Cardiovascular Diabetology - Latest Articles

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes

Erik Salum — 2012-05-25T00:00:00Z

Background: Diabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation. Methods: Male Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenousinfusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using aradioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis. Results: PWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 +/- 125 nmol/L vs 108 +/- 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated anduntreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation. Conclusion: PWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.

Increased myocardial SERCA expression in early type 2 diabetes mellitus is insulin dependent: In vivo and in vitro data

Sabine Fredersdorf — 2012-05-23T00:00:00Z

Background: Calcium (Ca2+) handling proteins are known to play a pivotal role in the pathophysiology of cardiomyopathy. However little is known about early changes in the diabetic heart and the impact of insulin treatment (Ins). Methods: Zucker Diabetic Fatty rats treated with or without insulin (ZDF +/- Ins, n = 13) and lean littermates (controls, n = 7) were sacrificed at the age of 19 weeks. ZDF + Ins (n = 6) were treated with insulin for the last 6 weeks of life. Gene expression of Ca2+ ATPase in the cardiac sarcoplasmatic reticulum (SERCA2a, further abbreviated as SERCA) and phospholamban (PLB) were determined by northern blotting. Ca2+ transport of thesarcoplasmatic reticulum (SR) was assessed by oxalate-facilitated 45Ca-uptake in left ventricular homogenates. In addition, isolated neonatal cardiomyocytes were stimulated in cell culture with insulin, glucose or triiodthyronine (T3, positive control). mRNA expression of SERCA and PLB were measured by Taqman PCR. Furthermore, effects of insulin treatment on force of contraction and relaxation were evaluated by cardiomyocytes grown in a three-dimensional collagen matrix (engineered heart tissue, EHT) stimulated for 5 days by insulin. By western blot phosphorylations status of Akt was determed and the influence of wortmannin. Results: SERCA levels increased in both ZDF and ZDF + Ins compared to control (control 100 +/- 6.2 vs. ZDF 152 +/- 26.6* vs. ZDF + Ins 212 +/- 18.5*# % of control, *p < 0.05 vs. control, #p < 0.05 vs. ZDF) whereas PLB was significantly decreased in ZDF and ZDF + Ins (control 100 +/- 2.8 vs. ZDF 76.3 +/- 13.5* vs. ZDF + Ins 79.4 +/- 12.9* % of control, *p < 0.05 vs control). The increase in the SERCA/PLB ratio in ZDF and ZDF +/- Ins was accompanied by enhanced Ca2+ uptake to the SR (control 1.58 +/- 0.1 vs. ZDF 1.85 +/- 0.06* vs. ZDF + Ins 2.03 +/- 0.1* mug/mg/min, *p < 0.05 vs. control). Interestingly, there was a significant correlation between Ca2+ uptake and SERCA2a expression. As shown by in-vitro experiments, the effect of insulin on SERCA2a mRNA expression seemed to have a direct effect on cardiomyocytes. Furthermore, long-term treatment of engineered heart tissue with insulin increased the SERCA/PLB ratio and accelerated relaxation time. Akt was significantly phosphorylated by insulin. This effect could be abolished by wortmannin. Conclusion: The current data demonstrate that early type 2 diabetes is associated with an increase in the SERCA/PLB ratio and that insulin directly stimulates SERCA expression and relaxation velocity. These results underline the important role of insulin and calcium handling proteins in the cardiac adaptation process of type 2 diabetes mellitus contributing to cardiac remodeling and show the important role of PI3-kinase- kt-SERCA2a signaling cascade.

Let's Prevent Diabetes: study protocol for a cluster randomised controlled trial of an educational intervention in a multi-ethnic UK population with screen detected impaired glucose regulation.

