Diabetes compromises tight junction protein claudin 14 in the urinary bladder.

Infections are common in patients with diabetes. Moreover, increasing incidence of antibiotic resistance impedes the complete bacterial clearance and calls for alternative treatment strategies. Along with antibacterial resistance, compromised host conditions create a favorable condition for the disease progression. In particular, cell junction proteins are of major importance as they contribute to a tight cell barrier, protecting against invading pathogens. However, the impact of high glucose on cell junction proteins has received little attention in the urinary bladder but merits closer investigation. Here, we report that during diabetes the expression of cell junction protein, claudin 14 is compromised in the human urine exfoliated cells and in the urinary bladder of type 2 diabetic mouse. Further in vitro analysis confirmed a direct correlation of lower intracellular calcium levels with claudin 14 expression in high glucose-treated human uroepithelial cells. Moreover, external calcium supplementation in high glucose-treated cells significantly affected the cell migration and restored the claudin 14 expression through focal adhesion and ß-1 integrins. Strengthening the epithelial barrier is essential, especially in individuals with diabetes where basal calcium levels could contribute.

Observational study of selective screening for prediabetes and diabetes in a real-world setting: an interprofessional collaboration method between public dental services and primary health care in Sweden.

OBJECTIVE: Describe a method in a real-world setting to identify persons with undiagnosed prediabetes and type 2 diabetes through an interprofessional collaboration between Public Dental Services and Primary Health Care in Regions Stockholm. DESIGN: A descriptive observational study. SETTING: The study was conducted at seven sites in the region of Stockholm, Sweden. Each collaborating site consisted of a primary health clinic and dental clinic. SUBJECTS: Study participants included adults over 18 years of age who visited the Public Dental Services and did not have a medical history of prediabetes or type 2 diabetes. MAIN OUTCOME MEASURES: Selective screening is conducted in accordance with a risk assessment protocol at the Public Dental Services. In the investigated method, DentDi (Dental and Diabetes), adults diagnosed with caries and/or periodontitis over a cut-off value are referred to the Primary Health Care clinic for screening of prediabetes and type 2 diabetes. RESULTS: DentDi, introduced at seven sites, between the years 2017 and 2020, all of which continue to use the method today. A total of 863 participants from the Public Dental Services were referred to the Primary Health Care. Of those 396 accepted the invitation to undergo screening at the primary health care centre. Twenty-four individuals did not meet the inclusion criteria, resulting in a total of 372 persons being included in the study. Among the 372 participants, 27% (101) had elevated glucose levels, of which 12 were diagnosed with type 2 diabetes and 89 with prediabetes according to the study classification. CONCLUSIONS: DentDi is a feasible method of interprofessional collaboration where each profession contributes with the competence included in everyday clinical practice for early identification of persons with prediabetes and type 2 diabetes with a complete chain of care. The goal is to disseminate this method throughout Stockholm County and even other regions in Sweden.

Type 2 diabetes and poor oral health have a bidirectional association. The number of persons with undetected prediabetes and type 2 diabetes is high and rising globally.Through collaboration between Public Dental Services and Primary Health Care we have developed a feasible and novel method of selectively screening for prediabetes and type 2 diabetes in a real-world setting.By utilizing everyday practice within each discipline, this method has been implemented at seven sites in Region Stockholm.From the original number of 863 participants referred from the Public Dental Services to Primary Health Care 396 attended the medical screening. After excluding 24 participants, a total of 372 participants underwent screening for prediabetes and type 2 diabetes.The results of this study showed that almost 30% who were screened for prediabetes and type 2 diabetes had elevated blood glucose levels.

Comparison of Framingham 10-year cardiovascular risks in Sweden- and foreign-born primary health care patients in Sweden.

