The increased risk of cardiovascular disease (CVD) in diabetic compared to non-diabetic subjects seems to decrease with age. Whether this age-related reduction applies to CVD risk factors, and whether it is limited to established diabetes mellitus (DM) or also applies to pre-diabetic conditions are not well known.
Using a cross-sectional design we compared the strength of the correlation between glucometabolic disturbances (by grouping), CVD risk factor burden and self-rated health, in two age groups: middle-aged (57-69 years) and older (70-86 years) subjects, (63% men), participating in the Malmö Preventive Project Re-examination Study (n = 18,238). Simple (unadjusted) logistic regression analysis was applied to estimate between-group differences and trends. Interaction analysis was applied to estimate differences between age groups.
CVD risk factor burden and the proportion of subjects reporting poor self-rated health increased with increasing glucometabolic disturbance for men and women in both age groups (p-trend < 0.0001 for all). The slope of the trend curve with increasing CVD risk factor burden was significantly steeper for older women than for older men (p-interaction = 0.002). The slope of the trend curve for poor self-rated health was significantly steeper for middle-aged than for older men (p-interaction = 0.005), while no difference was observed between the age groups among women (p-interaction = 0.97).
We found no reduction in risk factor accumulation with increasing glucometabolic disturbance between middle-aged and older subjects. Our results indicate life-long CVD risk factor clustering with increased glucometabolic disturbance, and suggest that previously observed age-related reduction in excess CVD risk for subjects with DM might be due to a survival bias. However, our observations indicate more pronounced risk factor clustering and worse self-rated health with increased glucometabolic disturbance in older women than in older men.
Age; cardiovascular disease; diabetes mellitus; gender; glucose; self-rated health
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic vascular disease, but it is unknown whether the other way around is true too. C57BL/6 (B6) and BALB/cJ (BALB) are two mouse strains that differ markedly in their susceptibility to atherosclerosis. In this study we investigated the development of diet-induced T2DM in these two strains.
Methods and Results
When deficient in apolipoprotein E (apoE-/-) and fed a Western diet for 12 weeks, atherosclerosis-susceptible B6 mice developed significant hyperglycemia. In contrast, atherosclerosis-resistant BALB apoE-/- mice had much lower plasma glucose levels than B6.apoE-/- mice on either chow or Western diet and during an intraperitoneal glucose tolerance test. In response to glucose BALB.apoE-/- mice displayed both the first and second phases of insulin secretion but the second phase of insulin secretion was absent in B6.apoE-/- mice. In response to insulin B6.apoE-/- mice showed a deeper and longer-lasting fall in blood glucose levels while BALB.apoE-/- mice showed little reduction in glucose levels. Pancreatic islet area of BALB.apoE-/- mice on light microscopy nearly doubled the area of B6.apoE-/- mice. Most circulating proinflammatory cytokines were lower in BALB.apoE-/- than in B6.apoE-/- mice on the Western diet, as determined by protein arrays. Increased macrophage infiltration in islets was observed in B6.apoE-/- mice by immunostaining for Mac2 and also by flow cytometry.
This study demonstrates that defects in insulin secretion rather than defects in insulin resistance explain the marketed difference in susceptibility to T2DM in the B6.apoE-/- and BALB.apoE-/- mouse model. A smaller islet mass and more prominent islet inflammation may explain the vulnerability of B6.apoE-/- mice to diet-induced diabetes.
This study investigates the associations between changes in serum Triglycerides (S-TG), -Urate (S-Urate), and -Glucose (S-Glu) and changes in serum Calcium (S-Ca), -Magnesium (S-Mg), and -Phosphate (S-P) in patients with type 2 diabetes compared with non-diabetic patients.
The analysis is based on data collected from a secondary prevention population of women and men (W/M) at risk for cardiovascular disease (type 2 diabetes, 212/200; non-diabetes 968/703). The whole population (n = 2083) had a mean age of 51.0 (9.7) years and was stratified for sex and according to type 2 diabetes or non-diabetes. The patients were followed for, either half a year or one year and changes in risk factors were calculated from follow-up to baseline, the time when patients were admitted to the health center. The pattern of relationships was evaluated using a structural equation model.
Higher S-TG and S-Glu but lower S-Urate was revealed at baseline in type 2 diabetes women and men as compared to their counterparts, non-diabetes patients. Women with type 2 diabetes had higher S-Ca and lower S-Mg than non-diabetes women. Changes in S-Glu were associated with changes in S-Ca (+), baseline S-Ca (+), and S-Urate (-) in type 2 diabetes men. Changes in S-Urate were associated with changes in S-Mg (+) in type 2 diabetes women and non-diabetes men. In men with non-diabetes, changes in S-Glu were associated with changes in S-Mg (-). In women with non-diabetes, changes in S-Glu were associated with changes in S-P (-) and changes in S-Urate with changes in S-Ca (+).