Laura Gray — 2012-05-20T00:00:00Z

Background: The prevention of type 2 diabetes is a globally recognised health care priority, but there is a lack of rigorous research investigating optimal methods of translating diabetes prevention programmes, based on the promotion of a healthy lifestyle, into routine primary care. The aim of the study is to establish whether a pragmatic structured education programme targeting lifestyle and behaviour change in conjunction with motivational maintenance via the telephone can reduce the incidence of type 2 diabetes in people with impaired glucose regulation (a composite of impaired glucose tolerance and/or impaired fasting glucose) identified through a validated risk score screening programme in primary care.DesignCluster randomised controlled trial undertaken at the level of primary care practices. Follow-up will be conducted at 12, 24 and 36 months. The primary outcome is the incidence of type 2 diabetes. Secondary outcomes include changes in HbA1c, Blood glucose levels, cardiovascular risk, the presence of the Metabolic Syndrome and the cost-effectiveness of the intervention. Methods: The study consists of screening and intervention phases within 44 general practices coordinated from a single academic research centre. Those at high risk of impaired glucose regulation or type 2 diabetes are identified using a risk score and invited for screening using a 75g-Oral Glucose Tolerance Test. Those with screen detected impaired glucose regulation will be invited to take part in the trial. Practices will be randomised to standard care or the intensive arm. Participants from intensive arm practices will receive a structured education programme with motivational maintenance via the telephone and annual refresher sessions. The study will run from 2009-2014.DiscussionThis study will provide new evidence surrounding the long-term effectiveness of a diabetes prevention programme conducted within routine primary care in the United Kingdom.

Estimation of plasma apolipoprotein B concentration using routinely measured lipid biochemical tests in apparently healthy Asian adults.

Dong-Sik Cho — 2012-05-18T00:00:00Z

Background Increased low-density lipoprotein cholesterol (LDL) concentration is associated with increased risk of coronary heart disease (CHD) but a substantial risk of cardiovascular disease often remains after LDL concentrations have been treated to target. Apolipoprotein B (apo B) is the major apolipoprotein contained within atherogenic lipoproteins such as LDL, and apo B is a more reliable indicator of cardiovascular risk than LDL concentration.Aim and methodsOur aim was to develop a formula for calculating apo B using lipid biochemistry measurements that are commonly available in clinical practice. We examined the clinical and laboratory data from 73,047 Koreans who underwent a medical health check that included apolipoprotein B concentration. The study sample was randomly divided into a training set for prediction model building and a validation set of equal size. Multivariable linear regression analysis was used to develop a prediction model equation for estimating apo B and to validate the developed model. Results: The best results for estimating apo B were derived from an equation utilising LDL and triglyceride (TG) concentrations [ApoB=-33.12+0.675*LDL+11.95*ln(tg)]. This equation predicted the apo B result with a concordance correlation coefficient (CCC and 95%CIs) = 0.936 (0.935,0.937)) Conclusion: Our equation for predicting apo B concentrations from routine analytical lipid biochemistry provides a simple method for obtaining precise information about an important cardiovascular risk marker.

Determinants of uncontrolled hypertension in adult type 2 diabetes mellitus: an analysis of the Malaysian diabetes registry 2009