BACKGROUND: The prevalence of cardiovascular disease around the world varies by ethnicity and region of birth. Immigrants living in Sweden may have a higher prevalence of cardiovascular diseases than native-born Swedes, but little is known about their actual cardiovascular risk. This study aimed to examine the relationship in Sweden between 10-year cardiovascular risk and birthplace. METHOD: This cross-sectional study was based on cardiovascular risk factor data obtained from the 4D Diabetes Project, a Programme 4D subproject in Sweden. Participants were recruited from two primary healthcare centres in Stockholm without a history of diabetes or pre-diabetes. The outcome variable was 10-year cardiovascular risk based on the calculation of a Framingham Risk Score with six risk factors: age, sex, LDL, HDL, BP, diabetes and smoking for each participant. Multiple linear regression was performed to generate ß-coefficients for the outcome. RESULTS: There was an average of 8.86% cardiovascular risk over 10 years in Sweden-born participants and a 5.45% 10-year risk in foreign-born, (P < 0.0001). Foreign-born participants were about 10 years younger (mean age 46 years vs. 56 years, P < 0.001), with a significantly higher proportion of smokers (23.9% vs. 13.7%; P = 0.001). To be born in Sweden (with parents born in Sweden) was significantly associated with a 10-year cardiovascular risk in the crude model (ß- coefficient = 3.40, 95% CI 2.59-4.22; P < 0.0001) and when adjusted for education and alcohol consumption (ß- coefficient = 2.70 95% CI 1.86-3.54; P < 0.0001). Regardless of the birthplace, 10-year cardiovascular risk was lower for those with higher education compared to those with less than 10 years of education. CONCLUSION: This study found a relationship between 10-year calculated cardiovascular risk and place of birth. Sweden-born participants had a higher association with 10-year cardiovascular risk than foreign-born participants. These results contradict previous reports of higher rates of CVD in residents of Middle-Eastern countries and Middle-Eastern immigrants living in Sweden.

Characterization of data-driven clusters in diabetes-free adults and their utility for risk stratification of type 2 diabetes.

BACKGROUND: The prevention of type 2 diabetes is challenging due to the variable effects of risk factors at an individual level. Data-driven methods could be useful to detect more homogeneous groups based on risk factor variability. The aim of this study was to derive characteristic phenotypes using cluster analysis of common risk factors and to assess their utility to stratify the risk of type 2 diabetes. METHODS: Data on 7317 diabetes-free adults from Sweden were used in the main analysis and on 2332 diabetes-free adults from Mexico for external validation. Clusters were based on sex, family history of diabetes, educational attainment, fasting blood glucose and insulin levels, estimated insulin resistance and ß-cell function, systolic and diastolic blood pressure, and BMI. The risk of type 2 diabetes was assessed using Cox proportional hazards models. The predictive accuracy and long-term stability of the clusters were then compared to different definitions of prediabetes. RESULTS: Six risk phenotypes were identified independently in both cohorts: very low-risk (VLR), low-risk low ß-cell function (LRLB), low-risk high ß-cell function (LRHB), high-risk high blood pressure (HRHBP), high-risk ß-cell failure (HRBF), and high-risk insulin-resistant (HRIR). Compared to the LRHB cluster, the VLR and LRLB clusters showed a lower risk, while the HRHBP, HRBF, and HRIR clusters showed a higher risk of developing type 2 diabetes. The high-risk clusters, as a group, had a better predictive accuracy than prediabetes and adequate stability after 20 years. CONCLUSIONS: Phenotypes derived using cluster analysis were useful in stratifying the risk of type 2 diabetes among diabetes-free adults in two independent cohorts. These results could be used to develop more precise public health interventions.

Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats.

INTRODUCTION: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. METHODS: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. RESULTS: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. CONCLUSIONS: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

Treatment with a ß-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity.

AIMS/HYPOTHESIS: Chronic stimulation of ß2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of ß2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of ß2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. METHODS: C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. RESULTS: Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg-1 day-1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). CONCLUSIONS/INTERPRETATION: Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective ß2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans. Graphical abstract.

IGFBP1 increases ß-cell regeneration by promoting α- to ß-cell transdifferentiation.

There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of ß cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during ß-cell regeneration. We then tested the proteins' ability to potentiate ß-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted ß-cell regeneration by potentiating α- to ß-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of ß-cell regeneration and highlight its clinical importance in diabetes.