With respect to metabolic disturbances in non-diabetes and the awareness of risk for type 2 diabetes, changes in S-Glu and changes in S-Ca, S-Mg, and S-P should be considered as risk factors for cardiovascular disease. Increased early detection and corrections of high S-Ca, low S-Mg, and S-P in obese patients may improve their metabolism and reduce the risk of CVD in patients with type 2 diabetes.
Trial registration number
Glucose fluctuations including robust postprandial hyperglycemia are a risk for promoting atherosclerosis and diabetic complications. The α-glucosidase inhibitors and the dipeptidyl peptidase-4 (DPP-4) inhibitors have been found to effectively decrease postprandial hyperglycemia independently. Therefore, glycemic control with the combination of these drugs is warranted.
Continuous glucose monitoring (CGM) was performed for 3 patients with type 2 diabetes and 1 control subject from the beginning to the end of the study. Medications were not administered to any of the subjects on the first day of the study. From the second day to the end of study (days 2-5), the subjects received miglitol (150 mg per day) and on days 4 and 5, sitagliptin (50 mg per day) was added to the treatment regimen. On the first, third, and fifth days of the study, blood was drawn at 0, 30, 60, 120, 180, and 240 min after breakfast for measurements of serum insulin, 1,5-anhydroglucitol (1,5-AG), plasma glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP).
Measurements of CGM and 1,5-AG levels showed that miglitol attenuated the escalation and fluctuation of glucose levels, and this was even more pronounced with the combination of miglitol and sitagliptin. The patterns of insulin secretion and glucagon secretion with miglitol alone or with a combination of miglitol and sitagliptin were various in the study subjects. Miglitol alone enhanced the release of GLP-1 in 1 patient with type 2 diabetes and the control subject, whereas the combination of miglitol and sitagliptin increased GLP-1 levels to varying degrees in all the subjects. Except for 1 subject, none of the subjects showed any change in GIP levels after the addition of sitagliptin, compared to the administration of miglitol alone.
In conclusion, CGM measurements revealed that a combination of the α-GI miglitol and the DPP-4 inhibitor sitagliptin effectively reduced postprandial glucose fluctuation and stabilized blood glucose levels. Completely different response patterns of insulin, glucagon, GLP-1, and GIP were observed among the study subjects with either medication alone or in combination, suggesting that individual hormone-dependent glycemic responses to the α-GI and DPP-4 inhibitors are complicated and multifactorial.
miglitol; sitagliptin; glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic peptide (GIP); continuous glucose monitoring (CGM)
Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs) which play important roles in various pathophysiological processes. Interestingly, CYP-derived eicosanoids are vasodilatory, at least in part through their ability to activate eNOS and subsequent NO release. This study investigated the roles of eNOS in CYP2J3 gene delivery reducing blood pressure and improving insulin resistance in fructose-treated rats. CYP2J3 overexpression in vivo increased EET generation, reduced blood pressure and reversed insulin resistance as determined by insulin resistance index (HOMA-IR). Furthermore, administration of eNOS inhibitor L-NMMA significantly and partially abolished the beneficial effects of CYP2J3 gene delivery on hypertension and insulin resistance induced by fructose intake, and possible mechanism is associated with increased ET-1, ETA-receptor mRNA expression and reduced sensitivity of insulin to peripheral tissues and organs characterized by reduced activity of IRS-1/PI3K/AKT and AMPK signalling pathways. These data provide direct evidence that CYP2J3-derived EETs may alleviate insulin resistance at least in part through upregulated eNOS expression.
Patients with type 2 diabetes mellitus (DM) have increased risk of endothelial dysfunction and arterial stiffness. Levels of circulating endothelial progenitor cells (EPCs) are also reduced in hyperglycemic states. However, the relationships between glycemic control, levels of EPCs and arterial stiffness are unknown.
We measured circulating EPCs and brachial-ankle pulse wave velocity (baPWV) in 234 patients with type 2 DM and compared them with 121 age- and sex-matched controls.
Patients with DM had significantly lower circulating Log CD34/KDR+ and Log CD133/KDR+ EPC counts, and higher Log baPWV compared with controls (all P < 0.05). Among those 120/234 (51%) of DM patients with satisfactory glycemic control (defined by Hemoglobin A1c, HbA1c < 6.5%), they had significantly higher circulating Log CD34/KDR+ and Log CD133/KDR+ EPC counts, and lower Log baPWV compared with patients with poor glycemic control (all P < 0.05). The circulating levels of Log CD34/KDR+ EPC (r = -0.46, P < 0.001) and Log CD133/KDR+ EPC counts (r = -0.45, P < 0.001) were negatively correlated with Log baPWV. Whilst the level of HbA1c positively correlated with Log baPWV (r = 0.20, P < 0.05) and negatively correlated with circulating levels of Log CD34/KDR+ EPC (r = -0.40, P < 0.001) and Log CD133/KDR+ EPC (r = -0.41, P < 0.001). Multivariate analysis revealed that HbA1c, Log CD34/KDR+ and Log CD133/KDR+ EPC counts were independent predictors of Log baPWV (P < 0.05).
