The non-hematopoietic erythropoietin analogue, ARA290, improves glucose tolerance by stimulating insulin secretion in spontaneously type 2 diabetic Goto-Kakizaki rats

Proteomic

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 A(1c) (Hb A(1c)) was reduced by similar to 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 beta-cell glucose metabolism and [Ca2+](i) handling, and thereby enhanced glucose-induced insulin release

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 A(1c) (Hb A(1c)) was reduced by similar to 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 beta-cell glucose metabolism and [Ca2+](i) handling, and thereby enhanced glucose-induced insulin release.Proteomic

Serum 25-hydroxyvitamin D relationships to carotid intima-media thickness (cIMT) and cIMT progression in a European high-risk population

Purpose: Vitamin D deficiency has been implicated in cardiovascular disease (CVD) as well as in promoting multiple cardiovascular risk factors such as obesity, dyslipoproteinemia, type-2 diabetes and hypertension. We investigated the relationships of serum 25-hydroxyvitamin D (25(OH)D) concentration to established and emerging cardiovascular risk indicators, baseline cIMT and cIMT progression in the IMPROVE study. Methods: IMPROVE is a European, multicentre, longitudinal cohort study, which enrolled individuals aged 54 to 80 years with at least three cardiovascular risk factors and no history of CVD from 7 centers in Finland, Sweden, the Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline, month 15 and month 30. Blood samples, clinical data and information about life style factors collected at baseline from a total 3430 subjects were used in the present substudy of 25(OH)D. Results: Serum 25(OH)D levels were positively correlated with latitude. Subjects having deficient levels of vitamin D (defined as serum 25(OH)D below 25 nmol/L) were more often women, smokers and diabetics, were more obese, had higher blood pressure, triglyceride, blood glucose and CRP levels, had lower HDL and were less physically active. Waist circumference, diastolic blood pressure, triglycerides, HDL, LDL, current smoking and high physical activity showed significant and independent associations with 25(OH)D in multiple robust regression analyses. Overall, there were no consistent independent relationships between 25(OH)D and segment-specific or composite IMT measures (baseline or progression) when age, sex, latitude and clinical and biochemical risk indicators (the latter selected by best subset analysis) were included in multivariable linear regression models. Conclusions: Levels of 25(OH)D differed across Europe, showed multiple associations with established and emerging cardiovascular risk factors but were not independently related to cIMT or cIMT progression. This argues against an independent causal role of vitamin D in early subclinical atherosclerosis in high-risk individuals

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents.

Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the β-cell primary cilium in type 2 diabetes susceptibility. We find impaired ​glucose handling in young ​Bbs4−/− mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. ​Insulin receptor is recruited to the cilium of stimulated β-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated β-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the β-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility

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

Long-term exposure to air pollution and cardiovascular mortality : An analysis of 22 European cohorts.

BACKGROUND:: Air pollution has been associated with cardiovascular mortality, but it remains unclear as to whether specific pollutants are related to specific cardiovascular causes of death. Within the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE), we investigated the associations of long-term exposure to several air pollutants with all cardiovascular disease (CVD) mortality, as well as with specific cardiovascular causes of death. METHODS:: Data from 22 European cohort studies were used. Using a standardized protocol, study area-specific air pollution exposure at the residential address was characterized as annual average concentrations of the following: nitrogen oxides (NO2 and NOx); particles with diameters of less than 2.5 μm (PM2.5), less than 10 μm (PM10), and 10 μm to 2.5 μm (PMcoarse); PM2.5 absorbance estimated by land-use regression models; and traffic indicators. We applied cohort-specific Cox proportional hazards models using a standardized protocol. Random-effects meta-analysis was used to obtain pooled effect estimates. RESULTS:: The total study population consisted of 367,383 participants, with 9994 deaths from CVD (including 4,992 from ischemic heart disease, 2264 from myocardial infarction, and 2484 from cerebrovascular disease). All hazard ratios were approximately 1.0, except for particle mass and cerebrovascular disease mortality; for PM2.5, the hazard ratio was 1.21 (95% confidence interval = 0.87-1.69) per 5 μg/m and for PM10, 1.22 (0.91-1.63) per 10 μg/m. CONCLUSION:: In a joint analysis of data from 22 European cohorts, most hazard ratios for the association of air pollutants with mortality from overall CVD and with specific CVDs were approximately 1.0, with the exception of particulate mass and cerebrovascular disease mortality for which there was suggestive evidence for an association