Long-term transportation noise exposure and incidence of ischaemic heart disease and stroke: a cohort study.

BACKGROUND: There is limited evidence from longitudinal studies on transportation noise from different sources and development of ischaemic heart disease (IHD) and stroke. OBJECTIVES: This cohort study assessed associations between exposure to noise from road traffic, railway or aircraft and incidence of IHD and stroke. METHODS: In a cohort of 20 012 individuals from Stockholm County, we estimated long-term residential exposure to road traffic, railway and aircraft noise. National Patient and Cause-of-Death Registers were used to identify IHD and stroke events. Information on risk factors was obtained from questionnaires and registers. Adjusted HR for cardiovascular outcomes related to source-specific noise exposure were computed using Cox proportional hazards regression. RESULTS: No clear or consistent associations were observed between transportation noise and incidence of IHD or stroke. However, noise exposure from road traffic and aircraft was related to IHD incidence in women, with HR of 1.11 (95% CI 1.00 to 1.22) and 1.25 (95% CI 1.09 to 1.44) per 10 dB Lden, respectively. For both sexes taken together, we observed a particularly high risk of IHD in those exposed to all three transportation noise sources at≥45 dB Lden, with a HR of 1.57 (95% CI 1.06 to 2.32), and a similar tendency for stroke (HR 1.42; 95% CI 0.87 to 2.32). CONCLUSION: No overall associations were observed between transportation noise exposure and incidence of IHD or stroke. However, there appeared to be an increased risk of IHD in women exposed to road traffic or aircraft noise as well as in those exposed to multiple sources of transportation noise.

Meal intake increases circulating procoagulant microparticles in patients with type 1 and type 2 diabetes mellitus.

Diabetes mellitus (DM) is associated with prothrombotic alterations, and postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We therefore investigated whether a standardized mixed meal alters circulating microparticles (MPs) and their procoagulant activity in DM patients. Patients with DM type 1 (T1DM, n = 11) and type 2 (T2DM; n = 9) were studied before and 90 min after a standardized meal (without premeal insulin). MPs in plasma derived from platelets (PMPs), endothelial cells (EMPs), or monocytes (MMPs) were measured by flow cytometry. MP-induced thrombin generation in plasma was assessed by a calibrated automated thrombogram. In the fasting state, MPs did not differ significantly between T1DM and T2DM. Meal intake increased the following microparticles: PMPs expressing phosphatidylserine (by 55%, on average), P-selectin (by 86%), and tissue factor (TF; by 112%); EMPs expressing E-selectin (by 96%) and MMPs expressing TF (by 164%), with no significant group differences between T1DM and T2DM. There were no increments in EMPs expressing phosphatidylserine or TF. Meal intake increased MP-induced thrombin generation similarly in T1DM and T2DM with increased endogenous thrombin potential (p = 0.02) and peak thrombin (p = 0.03) and shortened time to peak (p = 0.02). Phosphatidylserine inhibition by lactadherin completely abolished MP-induced thrombin generation, while an anti-TF antibody had no effect. In conclusion, meal intake increased several types of circulating MPs in patients with diabetes mellitus. These MPs have a procoagulant potential, which is related to phosphatidylserine expression and negatively charged MP surfaces rather than to TF.

Alcohol and type 2 diabetes: The role of socioeconomic, lifestyle and psychosocial factors.

