psychiatric disorder. METHODS: We searched PubMed, EMBASE, PsycINFO and the Cochrane Database of Systematic Reviews from inception to 17 January 2021 and screened reference lists of included systematic reviews. On the basis of prespecified criteria, we included systematic reviews investigating the prevalence of type 2 diabetes in adults (aged ≥18 years) with a psychiatric disorder. Titles and abstracts of 5155 identified records and full texts of 431 selected studies were screened by two independent reviewers, based on predefined eligibility criteria and an a priori developed extraction form, following the PRISMA and MOOSE guidelines. Risk of bias was assessed with the ROBIS instrument. Data extracted from primary studies were synthesised using random-effects meta-analyses. RESULTS: A total of 32 systematic reviews with 245 unique primary studies were identified and met inclusion criteria. Twelve had low risk of bias. They reported type 2 diabetes prevalence estimates ranging from 5% to 22% depending on the specific psychiatric disorder. We meta-analysed data for ten categories of psychiatric disorders and found the following prevalence estimates of type 2 diabetes: in people with a sleep disorder: 40%; binge eating disorder: 21%; substance use disorder: 16%; anxiety disorder: 14%; bipolar disorder: 11%; psychosis: 11%; schizophrenia: 10%; a mixed group of psychiatric disorders: 10%; depression: 9%; and in people with an intellectual disability 8%. All meta-analyses revealed high levels of heterogeneity. CONCLUSIONS/INTERPRETATION: Type 2 diabetes is a common comorbidity in people with a psychiatric disorder. Future research should investigate whether routine screening for type 2 diabetes and subsequent prevention initiatives for these people are warranted. PROSPERO registration no. CRD42020159870.

Non-invasive structural and metabolic retinal markers of disease activity in non-proliferative diabetic retinopathy.

PURPOSE: Metabolic and structural microvascular retinal alterations are essential components in diabetic retinopathy (DR). The present study aimed to measure changes at different stages of non-proliferative DR (NPDR) and to explore interactions of imaging-based metrics. METHODS: This cross-sectional, cohort study included 139 eyes from 80 diabetic patients. Each patient underwent dilated fundal examinations including colour fundus photography, retinal oximetry and optical coherence tomography angiography (OCTA), analysed by semi-automated and automated software. Diabetic retinopathy (DR) severity was classified according to the International Clinical Diabetic Retinopathy (ICDR) Severity Scale, ranging from no DR to severe NPDR (level 0-3). Retinal metabolism was evaluated by oximetry as retinal arteriolar (raSatO2 ) and venular oxygen saturation (rvSatO2 ), and macular microvascular structure was measured by OCTA as the area of foveal avascular zone (FAZ), vessel density (VD), vessel diameter index (VDI), FAZ circularity and fractal dimension (FD) in the superficial and deep retinal capillary plexus. RESULTS: A trend for increasing rvSatO2 was found with increasing DR severity (51.3%, 53.3%, 54.2%, 59.8%, p = 0.02). Increasing severity of DR associated with decreasing FD in the superficial and deep plexus (p < 0.001 and p = 0.014), and in the superficial plexus decreasing VD (p < 0.001), increasing VDI (p = 0.003) and decreasing FAZ circularity (p = 0.006). A few interactions were identified between raSatO2 , rvSatO2 and VDI, but only in the deep capillary plexus (p < 0.01 and p < 0.01). CONCLUSION: Alterations of the venular retinal vascular oxygen saturation and microvascular structural abnormities were found continuously throughout the DR-spectrum. Given the sparse correlations between metabolic and structural abnormalities, it seems that these occur independently in DR.

Cohort profile: the Funen Diabetes Database-a population-based cohort of patients with diabetes in Denmark.

PURPOSE: Detailed population-based data are essential to understanding the epidemiology of diabetes and its clinical course. This article describes the Funen Diabetes Database (FDDB). The purpose of the FDDB was to serve as a shared electronic medical record system for healthcare professionals treating patients with diabetes. The cohort can also be used for research. PARTICIPANTS: The FDDB covers a geographical area of almost 500 000 Danish inhabitants. It currently includes 3691 patients with type 1 diabetes, 19 085 patients with type 2 diabetes, 292 patients with other types of diabetes and 5992 patients with an unknown type of diabetes. Patients have been continuously enrolled from general practitioners and endocrinology departments in the Funen area in Denmark since 2003. Patients undergo a clinical work-up at their first diabetes contact and during follow-up visits. The information collected includes type of diabetes contact, blood pressure, height, weight, lifestyle factors (smoking, exercise), laboratory records (eg, haemoglobin A1c and cholesterol levels), results from foot examinations (eg, pulse, cutaneous sensitivity and ankle brachial index), results from eye examinations (eg, degree of retinopathy assessed by retinal photo and eye examination), glucose-lowering drugs and diabetic complications. FINDINGS TO DATE: The FDDB cohort was followed for a total of 212 234 person-years up to 2016. A cross-sectional study described the prevalence of diabetic retinopathy and its associated risk factors. The clinical outcomes of patients with type 1 diabetes, type 2 diabetes and latent autoimmune diabetes in adults have been assessed. Linkage to population-based medical registries with complete follow-up has enabled the collection of extensive continuous data on general practice contacts, diagnoses and procedures from hospital contacts, medication use and mortality. FUTURE PLANS: The FDDB serves as a strong data resource that will be used in future studies of diabetes epidemiology with focus on occurrence, risk factors, treatment, complications and prognosis.