In patients with type 2 DM, the level of circulating EPCs and arterial stiffness were closely related to their glycemic control. Furthermore, DM patients with satisfactory glycemic control had higher levels of circulating EPCs and were associated with lower arterial stiffness.
Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants.
Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping.
The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender.
Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.
PPARγ2; Pro12Ala; ACE I/D; polymorphism; Metabolic Syndrome; obesity; fat distribution
In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC.
Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11C-glucose and 11C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography.
Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/μU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/μU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001).
Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin.
NIH Clinical Trials NCT00656851
insulin resistance; cardiac metabolism and function; PET-imaging
Increased IL-18 serum levels have been associated with diabetes type 2, metabolic syndrome and the severity of atherosclerosis. The present study investigated the presence and influence of IL-18 genetic variants on gene- and protein expression in stable coronary artery disease (CAD) patients.
The +183 A/G (rs 5744292), -137 G/C (rs 187238) and -607 C/A (rs 1946518) polymorphisms were determined in 1001 patients with angiographically verified stable CAD, and in 204 healthy controls. IL-18 gene-expression was measured in circulating leukocytes in 240 randomly selected patients. Circulating IL-18 and IL-18 binding protein levels were measured immunologically in all patients.
The +183 G-allele associated significantly with lower serum levels of IL-18 (p = 0.002, adjusted for age, glucose, body mass index and gender) and a 1.13- fold higher IL-18 gene-expression (p = 0.010). No influence was observed for the -137 G/C and -607 C/A polymorphisms. The IL-18 binding protein levels were not influenced by IL-18 genotypes. IL-18 levels were significantly higher in men as compared to women, and in patients with diabetes type 2 and metabolic syndrome compared to those without (p ≤ 0.001, all). The reduction in IL-18 levels according to the +183 G-allele was 3-4 fold more pronounced in diabetes and metabolic syndrome as compared to unaffected patients.
Finally, the +183 AA genotype was more frequent in patients with hypertension (p = 0.042, adjusted for age, body mass index and gender).
The reduction in serum IL-18 levels across increasing numbers of +183G-alleles was especially apparent in patient with diabetes type 2 and metabolic syndrome, suggesting a beneficial GG genotype in relation to cardiovascular outcome in these patients.
Clinical Trial Registration Number
Single nucleotide polymorphisms; IL-18 mRNA; diabetes type 2; metabolic syndrome; hypertension
To examine the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on visceral fat adiposity, appetite, food preference, and biomarkers of cardiovascular system in Japanese patients with type 2 diabetes.
The study subjects were 20 inpatients with type 2 diabetes treated with liraglutide [age; 61.2 ± 14.0 years, duration of diabetes; 16.9 ± 6.6 years, glycated hemoglobin (HbA1c); 9.1 ± 1.2%, body mass index (BMI); 28.3 ± 5.2 kg/m2, mean ± SD]. After improvement in glycemic control by insulin or oral glucose-lowering agents, patients were switched to liraglutide. We assessed the estimated visceral fat area (eVFA) by abdominal bioelectrical impedance analysis, glycemic control by the 75-g oral glucose tolerance test (OGTT) and eating behavior by the Japan Society for the Study of Obesity questionnaire.
Treatment with liraglutide (dose range: 0.3 to 0.9 mg/day) for 20.0 ± 6.4 days significantly reduced waist circumference, waist/hip ratio, eVFA. It also significantly improved the scores of eating behavior, food preference and the urge for fat intake and tended to reduce scores for sense of hunger. Liraglutide increased serum C-peptide immunoreactivity and disposition index.
Short-term treatment with liraglutide improved visceral fat adiposity, appetite, food preference and the urge for fat intake in obese Japanese patients with type 2 diabetes.
liraglutide; glucagon-like peptide-1; obesity; eating behavior
There is controversy about the specific pathophysiology of metabolic syndrome (MS) but several authors have argued that hyperinsulinemia is a key feature of the cluster. We aimed to assess whether the baseline insulin levels could predict the development of MS in a well characterised cohort of otherwise healthy adults who were followed over a five year period.