Boon How Chew — 2012-05-18T00:00:00Z

Background: Uncontrolled blood pressure (BP) is a significant contributor of morbidity and even mortality in type 2 diabetes (T2D) patients. This study was done to determine the significant determinants of uncontrolled blood pressure in T2D patients in Malaysia. Methods: Between 1st January 2009 to 31st December 2009, data from 70 889 patients with Type 2 diabetes was obtained from the Adult Diabetes Control and Management Registry for analysis; 303 centers participated in the study. Their demographic characteristics, the nature of their diabetes, their state of hypertension, treatment modalities, risk factors, and complications are described. Based on their most recent BP values, subjects were divided into controlled BP and uncontrolled BP and their clinical determinants compared. Independent determinants were identified using multivariate logistic regression. Results: The mean age of patients at diagnosis of diabetes was 52.3 +/- 11.1 years old. Most were women (59.0%) and of Malay ethnicity (61.9%). The mean duration of diabetes was 5.9 +/- 5.6 years. A total of 57.4% were hypertensive. Of the 56 503 blood pressure (BP) measured, 13 280 (23.5%) patients had BP <130/80 mmHg. Eighteen percent was on > two anti-hypertensive agents. Health clinics without doctor, older age ([greater than or equal to] 50 years old), shorter duration of diabetes (< 5 years), Malay, overweight were determinants for uncontrolled blood pressure (BP [greater than or equal to]130/80mmHg). Patients who were on anti-hypertensive agent/s were 2.7 times more likely to have BP [greater than or equal to]130/80mmHg. Type 2 diabetes patients who had ischaemic heart disease or nephropathy were about 20% and 15% more likely to have their blood pressure treated to target respectively. Conclusions: Major independent determinants of uncontrolled BP in our group of T2D patients were Malay ethnicity, older age, recent diagnosis of diabetes, overweight and follow-up at health clinics without a doctor and possibly the improper use of anti hypertensive agent. More effort, education and resources, especially in the primary health care centres are needed to improve hypertensive care among our patients with diabetes.

Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

Yayoi Nishida — 2012-05-17T00:00:00Z

Background: Both angiotensin II type I receptor blockers (ARBs) and calcium channel blockers (CCBs) are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601) and propensity-score matched new CCB users (n = 601), with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG), total cholesterol (TC), non-fasting blood glucose, hemoglobin A1c (HbA1c), sodium, potassium, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), hemoglobin and hematocrit, and white blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts up to 12 months after the start of ARB or CCB monotherapy. Results: We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions: Our study suggested that hematological adverse effects and electrolyte imbalance are greater with ARB monotherapy than with CCB monotherapy.

Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: Cross-sectional analyses from the KEEPS Study

Gary Huang — 2012-05-15T00:00:00Z

Background: The published literature regarding the relationships between retinol-binding protein 4 (RBP4) and cardiometabolic risk factors and subclinical atherosclerosis is conflicting, likely due, in part, to limitations of frequently used RBP4 assays. Prior large studies have not utilized the gold-standard Western Blot analysis of RBP4 levels. Methods: Full-length serum RBP4 levels were measured by Western Blot in 709 postmenopausal women screened for the Kronos Early Estrogen Prevention Study. Cross-sectional analyses related RBP4 levels to cardiometabolic risk factors, carotid artery intima-media thickness (CIMT), and coronary artery calcification (CAC). Results: The mean age of women was 52.9 (+/- 2.6) years, and the median RBP4 level was 49.0 (interquartile range 36.9-61.5) ug/mL. Higher RBP4 levels were weakly associated with higher triglycerides (age, race, and smoking-adjusted partial Spearman correlation coefficient= 0.10; P=0.01), but were unrelated to blood pressure, cholesterol, C-reactive protein, glucose, insulin, and CIMT levels (all partial Spearman correlation coefficients [less than or equal to]0.06, P>0.05). Results suggested a curvilinear association between RBP4 levels and CAC, with women in the bottom and upper quartiles of RBP4 having higher odds of CAC (odds ratio [95% confidence interval] 2.10 [1.07-4.09], 2.00 [1.02-3.92], 1.64 [0.82-3.27] for the 1st, 3rd, and 4th RBP4 quartiles vs. the 2nd quartile). However, a squared RBP4 term in regression modeling was non-significant (P=0.10). Conclusions: In these healthy, recently postmenopausal women, higher RBP4 levels were weakly associated with elevations in triglycerides and with CAC, but not with other risk factors or CIMT. These data using the gold standard of RBP4 methodology only weakly support the possibility that perturbations in RBP4 homeostasis may be an additional risk factor for subclinical coronary atherosclerosis.Trial Registration: ClinicalTrials.gov number NCT00154180