AIMS: We investigate (a) alcohol consumption in association with type 2 diabetes, taking heavy episodic drinking (HED), socioeconomic, health and lifestyle, and psychosocial factors into account, and (b) whether a seemingly protective effect of moderate alcohol consumption on type 2 diabetes persists when stratified by occupational position. METHODS: This population-based longitudinal cohort study comprises 16,223 Swedes aged 18-84 years who answered questionnaires about lifestyle, including alcohol consumption in 2002, and who were followed-up for self-reported or register-based diabetes in 2003-2011. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated in a multivariable-adjusted logistic regression model for all participants and stratified by high and low occupational position. We adjusted for HED, socioeconomic (occupational position, cohabiting status and unemployment), health and lifestyle (body mass index (BMI), blood pressure, smoking, physical inactivity, poor general health, anxiety/depression and psychosocial (low job control and poor social support) characteristics one by one, and the sets of these factors. RESULTS: Moderate consumption was inversely associated with type 2 diabetes after controlling for health and lifestyle (OR=0.47; 95% CI: 0.29-0.79) and psychosocial factors (OR=0.40; 95% CI: 0.22-0.79) when compared to non-drinkers. When adjusting for socioeconomic factors, there was still an inverse but non-significant association (OR=0.59; 95% CI: 0.35-1.00). In those with high occupational position, there was no significant association between moderate consumption and type 2 diabetes after adjusting for socioeconomic (OR=0.67; 95% CI: 0.3-1.52), health and lifestyle (OR=0.70; 95% CI: 0.32-1.5), and psychosocial factors (OR=0.75; 95% CI: 0.23-2.46). On the contrary, in those with low occupational position, ORs decreased from 0.55 (95% CI: 0.28-1.1) to 0.35 (95% CI: 0.15-0.82) when adjusting for psychosocial factors, a decrease that was solely due to low job control. HED did not influence any of these associations. CONCLUSIONS: Moderate alcohol consumption is associated with a lower risk of type 2 diabetes, after adjusting for HED, health and lifestyle, and psychosocial characteristics. The association was inverse but non-significant after adjusting for socioeconomic factors. When stratified by occupational position, there was an inverse association only in those with low occupational position and after adjusting for low job control.

App-technology to improve lifestyle behaviors among working adults - the Health Integrator study, a randomized controlled trial.

BACKGROUND: Mobile health, mHealth is recognized as a strategy to improve lifestyle behaviors. Research targeting specific lifestyle behaviors has shown that interventions using smartphones can be effective. However, few studies have evaluated solutions with multicomponent interventions, tailoring the intervention to the specific needs of the participant using a combination of mHealth and conventional treatment. To accomplish this, we developed Health Integrator, an mHealth platform with services and offers in the areas of diet, physical activity, sleeping habits, stress, alcohol and tobacco use. In the system, the user selects an area of intervention together with a health coach and set weekly goals. This study protocol presents the design and methodology of the Health Integrator Study, a randomized controlled trial to promote improved lifestyle behaviors. METHODS: A three-arm parallel randomized controlled trial (1:1:1) is conducted in the Stockholm County, Sweden. In total, 209 employees at a four different companies representing both white and blue collar workers, have been recruited. Participants are randomized to either a control group or to one of two intervention groups receiving a 3-month lifestyle behavior change program including either 1) use of Health Integrator and monthly health coaching sessions or 2) only Health Integrator. At baseline and follow-up after 3- and 6-months, all participants answer questionnaires assessing lifestyle behaviors and quality of life. At baseline and the 3-month follow-up (end of intervention period), weight, height, waist circumference and blood pressure are measured, and all participants wear an Actigraph accelerometer for 7 days to assess physical activity. Blood lipid profile and HbA1c are measured among all participants at baseline. If baseline measures fall outside the normal range, a second measurement is done after 3 months. DISCUSSION: The Health Integrator Intervention Study will evaluate if a personalized intervention combining mHealth and conventional programs for lifestyle change, with or without additional health coach sessions, can improve lifestyle behaviors and quality of life. Based on the results from this trial, Health Integrator can easily be implemented within a broad public. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03579342 . Retrospectively registered, first submitted May 8, 2018.

Noninvasive in vivo Assessment of the Re-endothelialization Process Using Ultrasound Biomicroscopy in the Rat Carotid Artery Balloon Injury Model.