We identified 2, 350 Koreans subjects who did not have MS in 2003 and who were followed up in 2008. The subjects were divided into 4 groups according to the baseline quartiles of fasting insulin, and the predictors of the incidence of MS were analyzed using multivariate regression analysis.
Over the follow up period, 8.5% of the cohort developed MS. However, 16.4% of the subjects in the highest quartile of the insulin levels developed MS. In a model that included gender, age, the smoking status, the exercise level, alcohol consumption and the systolic blood pressure, the subjects in the highest quartile of the insulin levels had more than a 5 times greater risk of developing MS compared that of the subjects in the lowest quartile. This predictive importance remained significant even after correcting for all the individual features of MS.
These data suggest that high baseline fasting insulin levels are independent determinants for the future development of MS.
Metabolic syndrome; hyperinsulinemia; insulin Resistance
Bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with coronary heart disease are impaired with respect to number and mobilization. However, it is unknown whether the mobilization of BM-CPCs depends on the number of diseased coronary arteries. Therefore, in our study, we analysed the correlation between the diseased coronary arteries and the frequency of CD34/45+ BM-CPCs in peripheral blood (PB) in patients with ischemic heart disease (IHD).
The frequency of CD34/45+ BM-CPCs was measured by flow cytometry in 120 patients with coronary 1 vessel (IHD1, n = 40), coronary 2 vessel (IHD2, n = 40), coronary 3 vessel disease (IHD3, n = 40) and in a control group of healthy subjects (n = 40). There was no significant difference of the total number of cardiovascular risk factors between IHD groups, beside diabetes mellitus (DM), which was significantly higher in IHD3 group compared to IHD2 and IHD1 groups.
The frequency of CD34/45+ BM-CPCs was significantly reduced in patients with IHD compared to the control group (CD34/45+; p < 0.001). The frequency of BM-CPCs was impaired in patients with IHD3 compared to IHD1 (CD34/45+; p < 0.001) and to IHD2 (CD34/45+; p = 0.001). But there was no significant difference in frequency of BM-CPCs between the patients with IHD2 and IHD1 (CD34/45+; p = 0.28). In a subgroup we observed a significant negative correlation between levels of hemoglobin AIc (HbAIc) and the frequency of BM-CPCs (CD34/45+; p < 0.001, r = -0.8).
The frequency of CD34/45+ BM-CPCs in PB is impaired in patients with IHD. This impairment may augment with an increased number of diseased coronary arteries. Moreover, the frequency of CD34/45+ BM-CPCs in ischemic tissue is further impaired by diabetes in patients with IHD.
CD34/45+; ischemic heart disease; diabetes; frequency
The growing prevalence rate of pediatric obesity, which is frequently accompanied by several cardiometabolic risk factors, has become a serious global health issue. To date, little is known regarding differences for cardiometabolic risk factors (prevalence and means) in children from different countries. In the present review, we aimed to provide a review for the available evidence regarding cardiometabolic risk factors in overweight pediatric populations. We therefore provided information with respect to the prevalence of impaired fasting glucose/impaired glucose tolerance, high triglycerides, low HDL-cholesterol and hypertension (components of the metabolic syndrome) among cohorts from different countries. Moreover, we aimed to compare the means of glucose and lipid levels (triglycerides and HDL-cholesterol) and systolic/diastolic blood pressure values. After careful selection of articles describing cohorts with comparable age and sex, it was shown that both prevalence rates and mean values of cardiometabolic risk factors varied largely among cohorts of overweight children. After ranking for high/low means for each cardiometabolic risk parameter, Dutch-Turkish children and children from Turkey, Hungary, Greece, Germany and Poland were in the tertile with the most unfavorable risk factor profile overall. In contrast, cohorts from Norway, Japan, Belgium, France and the Dominican Republic were in the tertile with most favorable risk profile. These results should be taken with caution, given the heterogeneity of the relatively small, mostly clinical cohorts and the lack of information concerning the influence of the values of risk parameters on true cardiometabolic outcome measures in comparable cohorts. The results of our review present a fair estimation of the true differences between cardiometabolic risk profiles among pediatric cohorts worldwide, based on available literature.
Nicorandil, an anti-angina agent, reportedly improves outcomes even in angina patients with diabetes. However, the precise mechanism underlying the beneficial effect of nicorandil on diabetic patients has not been examined. We investigated the protective effect of nicorandil on endothelial function in diabetic rats because endothelial dysfunction is a major risk factor for cardiovascular disease in diabetes.
Male Sprague-Dawley rats (6 weeks old) were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg, once a day for 3 days) to induce diabetes. Nicorandil (15 mg/kg/day) and tempol (20 mg/kg/day, superoxide dismutase mimetic) were administered in drinking water for one week, starting 3 weeks after STZ injection. Endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anaesthetised rats. Cultured human coronary artery endothelial cells (HCAECs) were treated with high glucose (35.6 mM, 24 h) and reactive oxygen species (ROS) production with or without L-NAME (300 μM), apocynin (100 μM) or nicorandil (100 μM) was measured using fluorescent probes.
