IL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM.
In the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants.
Myocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration.
Elevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.
Diabetic cardiomyopathy; Endoplasmic reticulum stress; Apoptosis; IL-1; IRAK-2
Whether lowering glycosylated haemoglobin (HbA1c) level below 7.0 % improves macro-vascular outcomes in diabetes remains unclear. Here, we aimed to assess the effect of relatively tight glucose control resulting in a follow-up HbA1c level of less or more than 7.0 % on cardiovascular outcomes in diabetic patients.
Research design and methods
We systematically searched Medline, Web of science and Cochrane Library for prospective randomized controlled trials published between Jan 1, 1996 and July 1, 2015 that recorded cardiovascular outcome trials of glucose-lowering drugs or strategies in patients with type 2 diabetes mellitus.
Data from 15 studies involving 88,266 diabetic patients with 4142 events of non-fatal myocardial infarction, 6997 of major cardiovascular events, 3517 of heart failure, 6849 of all-cause mortality, 2084 of non-fatal stroke, 3816 of cardiovascular death were included. A 7 % reduction of major cardiovascular events was observed only when relatively tight glucose control resulted in a follow-up HbA1c level above 7.0 % (OR 0.93, 95 % CI 0.88–0.98; I2 = 33 %), however, the patients can benefit from reduction incidence of non-fatal myocardial infarction only when the follow-up HbA1c value below 7.0 % (OR 0.85, 95 % CI 0.74–0.96). Apart from the HbA1c value above 7.0 % (OR 1.22, 95 % CI 1.06–1.40), the application of thiazolidinediones (OR 1.39, 95 % CI 1.14–1.69) also increased the risk of heart failure, while the gliptins shows neutral effects to heart failure (OR 1.14, 95 % CI 0.97–1.34).
Relatively tight glucose control has some cardiovascular benefits. HbA1c below 7.0 % as the goal to maximize the cardiovascular benefits remains suspended.
Glucose control; Cardiovascular outcomes; HbA1c; Diabetes mellitus
Whole body cardiovascular MR (WB CVMR) combines whole body angiography and cardiac MR assessment. It is accepted that there is a high disease burden in patients with diabetes, however the quantification of the whole body atheroma burden in both arterial and cardiac disease has not been previously reported. In this study we compare the quantified atheroma burden in those individuals with and without diabetes by clinical cardiovascular disease (CVD) status.
158 participants underwent WB CVMR, and were categorised into one of four groups: (1) type 2 diabetes mellitus (T2DM) with CVD; (2) T2DM without CVD; (3) CVD without T2DM; (4) healthy controls. The arterial tree was subdivided into 31 segments and each scored according to the degree of stenosis. From this a standardised atheroma score (SAS) was calculated. Cardiac MR and late gadolinium enhancement images of the left ventricle were obtained for assessment of mass, volume and myocardial scar assessment.
148 participants completed the study protocol—61 % male, with mean age of 64 ± 8.2 years. SAS was highest in those with cardiovascular disease without diabetes [10.1 (0–39.5)], followed by those with T2DM and CVD [4 (0–41.1)], then those with T2DM only [3.23 (0–19.4)] with healthy controls having the lowest atheroma score [2.4 (0–19.4)]. Both groups with a prior history of CVD had a higher SAS and left ventricular mass than those without (p < 0.001 for both). However after accounting for known cardiovascular risk factors, only the SAS in the group with CVD without T2DM remained significantly elevated. 6 % of the T2DM group had evidence of silent myocardial infarct, with this subcohort having a higher SAS than the remainder of the T2DM group [7.7 (4–19) vs. 2.8 (0–17), p = 0.024].
Global atheroma burden was significantly higher in those with known cardiovascular disease and without diabetes but not in those with diabetes and cardiovascular disease suggesting that cardiovascular events may occur at a lower atheroma burden in diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0284-2) contains supplementary material, which is available to authorized users.