OBJECTIVES: Ultrasound biomicroscopy (UBM), or ultra high-frequency ultrasound, is a technique used to assess the anatomy of small research animals. In this study, UBM was used to assess differences in intimal hyperplasia thickness as a surrogate measurement of the re-endothelialization process after carotid artery balloon injury in rats. METHODS: Ultrasound biomicroscopic data from 3 different experiments and rat strains (Sprague Dawley, Wistar, and diabetic Goto-Kakizaki) were analyzed. All animals were subjected to carotid artery balloon injury and examined with UBM (30-70 MHz) 2 and 4 weeks after injury. Re-endothelialization on UBM was defined as the length from the carotid bifurcation to the most distal visible edge of the intimal hyperplasia. En face staining with Evans blue dye was performed at euthanasia 4 weeks after injury, followed by tissue harvesting for histochemical and immunohistochemical evaluations. RESULTS: A significant correlation (Spearman r = 0.63; P < .0001) was identified when comparing all measurements of re-endothelialization obtained from UBM and en face staining. The findings revealed a similar pattern for all rat strains: Sprague Dawley (Spearman r = 0.70; P < .0001), Wistar (Spearman r = 0.36; P < .081), and Goto-Kakizaki (Spearman r = 0.70; P < .05). A Bland-Altman test showed agreement between en face staining and UBM. Immunohistochemical staining confirmed the presence of the endothelium in the areas detected as re-endothelialized by the UBM assessment. CONCLUSIONS: Ultrasound biomicroscopy can be used for repeated in vivo assessment of re-endothelialization after carotid artery balloon injury in rats.

Air pollution and incidence of cancers of the stomach and the upper aerodigestive tract in the European Study of Cohorts for Air Pollution Effects (ESCAPE).

Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long-term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land-use regression models for particulate matter (PM) below 10 µm (PM10 ), below 2.5 µm (PM2.5 ), between 2.5 and 10 µm (PMcoarse ), PM2.5 absorbance and nitrogen oxides (NO2 and NOX ) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. During average follow-up of 14.1 years of 305,551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 µg/m3 of PM2.5 was 1.38 (95% CI 0.99; 1.92) for gastric and 1.05 (95% CI 0.62; 1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM2.5 was found in men (HR 1.98 [1.30; 3.01]) as compared to women (HR 0.85 [0.5; 1.45]). This large multicentre cohort study shows an association between long-term exposure to PM2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk.

App-technology to increase physical activity among patients with diabetes type 2 - the DiaCert-study, a randomized controlled trial.

BACKGROUND: Physical activity can decrease the risk of complications related to diabetes type 2. Feasible and scalable strategies to implement support for a healthy lifestyle for patients in primary care are needed. The aim of the DiaCert-study is to evaluate a digital healthcare platform and the effect of a 12-week long smartphone-app physical activity intervention aiming at increasing physical activity (primary outcome) and improve levels of HbA1c (glycated hemoglobin), blood lipids, blood pressure, body composition, as well as other lifestyle factors and overall health in patients with diabetes type 2. METHODS/DESIGN: The DiaCert-study is a two-arm, randomized controlled trial that will include 250 patients with diabetes type 2. At baseline, participants are randomized 1:1 to intervention, i.e. use of the smartphone-app, during 12 weeks, or to a control group receiving only standard care. Physical activity and sedentary behavior, is objectively measured using the Actigraph GT3X. Biomarkers including HbA1c and blood lipids are measured in fasting blood samples. Anthropometrics include height, weight, waist circumference and body composition, and a number of lifestyle factors including sleep, diet, self-efficacy, and quality of life, are assessed through an extensive questionnaire. Measurements are made at baseline and at follow-up after 3, 6 and 12 months. DISCUSSION: Using new technology, is one way to bridge the gap between what patients need and what health care can offer. This study evaluates a new digital health care platform and will show if use of a smartphone-app to promote daily steps is an effective and feasible method to increase physical activity and improve clinical markers in patients with diabetes type 2. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03053336 ; 7 Feb, 2017.

Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE).

Aims: We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results: We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion: Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.

Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction.

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts.