Endothelial function as evaluated by FMD was significantly reduced in diabetic as compared with normal rats (diabetes, 9.7 ± 1.4%; normal, 19.5 ± 1.7%; n = 6-7). There was a 2.4-fold increase in p47phox expression, a subunit of NADPH oxidase, and a 1.8-fold increase in total eNOS expression in diabetic rat femoral arteries. Nicorandil and tempol significantly improved FMD in diabetic rats (nicorandil, 17.7 ± 2.6%; tempol, 13.3 ± 1.4%; n = 6). Nicorandil significantly inhibited the increased expressions of p47phox and total eNOS in diabetic rat femoral arteries. Furthermore, nicorandil significantly inhibited the decreased expression of GTP cyclohydrolase I and the decreased dimer/monomer ratio of eNOS. ROS production in HCAECs was increased by high-glucose treatment, which was prevented by L-NAME and nicorandil suggesting that eNOS itself might serve as a superoxide source under high-glucose conditions and that nicorandil might prevent ROS production from eNOS.
These results suggest that nicorandil improved diabetes-induced endothelial dysfunction through antioxidative effects by inhibiting NADPH oxidase and eNOS uncoupling.
Endothelial dysfunction; Diabetes; Nicorandil; Reactive oxidative species; eNOS; NADPH oxidase
Adipokines contribute directly to the atherosclerotic process, connecting metabolic disorders such as obesity and diabetes to cardiovascular disease. Omentin-1 is a recently discovered novel adipokine, so data about the relationship of this adipokine to vascular health in type 2 diabetes is limited.
We enrolled 60 people with type 2 diabetes, with or without carotid plaque, and 30 participants with normal glucose tolerance. We measured serum omentin-1, high-sensitivity C-reactive protein (hsCRP) levels, and the homeostasis model assessment of insulin resistance (HOMA-IR), as well as other cardiovascular risk factors. Vascular health was assessed by brachial ankle pulse wave velocity (baPWV) and carotid intima-media thickness (IMT).
Serum omentin-1 levels were significantly decreased in type 2 diabetes patients compared to normal glucose controls and was further reduced in type 2 diabetes patients with carotid plaque compared to those without carotid plaque. Multiple stepwise regression analysis showed that age, systolic blood pressure, history of use of statins, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors, and serum omentin-1 level were independent factors determining baPWV in people with type 2 diabetes (r2 = 0.637). Furthermore, in multivariate logistic regression analysis, circulating omentin-1 level was an independent decisive factor for the presence of carotid plaque in type 2 diabetes patients, even after adjusting for age, gender, body mass index, systolic blood pressure, fasting blood glucose, low density lipoprotein cholesterol, and history of smoking and medication (odds ratio, 0.621; 95% confidence interval, 0.420-0.919; P = 0.017).
Circulating omentin-1 level was independently correlated with arterial stiffness and carotid plaque in type 2 diabetes, even after adjusting for other cardiovascular risk factors and detailed medication history.
omentin-1; pulse wave velocity; carotid intima media thickness; type 2 diabetes
Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV).
Systemic inflammation and glycemia influence circadian blood pressure variability.
Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP) and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP).
[mean(SEM)]: The AD fed group displayed significant increase in body weight (after 90 days; p < 0.01). Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased (at 90 and 172 days; all p < 0.05), along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR (all p < 0.05).
These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system) which generate abnormal CBPV.
caloric excess; adipose tissue dysfunction; insulin resistance; renin-aldosterone-angiotensin system; circadian blood pressure variability; adipokines; leptin; adiponectin; pro-inflammatory cytokines; MCP-1; TNF-α; early CVD risk
Soluble ST2, a member of the of the Toll/IL-1 superfamily, is a novel biomarker with exceptional predictive value in heart failure and myocardial infarction- related mortality as well as in acute dyspneic states. Soluble ST2 is considered a decoy receptor of IL 33 that blocks the protective effects of the cytokine in atherosclerosis and cardiac remodeling. In the present study we investigated the differences in the levels of soluble ST2, BNP and hs-CRP between healthy controls and patients with type 2 diabetes with and without left ventricular diastolic dysfunction. A secondary aim was to investigate correlations between sST2 and other biomarkers of type 2 diabetes, such as HbA1c.