Whole body MRI; Magnetic resonance angiography; CMR; LVA; WB CVMR; Cardiovascular disease; Atherosclerosis; Atheroma score; Type 2 diabetes mellitus; T2DM
Type 2 diabetes mellitus (T2DM) complicated by retinopathy is associated with altered left ventricular (LV) structure and resting myocardial dysfunction unlike T2DM without retinopathy. The myocardial response to stress has not been compared in patients with and without diabetic retinopathy. The aim of this retrospective study was to determine the relationship between retinopathy and myocardial function in patients with T2DM at rest and during exercise echocardiography.
134 patients with T2DM and no evidence of underlying coronary artery disease were recruited. All patients underwent retinal photography to screen for diabetic retinopathy, and resting and exercise echocardiography. Resting echocardiography was analyzed by conventional echocardiographic parameters and speckle tracking derived global longitudinal strain (GLS). Exercise echocardiography parameters included diastolic function reserve index (DFRI) and stress GLS.
The mean age of participants was 60 years and 49 % were male. Diabetic retinopathy was identified in 43 patients (32 %). Resting echocardiography revealed that those with diabetic retinopathy had a higher prevalence of impaired diastolic function, higher E/E′ ratio (LV filling pressures) and impaired resting GLS compared with those without. Exercise echocardiography revealed that those with diabetic retinopathy also had more impaired DFRI and stress GLS. Multivariable analysis showed that the presence of diabetic retinopathy was independently associated with high resting E/E′, diastolic dysfunction grade, impaired resting GLS, low DFRI and impaired stress GLS.
In conclusion, the presence of diabetic retinopathy was independently associated with impaired resting myocardial function (diastolic and systolic function) and myocardial function during stress (evaluated by DFRI and stress GLS).
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0281-5) contains supplementary material, which is available to authorized users.
Diabetic cardiomyopathy; Cardiac dysfunction; Exercise echocardiography; Diabetic retinopathy; Cardiac function reserve
The glycoprotein YKL-40 is a new marker of early inflammation and endothelial dysfunction. Adiponectin is a collagen-like protein with anti-atherogenic and anti-inflammatory effects. Increased concentrations of both markers have been reported in patients with type 1 diabetes (T1D).
To assess the possible role of YKL-40 and adiponectin as a marker of subclinical cardiovascular disease in asymptomatic patients with type 1 diabetes with no history of ischemic or macrovascular heart disease and its relationship with other classic inflammatory biomarkers.
Concentrations of YKL-40, adiponectin, IL-6, IL-1β, TNF- α, hsCRP and homocysteine were determined in 150 T1D patients (58 % men, age: 38.6 ± 8.1 years, 20.4 ± 8.1 years of evolution, BMI: 25.1 ± 3.6 kg/m2; HbA1c 8.1 ± 2.3 %, 48 % smokers; 26 % retinopathy, microalbuminuria 9 %) and 50 controls age, sex and smoke condition matched. Subclinical atherosclerosis was assessed by a carotid ultrasonography and a computed tomography for evaluation of calcium artery calcification score (CACS).
82 % of T1D patients and 92 % of controls had a calcium score of 0. T1D patients showed a significantly higher mean common carotid artery intima media thickness (CIMT) compared to controls (0.55 ± 0.14 vs 0.48 ± 0.14 mm, p = 0.01). Concentrations of YKL-40 and adiponectin were significantly higher in T1D [42.6 (10.4–195.0) vs ±28.7 (11.0–51.2) ng/ml, p = 0.001 and 15.8 ± 9.1 vs. 12.4 ± 5.3 mg/ml, p = 0.008], with no differences when compared to other inflammatory parameters. In T1D patients no association was found between YKL-40 and adiponectin and screening test for subclinical arterial disease (neither CACS nor CIMT). A positive correlation was found between levels of YKL-40 and age and duration of disease (r = 0.28, p = 0.003; r = 0.35, p = 0.001). There were no differences in the YKL-40 in relation to the presence or absence of retinopathy or nephropathy. Levels of adiponectin were higher in patients with nephropathy (21.84 ± 8.15 vs. 14.88 ± 8.27 mg/ml, p = 0.008).
Type 1 diabetes patients from a Mediterranean area with a longer disease evolution, although a lower degree of subclinical disease, showed significatively higher concentrations of YKL-40 and adiponectin compared with the controls. Therefore, we conclude that YKL-40 and adiponectin are early inflammatory markers in diabetic subjects even in the presence of a low atherosclerotic background.