Psychiatric disorders as risk factors for the development of type 2 diabetes mellitus: an umbrella review protocol.

INTRODUCTION: Numerous longitudinal studies, systematic reviews and meta-analyses have examined psychiatric disorders as risk factors for the development of type 2 diabetes mellitus. A more comprehensive overview of the area is warranted to summarise current evidence and discuss strengths and weaknesses to guide future research. AIM: The aim of this umbrella review is to determine whether and to what extent different psychiatric disorders are associated with the development of type 2 diabetes mellitus. Furthermore, the umbrella review also assesses the evidence on potential mediating mechanisms. METHODS AND ANALYSIS: The present umbrella review will consist of a comprehensive systematic search of published systematic reviews and meta-analyses of observational longitudinal studies investigating whether a psychiatric disorder is associated with the risk of developing type 2 diabetes. PubMed, Embase, PsychINFO and the Cochrane Database of Systematic Reviews will be searched, and the results will be screened for inclusion by two independent reviewers. Furthermore, the reference lists of included publications will be manually searched. Two independent reviewers will extract data and assess the methodological quality in the included systematic reviews and meta-analyses. Evidence on potential mediating mechanisms included in the systematic reviews and meta-analyses will also be reviewed. The implications of the overview will be discussed in light of the quality of the included studies, and suggestions for clinical practice and future research will be made. ETHICS AND DISSEMINATION: Ethical approval is not required for this umbrella review. Our review will be submitted for publication in a peer-reviewed international journal using open access option if available. The results will also be disseminated at international conferences. PROSPERO REGISTRATION NUMBER: CRD42018096362.

Insulin allergy can be successfully managed by a systematic approach.

BACKGROUND: Type I insulin allergy can be a challenging condition, and there is no international consensus on how to establish the diagnosis. Measurement of specific IgE and skin testing have been cornerstones in the diagnostic work-up. However, these tests have limitations, mainly lack of correlation between test results and clinical findings. At the Allergy Centre, Odense University Hospital, patients with suspected insulin allergy have been evaluated since 2003. The aim of this study was to establish a systematic approach to diagnose and treat patients with insulin allergy. METHODS: The study was conducted retrospectively by retrieving data from the Allergy Centre database on patients with suspected insulin allergy evaluated from 2003 to 2017. The examination comprised a comprehensive medical history, specific IgE against insulin and intracutaneous tests (ICT) with different insulins. RESULTS: A total of 144 patients were examined on suspicion of insulin allergy of which 110 had negative specific IgE in serum. Of the remaining 34 patients, 33 had ICT performed; 2 had negative ICTs, while 31 had one or more positive ICT. All 34 patients had mild symptoms, and 4 could obtain symptom relief with antihistamines or local steroids, 9 could be managed with oral antidiabetics, and 7 were switched to other insulins. The final 14 patients were offered an insulin pump because of reactions to many different insulins, many positive ICTs, unmanageable diabetes, young age and compliance, or convenience. CONCLUSION: Insulin allergy can be managed by a systematic approach, and symptom relief is obtainable in most patients.

Protocol for the specialist supervised individualised multifactorial treatment of new clinically diagnosed type 2 diabetes in general practice (IDA): a prospective controlled multicentre open-label intervention study.