158 volunteers were recruited and underwent a complete Doppler-echocardiographic evaluation of both systolic & diastolic cardiac function. All subjects with ejection fraction < 50% were excluded. The study population was divided in 4 groups as follows: A: 42 healthy controls, B: 18 subjects without diabetes with LVDD, C: 48 patients with type 2 diabetes without LVDD & D: 50 patients with type 2 diabetes & LVDD. ELISA technique was performed to measure sST2 levels. Statistical analysis was performed with Kruskal-Wallis & Mann-Whitney test (continuous variables), chi squared & Fischer exact test (discrete variables), Spearman coefficient (univariate analysis) and step-wise backward method (multivariate analysis).
Patients with type 2 diabetes with (p < 0.001) or without LVDD (p = 0.007) had higher serum ST2 levels compared to healthy controls, state found also for hs-CRP levels but not for the corresponding BNP levels (p = 0.213 & p = 0.207 respectively). Patients with type 2 diabetes & LVDD had higher serum ST2 in relation to diabetic patients without LVDD (p = 0.001). In multivariate analysis HbA1c positively and independently correlated with sST2 levels in both groups of patients with type 2 diabetes.
Patients with type 2 diabetes exhibit higher sST2 levels compared to healthy controls. The presence of LVDD in patients with type 2 diabetes is associated with even higher sST2 levels. A significant correlation between glycemic control and sST2 levels was also revealed.
Soluble ST2; BNP; hs-CRP; type 2 diabetes; diastolic dysfunction
Insulin resistance is accompanied by a cluster of metabolic changes, often referred to as metabolic syndrome. Metabolic syndrome is associated with an increased cardiovascular risk in patients with manifest arterial disease. We investigated whether insulin resistance is associated with an increased risk for cardiovascular events in patients with manifest arterial disease without known diabetes and whether this can be explained by the components of the metabolic syndrome or by inflammation.
Prospective cohort study in 2611 patients with manifest arterial disease without known diabetes. Homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. The relation of HOMA-IR with cardiovascular events (vascular death, myocardial infarction or stroke) and all cause mortality was assessed with Cox regression analysis. In additional models adjustments were performed for the single components constituting the metabolic syndrome and for inflammation.
HOMA-IR increases with the number of metabolic syndrome components (mean HOMA-IR ± SD in groups with 0, 1, 2, 3, 4 and 5 metabolic syndrome components: 1.4 ± 0.7; 1.8 ± 1.2; 2.4 ± 1.5; 3.1 ± 1.8; 4.0 ± 2.6; and 5.6 ± 3.6 respectively). High HOMA-IR was independently associated with an increased risk of cardiovascular events (tertile 2 vs. 1 HR 1.92; 95%CI 1.20-3.08) (tertile 3 vs.1 HR 1.78; 95%CI 1.10-2.89) and with all cause mortality (tertile 2 vs. 1 HR 1.80; 95%CI 1.04-3.10) (tertile 3 vs.1 HR 1.56; 95%CI 0.88-2.75). These relations were not influenced by the individual components of metabolic syndrome or by inflammation.
In patients with manifest arterial disease without known diabetes, insulin resistance increases with the number of metabolic syndrome components, and elevated insulin resistance increases the risk of new cardiovascular events.
Insulin resistance; Manifest arterial disease; Metabolic syndrome
Patients with the metabolic syndrome are more likely to develop type 2 diabetes and may have an increased risk of cardiovascular disease (CVD) events.We aimed to establish whether CVD event rates were influenced by the metabolic syndrome as defined by the World Health Organisation (WHO), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF) and to determine which component(s) of the metabolic syndrome (MS) conferred the highest cardiovascular risk in in 4900 patients with type 2 diabetes allocated to placebo in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.
Research design and methods
We determined the influence of MS variables, as defined by NCEP ATPIII, IDF and WHO, on CVD risk over 5 years, after adjustment for CVD, sex, HbA1c, creatinine, and age, and interactions between the MS variables in a Cox proportional-hazards model.
About 80% had hypertension, and about half had other features of the metabolic syndrome (IDF, ATPIII). There was no difference in the prevalence of metabolic syndrome variables between those with and without CVD at study entry. The WHO definition identified those at higher CVD risk across both sexes, all ages, and in those without prior CVD, while the ATPIII definition predicted risk only in those aged over 65 years and in men but not in women. Patients meeting the IDF definition did not have higher risk than those without IDF MS.
CVD risk was strongly influenced by prior CVD, sex, age (particularly in women), baseline HbA1c, renal dysfunction, hypertension, and dyslipidemia (low HDL-c, triglycerides > 1.7 mmol/L). The combination of low HDL-c and marked hypertriglyceridemia (> 2.3 mmol/L) increased CVD risk by 41%. Baseline systolic blood pressure increased risk by 16% per 10 mmHg in those with no prior CVD, but had no effect in those with CVD. In those without prior CVD, increasing numbers of metabolic syndrome variables (excluding waist) escalated risk.