YKL-40; Adiponectin; Subclinical atherosclerosis; Type 1 diabetes
Diabetes and impaired glucose tolerance (IGT) are major risk factors for atherosclerosis including coronary artery disease (CAD). The present study’s aim was to investigate the importance of glucose tolerance for long-term clinical outcome in patients with acute coronary syndrome (ACS).
A total 1062 consecutive patients, 781 men and 281 women, aged 32–80 years, admitted to the coronary care unit at Danderyd University Hospital, Stockholm, for ACS from 2006 to 2008 were included. At discharge, the patients were categorized according to an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT), n = 295 (28 %); impaired fasting glucose (IFG) and IGT, n = 299 (28 %); diabetes discovered by OGTT, n = 156 (15 %); or known diabetes at admission, n = 312 (29 %). Mortality and reinfarction rates were studied during a mean follow-up time of 4.0 (±0.8) years. Clinical outcome data were obtained from the Swedish Coronary Angiography and Angioplasty Registry and the Swedish National Registry.
There was significantly higher (p < 0.001) mortality within, 30 days, 1 and 3 years in patients with known diabetes as compared to the other groups. During the follow-up, 86 patients (28 %) with known diabetes had reinfarction as compared to 36 patients (12 %) with NGT and 79 patients (17 %) with dysglycaemia (IFG, IGT and diabetes) discovered by OGTT.
A majority (72 % in this study) of patients admitted for ACS have disturbed glucose metabolism, including diabetes, with high prevalence of previously undiagnosed dysglycaemia. Both patients with known diabetes and dysglycaemia discovered by OGTT show a high risk for poor clinical prognosis.
Cardiovascular disease; Diabetes mellitus; Impaired glucose tolerance; Prognosis
Left ventricular (LV) diastolic dysfunction (LVDD) is a well-established and early echocardiographic characteristic of diabetic cardiomyopathy. However, there are limited data on the association between impaired fasting glucose (IFG) and LVDD.
To determine whether IFG is associated with LVDD among middle age adults.
Amongst 3781 subjects screened in an annual health survey program and referred for an echocardiogram, 2971 individuals without LV systolic dysfunction or valvular heart disease were selected. Mean age of study population was 59 ± 12 years and 75 % were men. The subjects were categorized into three groups: euglycemia (N = 2025), IFG (N = 534) and diabetes mellitus (DM; N = 412). Doppler echocardiography readers were blinded to glycemic state. Subjects with impaired LV relaxation, pseudo-normal or restrictive filling patterns were defined as having LVDD.
LVDD was diagnosed in 574 (19 %) of subjects and it was more prevalent among patients with IFG and DM than in euglycemic individuals (27, 30 and 15 %, respectively; p < 0.001). Patients with IFG and DM had lower ratios of early (E) to late (A) trans-mitral flow (0.9 ± 0.3 and 0.9 ± 0.3 vs. 1.1 ± 0.4, respectively, p < 0.001). LV hypertrophy (LVH) was also more prevalent among patients with IFG and DM (11 and 18 %, respectively, vs. 9 %; p < 0.001). Multivariate binary logistic regression model adjusted to age, gender, obesity, LVH, renal function, total, high and low density lipoprotein cholesterol, triglycerides, ischemic heart disease, hypertension and LV ejection fraction showed that patients with IFG were 43 % more likely to have LVDD compared with euglycemic subjects (95 % confidence interval 1.12–1.83, p = 0.004).
IFG is independently associated with a significant increase in the likelihood for the presence of LVDD in middle aged adults.
Diastolic dysfunction; Diabetes mellitus; Impaired fasting glucose
The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study.
Research design and methods
Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated.
Over 36 months, twice-daily exenatide was associated with improved body weight (−3.9 kg), waist circumference (−3.6 cm), systolic/diastolic BP (−2.5/−2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (−0.2 mmol/L), and hsCRP (−1.7 mg/L). Heart rate did not increase (−0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4 %; P = 0.026) or lipid-lowering medication (8.4 vs 12.8 %; P = 0.025).
Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride.
Clinical trial registration: NCT00359762, http://www.ClinicalTrials.gov
Type 2 diabetes; GLP-1 receptor agonist; Exenatide twice daily; Cardiovascular risk; High-sensitivity C-reactive protein
It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes.
This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors.
In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = −0.243; SDANN5: r = −0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = −0.243; SDANN5: r = −0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (β = −0.279 and −0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters.
Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.
Leptin; Heart rate variability; Cardiac autonomic dysfunction; Type 2 diabetes; Visceral fat accumulation
Data regarding the prevalence of hypertriglyceridemia in the Russian population are lacking, despite triglyceride (TG)-mediated pathways being causal in cardiovascular disease. The prevalence of mixed dyslipidemia and severe hypertriglyceridemia in the Russian population (PROMETHEUS) was undertaken to address this gap.
This was an observational, cross-sectional retrospective study. Data from adults with a full/partial lipoprotein record who had blood analyses done at an INVITRO laboratory in Russia between January 1, 2011 and December 31, 2013 were analyzed. The primary endpoint was the prevalence of hypertriglyceridemia (TG ≥ 1.7 mmol/L); secondary endpoints included prevalence of borderline high, high, and very high TG and severe hypertriglyceridemia, defined as a TG level of 1.7 to <2.3, 2.3 to <5.6, ≥5.6, and ≥10.0 mmol/L, respectively. Statistical analyses involved the Wilcoxon and the Chi square tests. Correlations between log-transformed TG and low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) and total cholesterol (TC) were assessed. The correlation between glycated hemoglobin (HbA1c) and TG levels in a nested sample of subjects with HbA1c and TG data was also assessed using a log-linear model.
The full dataset and nested sample comprised 357,072 and 54,602 individuals, respectively. Prevalence of hypertriglyceridemia, borderline high TG, high TG, very high TG, and severe hypertriglyceridemia in the full dataset was 29.2, 16.2, 12.9, 0.11, and 0.011 %, respectively; corresponding rates in the nested sample were 19.0, 17.2, 0.25, and 0.016 %, respectively. TG levels were 16.4 % higher in males versus females; males had a greater risk of hypertriglyceridemia (risk ratio 1.25; 95 % CI 1.24, 1.26; P < 0.0001). Prevalence of hypertriglyceridemia increased with age, peaking at 40–49 years in males (42.8 %) and 60–69 years in females (34.4 %); a 0.61 % increase in TG levels for each year of life was predicted. Hypertriglyceridemia prevalence increased over time. Correlations between TG and LDL-C, HDL-C, TC, and HbA1c (nested sample only) were observed.
Almost one-third of Russians have hypertriglyceridemia, but severe disease (TG ≥ 10.0 mmol/L) is rare. Although the risk of hypertriglyceridemia was greater in males versus females, its prevalence increased with age, regardless of sex. TG was associated with HbA1c, LDL-C, HDL-C, and TC.
Hypertriglyceridemia; Prevalence; Russia; Triglycerides; Glycated hemoglobin
Hyperglycemia is the hallmark of diabetes and its cardiovascular complications. Insulin plays an important role in the regulation of vascular homeostasis and maintenance of endothelial function. Insulin signaling occurs after binding to the insulin receptor, causing activation of two separate and parallel pathways: PI3K/AKT/eNOS and Ras/Raf/MAPK pathways. AKT phosphorylates eNOS at Ser1177, resulting in increased nitric oxide production and vasodilation. The MAPK pathway results in endothelin-1 production and vasoconstriction and mitogenic effects.
We studied the effects of physiological insulin treatment in human umbilical vein endothelial cells (HUVECs) on the two pathways under high glucose conditions, which mimic the in vivo condition of hyperglycemia. HUVECs were incubated with insulin at different physiological concentrations (from 10−10 to 10−8 M) for 30 min after 24 h of exposition to normal (5 mmol/L, NG) or high glucose (25 mmol/L, HG). Phosphorylated forms of AKT, eNOS, ERK1/2, p38, JNK and insulin receptor-β subunit (IRβ) were evaluated.