Gender difference in carotid intima-media thickness in type 2 diabetic patients: a 4-year follow-up study

Bo Zhao — 2012-05-14T00:00:00Z

Background: Different population studies have reported gender difference in carotid intima-media thickness (CIMT), which is proved to be a risk factor of cardiovascular diseases. However, few longitudinal researches examine this gender difference in type 2 diabetes mellitus (T2DM) patients. Therefore, we prospectively analyzed CIMT in T2DM patients over a 4-year follow-up period. Methods: 355 T2DM patients (mean age 59 years; 54.9% women) were included in the present study. CIMT were measured using Color Doppler ultrasound. CIMT was measured at baseline (CIMT) in 2006 and at follow-up in 2010. Biochemical and clinical measurements were collected at baseline. Results: Mean value of CIMT1 and CIMT2 were 0.740+/-0.148mm and 0.842+/-0.179mm, respectively. Men had higher CIMT than women both at baseline and at follow-up (CIMT1: 0.762+/-0.149 vs 0.723+/-0.146 mm, P=0.0149; CIMT2: 0.880+/-0.189 vs 0.810+/-0.164 mm, P=0.0002). Mean annual progression of CIMT (dCIMT) was 0.025+/-0.022 mm/year. dCIMT was larger in men than in women (0.030+/-0.025 vs 0.022+/-0.019 mm, P=0.0006). In multiple regression analyses, age was an independent risk factor of CIMT in both genders, while dCIMT was associated with age only in men. Conclusions: Gender difference in CIMT was confirmed in T2DM patients. Moreover, impact of ageing on CIMT progression only existed in men, which might be the reason that gender difference in CIMT increased with age.

Blood pressure and lipid management fall far short in persons with type 2 diabetes: Results from the DIAB-CORE Consortium including six German population-based studies

Ina-Maria Rückert — 2012-05-08T00:00:00Z

Background Although most deaths among patients with type 2 diabetes (T2D) are attributable to cardiovascular disease, modifiable cardiovascular risk factors appear to be inadequately treated in medical practice. The aim of this study was to describe hypertension, dyslipidemia and medical treatment of these conditions in a large population-based sample.Methods The present analysis was based on the DIAB-Core project, in which data from five regional population-based studies and one nationwide German study were pooled. All studies were conducted between 1997 and 2006. We assessed the frequencies of risk factors and co-morbidities, especially hypertension and dyslipidemia, in participants with and without T2D. The odds of no or insufficient treatment and the odds of pharmacotherapy were computed using multivariable logistic regression models. Types of medication regimens were described.Results The pooled data set comprised individual data of 15,071 participants aged 45-74 years, including 1287 (8.5%) participants with T2D.Subjects with T2D were significantly more likely to have untreated or insufficiently treated hypertension, i.e. blood pressure of >= 140/90 mmHg (OR = 1.43, 95% CI 1.26-1.61) and dyslipidemia i.e. a total cholesterol/HDL-cholesterol ratio >= 5 (OR = 1.80, 95% CI 1.59-2.04) than participants without T2D.Untreated or insufficiently treated blood pressure was observed in 48.9% of participants without T2D and in 63.6% of participants with T2D. In this latter group, 28.0% did not receive anti-hypertensive medication and 72.0% were insufficiently treated.In non-T2D participants, 28.8% had untreated or insufficiently treated dyslipidemia. Of all participants with T2D 42.5% had currently elevated lipids, 80.3% of these were untreated and 19.7% were insufficiently treated.Conclusions Blood pressure and lipid management fall short especially in persons with T2D across Germany. The importance of sufficient risk factor control besides blood glucose monitoring in diabetes care needs to be emphasized in order to prevent cardiovascular sequelae and premature death.

Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways

Jia-Shiong Chen — 2012-05-03T00:00:00Z

Background: Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation.Materials and methods: Human aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated. Results: Either high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes. Conclusions: Long-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.