Absence of the metabolic syndrome (by the WHO definition) identifies diabetes patients without prior CVD, who have a lower risk of future CVD events. Hypertension and dyslipidemia increase risk.
Coronary artery disease has been linked with genotypes for haptoglobin (Hp) which modulates extracorpuscular hemoglobin. We hypothesized that the Hp genotype would predict progression of coronary artery calcification (CAC), a marker of subclinical atherosclerosis.
CAC was measured three times in six years among 436 subjects with type 1 diabetes and 526 control subjects participating in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Hp typing was performed on plasma samples by polyacrylamide gel electrophoresis.
The Hp 2-2 genotype predicted development of significant CAC only in subjects with diabetes who were free of CAC at baseline (OR: 1.95, 95% CI: 1.07-3.56, p = 0.03), compared to those without the Hp 2-2 genotype, controlling for age, sex, blood pressure and HDL-cholesterol. Hp 2 appeared to have an allele-dose effect on development of CAC. Hp genotype did not predict CAC progression in individuals without diabetes.
Hp genotype may aid prediction of accelerated coronary atherosclerosis in subjects with type 1 diabetes.
Cardiovascular disease; type 1 diabetes mellitus; coronary artery calcium; hyperglycemia; genetics; Haptoglobin
The prognostic value of hemoglobin A1c (HbA1c) in coronary artery disease (CAD) remains controversial. Herein, we conducted a systematic review to quantify the association between elevated HbA1c levels and all-cause mortality among patients hospitalized with CAD.
A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to May 2011 was performed. Cohort, case-control studies, and randomized controlled trials that examined the effect of HbA1c on all-cause mortality were included.
Twenty studies met final inclusion criteria (total n = 13, 224). From the pooled analyses, elevated HbA1c level was significantly associated with increased short-term (OR 2.32, 95% CI, 1.61 to 3.35) and long-term (OR 1.54, 95% CI, 1.23 to 1.94) mortality risk. Subgroup analyses suggested elevated HbA1c level predicted higher mortality risk in patients without diabetes (OR 1.84, 95% CI, 1.51 to 2.24). In contrast, in patients with diabetes, elevated HbA1c level was not associated with increased risk of mortality (OR 0.95, 95% CI, 0.70 to 1.28). In a risk-adjusted sensitivity analyses, elevated HbA1c was also associated with a significantly high risk of adjusted mortality in patients without diabetes (adjusted OR 1.49, 95% CI, 1.24 to 1.79), but had a borderline effect in patients with diabetes (adjusted OR 1.05, 95% CI, 1.00 to 1.11).
Our findings demonstrate that elevated HbA1c level is an independent risk factor for mortality in CAD patients without diabetes, but not in patients with established diabetes. Prospective studies should further investigate whether glycemic control might improve outcomes in CAD patients without previously diagnosed diabetes.
hemoglobin A1c; mortality; coronary artery disease; acute coronary syndrome
Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition.
This study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence.
Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment.
Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.
Azelnidipine; Apoptosis; Ca2+ homeostasis; diabetic cardiomyopathy; mitochondria; oxidative stress
Both genetic and environmental factors play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. The magnitude of genetic and environmental influences may vary in different populations and can be investigated by twin studies.
In this cross-sectional study, 101 (63 monozygotic and 38 dizygotic) adult twin pairs (n = 202; mean age: 44.3 ± 15.8 years) were investigated. Past medical history was recorded and physical examination was performed. Fasting venous blood samples were taken for measuring laboratory parameters. For assessing heritability of 14 cardiovascular risk factors, the structural equation (A-C-E) model was used.
The following risk factors were highly (> 70.0%) or moderately (50.0 - 69.0%) heritable: weight (88.1%), waist circumference (71.0%), systolic blood pressure (57.1%), diastolic blood pressure (57.7%), serum creatinine (64.1%), fibrinogen (59.9%), and serum C-reactive protein (51.9%). On the other hand, shared and unique environmental influences had the highest proportion of total phenotypic variance in serum total cholesterol (46.8% and 53.2%), serum HDL-cholesterol (58.1% and 14.9%), triglycerides (0.0% and 55.9%), fasting blood glucose (57.1% and 42.9%), fasting insulin (45.4% and 54.5%), serum uric acid (46.0% and 31.3%), and serum homocysteine (71.8% and 28.2%, respectively).