In normal glucose, the active phosphorylated forms of AKT, eNOS, ERK1/2, p38 and JNK were increased in insulin treated cells, in a dose-dependent manner. In high glucose, insulin was not able to activate the PI3K/AKT/eNOS pathway, with the phosphorylated form of eNOS reduced with respect to the control. However, insulin was able to induce the up-regulation of phospho-ERK1/2, -p38 and -JNK. Moreover, we found reduced levels of IRβ phosphorylated form in high glucose as compared to the control. Insulin was able to increase phospho-IRβ in normal glucose but not in high glucose, in which the total protein levels remained reduced.
Exposure to short-term high glucose negatively affects insulin signaling even when physiological insulin concentrations are added. The impairment of the PI3K/AKT/eNOS pathway after physiological insulin treatment could contribute to detrimental effects on cardiovascular homeostasis under high glucose conditions, and might shift toward the activation of certain mitogenic effectors, such as ERK1/2, p38 and JNK, the only ones that respond to physiological insulin treatment in high glucose.
Physiological insulin; High glucose; eNOS; Endothelium; HUVECs
The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program.
Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m2, underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry.
Weight loss averaged −8.3 ± 0.6 % of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9 %, P = 0.04) and exogenous insulin clearance (by 12 ± 5 %, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by −12 ± 5 %, whole-body norepinephrine spillover rate by −14 ± 8 %, and MSNA by −9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = −0.63, P = 0.01) which explained 40 % of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64 % of the variance.
Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention.
Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850
Insulin clearance; Weight loss; Vascular resistance; Obesity; Norepinephrine kinetics
Blood glucose variability is receiving considerable attention as a new risk factor for coronary artery disease. This study aimed to investigate the association between blood glucose variability and coronary plaque tissue characteristics.
In 57 patients with acute coronary syndrome, integrated backscatter intravascular ultrasound (IB-IVUS) and gray-scale IVUS were performed before balloon dilatation or stent implantation in the culprit vessels. Standard IVUS indices were evaluated for volume index (volume/length), and plaque components were measured by IB-IVUS for percent tissue volume. In addition to conventional glucose indicators, blood glucose variability in a stable state was determined by calculating the mean amplitude of glycemic excursions (MAGE) using a continuous glucose monitoring system.
Higher MAGE values were significantly correlated with larger percent plaque volumes (r = 0.32, p = 0.015), and increased lipid (r = 0.44, p = 0.0006) and decreased fibrous (r = −0.45, p = 0.0005) plaque components. In contrast, HbA1c or fasting plasma glucose values were not significantly correlated with plaque volumes and percent plaque components. Homeostasis model assessment of insulin resistance values were positively correlated with vessel (r = 0.35, p = 0.007) and plaque (r = 0.27, p = 0.046) volumes, but not with percent plaque components. In multiple regression analysis, higher MAGE values were independently associated with increased lipid (β = 0.80, p = 0.0035) and decreased fibrous (β = -0.79, p = 0.0034) contents in coronary plaques.
Among all glucose indicators studied, only higher blood glucose variability was an independent determinant of increased lipid and decreased fibrous contents with larger plaque burden, suggesting blood glucose variability as one of the important factors related to coronary plaque vulnerability.
Glucose variability; Vulnerable plaque; Acute coronary syndrome; IB-IVUS
Betatrophin has been suggested as an inducer of β-cell proliferation in mice in addition to its function in regulating triglyceride. Recent data showed that betatrophin was increased in Type 2 Diabetes (T2D), however, its ability to induce insulin production has been questioned. We hypothesized that the increased betatrophin in T2D is not affecting insulin production from β-cells. To test this hypothesis, we investigated the association between betatrophin and C-peptide level in humans, which acts as a measure of endogenous insulin production from β-cells.
This study was designed to examine the association between plasma betatrophin level and C-peptide in 749 T2D and non-diabetics.