INTRODUCTION: We present the protocol for a multifactorial intervention study designed to test whether individualised treatment, based on pathophysiological phenotyping and individualised treatment goals, improves type 2 diabetes (T2D) outcomes. METHODS AND ANALYSIS: We will conduct a prospective controlled multicentre open-label intervention study, drawing on the longitudinal cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2). New clinically diagnosed patients with T2D in the intervention group will be assigned to receive individualised treatment by their general practitioner. Intervention patients will be compared with a matched control cohort of DD2 patients receiving routine clinical care. Among intervention patients, we will first do pathophysiological phenotyping to classify patients into WHO-defined T2D or other specific types of diabetes (monogenic diabetes, secondary diabetes etc). Patients with WHO-defined T2D will then be further subcharacterised by their beta-cell function (BCF) and insulin sensitivity (IS), using the revised homeostatic assessment model, as having either insulinopaenic T2D (high IS and low BCF), classical T2D (low IS and low BCF) or hyperinsulinaemic T2D (low IS and high BCF). For each subtype, a specific treatment algorithm will target the primary pathophysiological defect. Similarly, antihypertensive treatment will be targeted at the specific underlying pathophysiology, characterised by impedance cardiography (relative importance of vascular resistance, intravascular volume and cardiac inotropy). All treatment goals will be based on individual patient assessment of expected positive versus adverse effects. Web-based and face-to-face individualised lifestyle intervention will also be implemented to empower patients to make a sustainable improvement in daily physical activity and to change to a low-carbohydrate diet. ETHICS AND DISSEMINATION: The study will use well-known pharmacological agents according to their labels; patient safety is therefore considered high. Study results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02015130; Pre-results.

Prevalence and risk factors for diabetic retinopathy in 17 152 patients from the island of Funen, Denmark.

PURPOSE: This study aims to estimate the prevalence and risk factors of diabetic retinopathy (DR) in patients enrolled in a large Danish quality-assuring database for diabetes: the Funen Diabetes Database (FDDB). METHODS: All patients with type 1 (T1DM) and type 2 DM (T2DM) diabetes mellitus (DM) were included in a cross-sectional study. The level of DR per patient was determined based on the eye with highest level of DR. All ocular and non-ocular data were extracted at the latest examination that corresponded to the most recent DR-grading data. RESULTS: Data from 17 152 patients were analysed; 83.1% had T2DM. Prevalence of DR was 23.8% (T1DM: 54.3%, T2DM: 21.2%). T1/T2DM patients were statistically significantly different regarding age, duration of diabetes, BMI, systolic blood pressure (BP), cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, s-creatinine and u-albumin (p < 0.001 for all). Increasing level of DR showed statistically significant association with age, duration of diabetes, systolic BP, HbA1c, s-creatinine and u-albumine with increasing level of DR (all are p < 0.001) both T1DM/T2DM patients. CONCLUSION: The patients in FDDB had good systemic control with median values of BP, serum lipids, cholesterol and HbA1c all close to or below national guidelines at the time of data extraction, but still a high level of DR was found in this cohort. DR was more common in patients with T1DM than T2DM, but as T2DM patients are more numerous, their level of DR despite acceptable control is still concerning. Most important associated factors for higher levels of DR were age, duration of diabetes, HbA1c, s-creatinine and u-albumine.

Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with aberrant glomerular filtration of serine proteases. The study was designed to test the hypothesis that the epithelial sodium channel is activated proteolytically by urine plasmin in diabetic nephropathy and mediates renal sodium retention. METHODS: In an open-label intervention study on type 1 diabetes patients on standardized NaCl intake (200 mmol/day) with (n = 15) and without diabetic nephropathy (control, n = 12), urinary Na excretion in response to oral amiloride (20 or 40 mg/day for 2 days) was compared. RESULTS: A total of 27 patients completed the study and nine diabetic nephropathy and eight control study participants were compliant (24-h urine Na excretion of 200 mmol ±â€Š30%). Amiloride increased significantly total and fractional Na excretion in both groups. Total natriuresis and weight loss were significantly larger in the control group compared with diabetic nephropathy at day 1 of amiloride, whereas fractional Na excretion did not differ. Amiloride intervention increased plasma renin concentration only in diabetic nephropathy group; it reduced SBP in both groups, whereas DBP was reduced in diabetic nephropathy group only. Albuminuria was reduced significantly by amiloride in diabetic nephropathy group. Urine total amiloride concentration was not different between groups (12 ±â€Š1 and 16 ±â€Š1 µmol/l, respectively). Urine total plasminogen and active plasmin were reduced after amiloride in diabetic nephropathy. CONCLUSION: Amiloride increased renal Na excretion, reduced blood pressure, albuminuria, and total and active plasmin in urine. It is concluded that epithelial sodium channel is an attractive target to attain blood pressure control in long-term type I diabetes with no enhanced activity associated with nephropathy.

Prevalence and possible mechanisms of reactive hypoglycemia in polycystic ovary syndrome.

STUDY QUESTION: What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls. SUMMARY ANSWER: The prevalence of RH was increased in PCOS versus controls. WHAT IS KNOWN ALREADY: Previous studies suggested an increased prevalence of RH in PCOS. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, ß-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT. MAIN RESULTS AND THE ROLE OF CHANCE: RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls. LIMITATIONS, REASONS FOR CAUTION: The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test. WIDER IMPLICATIONS OF THE FINDINGS: The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Jacob Madsen's and Olga Madsen's Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller's Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)).