Some cardiometabolic risk factors have strong heritability while others are substantially influenced by environmental factors. Understanding the special heritability characteristics of a particular risk factor can substantiate further investigations, especially in molecular genetics. Moreover, identifying genetic and environmental contribution to certain cardiometabolic risk factors can help in designing prevention and treatment strategies in the population investigated.
cardiometabolic risk; diabetes mellitus; cardiovascular diseases; twin study; heritability; cardiovascular prevention
Diabetes mellitus and renal dysfunction are prognostic factors after acute myocardial infarction (AMI). However, few studies have assessed the effects of renal insufficiency in association with diabetes in the context of AMI. Here, we investigated the clinical outcomes according to the concomitance of renal dysfunction and diabetes mellitus in patients with AMI.
From November 2005 to August 2008, 9905 patients (63 ± 13 years; 70% men) with AMI were enrolled in a nationwide prospective Korea Acute Myocardial Infarction Registry (KAMIR) and were categorized into 4 groups: Group I (n = 5700) had neither diabetes nor renal insufficiency (glomerular filtration rate [GFR] ≥ 60 ml/min/1.73 m2), Group II (n = 1730) had diabetes but no renal insufficiency, Group III (n = 1431) had no diabetes but renal insufficiency, and Group IV (n = 1044) had both diabetes and renal insufficiency. The primary endpoints were major adverse cardiac events (MACE), including a composite of all cause-of-death, myocardial infarction, target lesion revascularization, and coronary artery bypass graft after 1-year clinical follow-up.
Primary endpoints occurred in 1804 (18.2%) patients. There were significant differences in composite MACE among the 4 groups (Group I, 12.5%; Group II, 15.7%; Group III, 30.5%; Group IV, 36.5%; p < 0.001). In a Cox proportional hazards model, after adjusting for multiple covariates, the 1-year mortality increased stepwise from Group III to IV as compared with Group I (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.34-2.86; p = 0.001; and HR, 2.42; 95% CI, 1.62-3.62; p < 0.001, respectively). However, Kaplan-Meier analysis showed no significant difference in probability of death at 1 year between Group III and IV (p = 0.288).
Renal insufficiency, especially in association with diabetes, is associated with the occurrence of composite MACE and indicates poor prognosis in patients with AMI. Categorization of patients with diabetes and/or renal insufficiency provides valuable information for early-risk stratification of AMI patients.
acute myocardial infarction; diabetes mellitus; major adverse cardiac events; renal insufficiency
Aldosterone levels are elevated in a rat model of type 2 diabetes mellitus, the Zucker Diabetic fatty rat (ZDF). Moreover blood pressure in ZDF rats is salt-sensitive. The aim of this study was to examine the effect of the aldosterone antagonist eplerenone on structural and mechanical properties of resistance arteries of ZDF-rats on normal and high-salt diet.
After the development of diabetes, ZDF animals were fed either a normal salt diet (0.28%) or a high-salt diet (5.5%) starting at an age of 15 weeks. ZDF rats on high-salt diet were randomly assigned to eplerenone (100 mg/kg per day, in food) (ZDF+S+E), hydralazine (25 mg/kg per day) (ZDF+S+H), or no treatment (ZDF+S). Rats on normal salt-diet were assigned to eplerenone (ZDF+E) or no treatment (ZDF). Normoglycemic Zucker lean rats were also divided into two groups receiving normal (ZL) or high-salt diet (ZL+S) serving as controls. Systolic blood pressure was measured by tail cuff method. The experiment was terminated at an age of 25 weeks. Mesenteric resistance arteries were studied on a pressurized myograph. Specifically, vascular hypertrophy (media-to-lumen ratio) and vascular stiffness (strain and stress) were analyzed. After pressurized fixation histological analysis of collagen and elastin content was performed.
Blood pressure was significantly higher in salt-loaded ZDF compared to ZDF. Eplerenone and hydralazine prevented this rise similarily, however, significance niveau was missed. Media-to-lumen ratio of mesenteric resistance arteries was significantly increased in ZDF+S when compared to ZDF and ZL. Both, eplerenone and hydralazine prevented salt-induced vascular hypertrophy. The strain curve of arteries of salt-loaded ZDF rats was significantly lower when compared to ZL and when compared to ZDF+S+E, but was not different compared to ZDF+S+H. Eplerenone, but not hydralazine shifted the strain-stress curve to the right indicating a vascular wall composition with less resistant components. This indicates increased vascular stiffness in salt-loaded ZDF rats, which could be prevented by eplerenone but not by hydralazine. Collagen content was increased in ZL and ZDF rats on high-salt diet. Eplerenone and hydralazine prevented the increase of collagen content. There was no difference in elastin content.
Eplerenone and hydralazine prevented increased media-to-lumen ratio in salt-loaded ZDF-rats, indicating a regression of vascular hypertrophy, which is likely mediated by the blood pressure lowering-effect. Eplerenone has additionally the potential to prevent increased vascular stiffness in salt-loaded ZDF-rats. This suggests an effect of the specific aldosterone antagonist on adverse vascular wall remodelling.