Betatrophin and C-peptide levels were higher in T2D subjects compared with non-diabetics subjects. Betatrophin showed strong correlation with C-peptide in non-diabetics subjects (r = 0.28, p = < 0.0001). No association between betatrophin and C-peptide were observed in T2D subjects (r = 0.07, p = 0.3366). Dividing obese and non-obese subjects into tertiles according to betatrophin level showed significantly higher C-peptide levels at higher tertiles of betatrophin in obese non-diabetics subjects P-trend = 0.0046. On the other hand, C-peptide level was significantly higher in subject with higher betatrophin level in non-diabetics subjects across all age groups but not in T2D subjects. Multiple logistic regression models adjusted for age, BMI, gender, ethnicity as well as C-peptide level showed that subjects in the highest tertiles of betatrophin had higher odds of having T2D [odd ratio (OR) = 7.3, 95 % confidence interval (CI) 4.0–13.3].
Increased betatrophin level in obese subjects is correlated with an increase in C-peptide level; which is possibly caused by the increased insulin resistance. On the other hand, no correlation is observed between increased betatrophin level and C-peptide in T2D subjects. In conclusion, the increased betatrophin in T2D subject does not cause any increase in insulin production as indicated by C-peptide level.
The Global Registry of Acute Coronary Events (GRACE) risk score is widely recommended for risk assessment in patients with acute coronary syndrome (ACS). Chronic hyperglycemia [hemoglobinA1c (HbA1c)] can independently predict major adverse cardiac events (MACEs) in patients with ACS. We investigated whether the prediction of MACEs with the GRACE score could be improved with the addition of HbA1c content in ACS patients without diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI).
We enrolled 549 ACS patients without DM who underwent PCI. The GRACE score and HbA1c content were determined on admission. Correlation was analyzed by Spearman’s rank correlation. Cumulative MACE curve was calculated using the Kaplan–Meier method. Multivariate Cox regression was used to identify predictors of MACEs. Additionally, the predictive value of HbA1c content alone and combined with GRACE score was estimated by the area under the receiver-operating characteristic curve (AUC), continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI).
During a median of 42.3 months (interquartile range 39.3–44.2 months), 16 (2.9 %) were lost to follow-up, and patients experienced 69 (12.9 %) MACEs: 51 (9.6 %) all-cause deaths and 18 (3.4 %) nonfatal myocardial infarction cases. The GRACE score was positively associated with HbA1c content. Multivariate Cox analysis showed that both GRACE score and HbA1c content were independent predictors of MACEs (hazard ratio 1.030; 95 % CI 1.020–1.040; p < 0.001; 3.530; 95 % CI 1.927–6.466; p < 0.001, respectively). Furthermore, Kaplan–Meier analysis demonstrated increased risk of MACEs with increasing HbA1c content (log-rank 33.906, p < 0.001). Adjustment of the GRACE risk estimate by HbA1c improved the predictive value of the GRACE score [increase in AUC from 0.75 for the GRACE score to 0.80 for the GRACE score plus HbA1c, p = 0.012; IDI = 0.055, p < 0.001; NRI (>0) = 0.70, p < 0.001].
HbA1c content is positively associated with GRACE risk score and their combination further improved the risk stratification for ACS patients without DM undergoing PCI.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0274-4) contains supplementary material, which is available to authorized users.
We previously showed that unesterified-cholesterol transfer to high-density lipoprotein (HDL), a crucial step in cholesterol esterification and role in reverse cholesterol transport, was diminished in non-diabetic patients with coronary artery disease (CAD). The aim was to investigate whether, in patients with type 2 diabetes mellitus (T2DM), the occurrence of CAD was also associated with alterations in lipid transfers and other parameters of plasma lipid metabolism.
Seventy-nine T2DM with CAD and 76 T2DM without CAD, confirmed by cineangiography, paired for sex, age (40–80 years), BMI and without statin use, were studied. In vitro transfer of four lipids to HDL was performed by incubating plasma of each patient with a donor emulsion containing radioactive lipids during 1 h at 37 °C. Lipids transferred to HDL were measured after chemical precipitation of non-HDL fractions and the emulsion. Results are expressed as % of total radioactivity of each lipid in HDL.