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.

Intentional Weight Loss and Longevity in Overweight Patients with Type 2 Diabetes: A Population-Based Cohort Study.

OBJECTIVE: This study examined the influence of weight loss on long-term morbidity and mortality in overweight (BMI≥25 kg/m2) patients with type 2 diabetes, and tested the hypothesis that therapeutic intentional weight loss supervised by a medical doctor prolongs life and reduces the risk for cardiovascular disease in these patients. METHODS: This is a 19 year cohort study of patients in the intervention arm of the randomized clinical trial Diabetes Care in General Practice. Weight and prospective intentions for weight loss were monitored every third month for six years in 761 consecutive patients (≥40 years) newly diagnosed with diabetes in general practices throughout Denmark in 1989-92. Multivariable Cox regression was used to estimate the association between weight change during the monitoring period (year 0 to 6) and the outcomes during the succeeding 13 years (year 6 to 19) in 444 patients who were overweight at diagnosis and alive at the end of the monitoring period (year 6). The analysis was adjusted for age, sex, education, BMI at diagnosis, change in smoking, change in physical activity, change in medication, and the Charlson comorbidity 6-year score. Outcomes were from national registers. RESULTS: Overall, weight loss regardless of intention was an independent risk factor for increased all-cause mortality (P<0.01). The adjusted hazard ratio for all-cause mortality, cardiovascular mortality, and cardiovascular morbidity attributable to an intentional weight loss of 1 kg/year was 1.20 (95%CI 0.97-1.50, P = 0.10), 1.26 (0.93-1.72, P = 0.14), and 1.06 (0.79-1.42, P = 0.71), respectively. Limiting the analysis to include only those patients who survived the first 2 years after the monitoring period did not substantially change these estimates. A non-linear spline estimate indicated a V-like association between weight change and all-cause mortality, suggesting the best prognosis for those who maintained their weight. CONCLUSIONS: In this population-based cohort of overweight patients with type 2 diabetes, successful therapeutic intentional weight loss, supervised by a doctor over six years, was not associated with reduced all-cause mortality or cardiovascular morbidity/mortality during the succeeding 13 years.

Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease.

OBJECTIVE AND DESIGN: Patients with type 2 diabetes mellitus (T2D) have an increased fracture risk despite a normal or elevated bone mineral density (BMD). The aim of this cross-sectional in vivo study was to assess parameters of peripheral bone microarchitecture, estimated bone strength and bone remodeling in T2D patients with and without diabetic microvascular disease (MVD+ and MVD- respectively) and to compare them with healthy controls. METHODS: Fifty-one T2D patients (MVD+ group: n=25) were recruited from Funen Diabetic Database and matched for age, sex and height with 51 healthy subjects. High-resolution peripheral quantitative tomography (HR-pQCT) was used to assess bone structure at the non-dominant distal radius and tibia. Estimated bone strength was calculated using finite element analysis. Biochemical markers of bone turnover were measured in all participants. RESULTS: After adjusting for BMI, MVD+ patients displayed lower cortical volumetric BMD (P=0.02) and cortical thickness (P=0.02) and higher cortical porosity at the radius (P=0.02) and a trend towards higher cortical porosity at the tibia (P=0.07) compared to controls. HR-pQCT parameters did not differ between MVD- and control subjects. Biochemical markers of bone turnover were significantly lower in MVD+ and MVD- patients compared to controls (all P<0.01). These were no significant correlations between disease duration, glycemic control (average glycated hemoglobin over the previous 3 years) and HR-pQCT parameters. CONCLUSION: Cortical bone deficits are not a characteristic of all T2D patients but of a subgroup characterized by the presence of microvascular complications. Whether this influences fracture rates in these patients needs further investigation.

Patient explanations for non-attendance at type 2 diabetes self-management education: a qualitative study.

AIM: To explore reasons for non-attendance at type 2 diabetes self-management education. METHODS: To elicit the main themes explaining non-attendance, 15 semi-structured interviews were conducted with persons referred to, but not attending, self-management education. Systematic text condensation was applied to code and generate themes subsequently organised under individual and organisational factors. RESULTS: Individual (illness, lack of perceived benefit) and organisational factors relating to schedule (four whole days, time of day, notification) and content (supermarket visit) were cited as reasons for non-attendance. CONCLUSIONS: In this study, patients cited both individual and organisational factors as explaining non-attendance at type 2 diabetes self-management education. Further studies should take into account the importance of timing and of tailoring schedules and content to individuals' life situations and resources. As organisational factors are likely to vary across programmes and settings, more case studies are needed to further elucidate the dynamic relationship between individual and organisational factors to explain non-attendance at type 2 diabetes self-management education.