Several studies have indicated weakly increased risk for kidney cancer among occupational groups exposed to gasoline vapors, engine exhaust, polycyclic aromatic hydrocarbons and other air pollutants, although not consistently. It was the aim to investigate possible associations between outdoor air pollution at the residence and the incidence of kidney parenchyma cancer in the general population. We used data from 14 European cohorts from the ESCAPE study. We geocoded and assessed air pollution concentrations at baseline addresses by land-use regression models for particulate matter (PM10 , PM2.5 , PMcoarse , PM2.5 absorbance (soot)) and nitrogen oxides (NO2 , NOx ), and collected data on traffic. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses to calculate summary hazard ratios (HRs). The 289,002 cohort members contributed 4,111,908 person-years at risk. During follow-up (mean 14.2 years) 697 incident cancers of the kidney parenchyma were diagnosed. The meta-analyses showed higher HRs in association with higher PM concentration, e.g. HR = 1.57 (95%CI: 0.81-3.01) per 5 µg/m3 PM2.5 and HR = 1.36 (95%CI: 0.84-2.19) per 10-5 m-1 PM2.5 absorbance, albeit never statistically significant. The HRs in association with nitrogen oxides and traffic density on the nearest street were slightly above one. Sensitivity analyses among participants who did not change residence during follow-up showed stronger associations, but none were statistically significant. Our study provides suggestive evidence that exposure to outdoor PM at the residence may be associated with higher risk for kidney parenchyma cancer; the results should be interpreted cautiously as associations may be due to chance.

Effects of Linagliptin on Vessel Wall Healing in the Rat Model of Arterial Injury Under Normal and Diabetic Conditions.

Diabetic patients suffer an increased risk of restenosis and late stent thrombosis after angioplasty, complications which are related to a defective reendothelialization. Dipeptidyl peptidase-4 inhibitors have been suggested to exert a direct effect on endothelial and smooth muscle cells (SMCs). Therefore, the objective was to study if the dipeptidyl peptidase-4 inhibitor linagliptin could influence vascular repair and accelerate reendothelialization after arterial injury in healthy and diabetic animals. Diabetic Goto-Kakizaki and healthy Wistar rats were subjected to arterial injury and treated with linagliptin or vehicle. Vessel wall healing was monitored noninvasively using ultrasound, and on sacrifice, with Evans blue staining and immunohistochemistry. The effect of linagliptin on SMCs was also studied in vitro. We found that linagliptin reduced the proliferation and dedifferentiation of SMCs in vitro, and modulated the inflammatory response in the SMCs after arterial injury in vivo. However, these effects of linagliptin did not affect the neointima formation or the reendothelialization under normal and diabetic conditions. Although linagliptin did not influence vessel wall healing, it seems to possess a desirable antiproliferative influence on SMCs in vitro and an antiinflammatory effect in vivo. These pharmacological properties might carry a potential significance for favorable outcome after vascular interventions in diabetic patients.

ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats.

Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A1c (Hb A1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca2+ concentrations, [Ca2+]i, were higher and the frequency of [Ca2+]i oscillations enhanced compared with placebo. ARA290 also improved stimulus-secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose-stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP-sensitive potassium (KATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when KATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved γ-cell glucose metabolism and [Ca2+]i handling, and thereby enhanced glucose-induced insulin release.

ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes.

Although erythropoietin ameliorates experimental type 2 diabetes with neuropathy, serious side effects limit its potential clinical use. ARA 290, a nonhematopoietic peptide designed from the structure of erythropoietin, interacts selectively with the innate repair receptor that mediates tissue protection. ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. To evaluate the potential activity of ARA 290 in type 2 diabetes and painful neuropathy, subjects were enrolled in this phase 2 study. ARA 290 (4 mg) or placebo were self-administered subcutaneously daily for 28 d and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Subjects receiving ARA 290 exhibited an improvement in hemoglobin A(1c) (Hb A(1c)) and lipid profiles throughout the 56 d observation period. Neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly in the ARA 290 group. Mean corneal nerve fiber density (CNFD) was reduced significantly compared with normal controls and subjects with a mean CNFD >1 standard deviation from normal showed a significant increase in CNFD compared with no change in the placebo group. These observations suggest that ARA 290 may benefit both metabolic control and neuropathy in subjects with type 2 diabetes and deserves continued clinical evaluation.