In T2DM + CAD, LDL-cholesterol and apo B were higher than in T2DM. T2DM + CAD also showed diminished transfer to HDL of unesterified cholesterol (T2DM + CAD = 7.6 ± 1.2; T2DM = 8.2 ± 1.5 %, p < 0.01) and of cholesteryl-esters (4.0 ± 0.6 vs 4.3 ± 0.7, p < 0.01). Unesterified cholesterol in the non-HDL serum fraction was higher in T2DM + CAD (0.93 ± 0.20 vs 0.85 ± 0.15, p = 0.02) and CETP concentration was diminished (2.1 ± 1.0 vs 2.5 ± 1.1, p = 0.02). Lecithin-cholesterol acyltransferase activity, HDL size and lipid composition were equal.
Reduction in T2DM + CAD of cholesterol transfer to HDL may impair cholesterol esterification and reverse cholesterol transport and altogether with simultaneous increased plasma unesterified cholesterol may facilitate CAD development in T2DM.
Coronary artery disease; Type 2 diabetes; Lipid transfers; High-density lipoprotein; HDL; Nanoparticles; Cholesterol
With the increasing trend of metabolic syndrome (MetS) and atherothrombotic stroke (which can manifest as stroke lesion multiplicity), studies on the association between MetS and the clinical aspects of atherothrombotic stroke are of great interest. The present study aimed to investigate the association between MetS and multiple atherothrombotic strokes in patients with intracranial atherothrombotic stroke.
A retrospective study based on medical charts was conducted among patients (n = 202: 137 men/65 women) who were symptomatically admitted to the hospital with the first-ever atherothrombotic stroke. For the occurrence of multiple lesions of stroke, odds ratio [OR: 95 % confidence interval (CI)] of MetS or its respective components was calculated using logistic regression models.
Fifty-one percent of the men and 38 % of women with stroke presented multiple regions. MetS was a significant factor that was associated with an increased risk of multiple regions in women [OR 4.3 (95 % CI 1.4–13.5)], but not in men. According to the components of MetS, dyslipidemia was a significant factor that was positively associated with multiple regions in both men [OR 2.0 (95 % CI 1.1–3.7)] and women [OR 3.2 (95 % CI 1.1–9.1)].
MetS may be pathophysiologically associated with intracranial atherothrombotic stroke multiplicity in women in particular. Future studies are warranted to confirm the findings.
Insulin resistance; Obesity; Triglyceride; HDL-cholesterol; Dyslipidemia; Ischemic stroke
Studies on the long-term
effectiveness of multidisciplinary risk-stratification based management in Chinese population were rare. This study aimed to evaluate the effectiveness of a multidisciplinary risk assessment and management program for patients with diabetes mellitus (RAMP-DM) in reducing the risks of cardiovascular complications and all-cause mortality.
A prospective cohort study was conducted in 18,188 propensity score matched RAMP-DM participants and subjects with diabetes under usual primary care (9,094 subjects in each group). The study endpoints were the first occurrence of coronary heart disease (CHD), stroke, heart failure (HF), total cardiovascular disease (CVD) and all-cause mortality. We constructed multivariable Cox proportional hazard regressions to estimate the association between the RAMP-DM intervention and the first occurrence of study endpoints.
The median follow-up period was 36 months. Three hundred and ninety-nine CVD events occurred in the RAMP-DM group, as compared with 608 in the control group [adjusted hazard ratio, 0.629; 95 % confidence interval (CI) 0.554–0.715; P < 0.001]. The total number of all-cause deaths in RAMP-DM group was less than half that of control group (202 vs 552, adjusted hazard ratio, 0.363; 95 % CI, 0.308–0.428; P < 0.001). The adjusted hazard ratios of the RAMP-DM group for CHD, stroke, and HF were 0.570 (95 % CI, 0.470–0.691; P < 0.001), 0.652 (95 % CI, 0.546–0.780; P < 0.001), and 0.598 (95 %CI, 0.446–0.802; P = 0.001), respectively.
The RAMP-DM intervention was associated with lower incidences of individual and total cardiovascular complications, as well as all-cause mortality over 3 years follow-up. The encouraging results provided evidence to support that the structured risk-stratification management leading by a multidisciplinary clinical team was an effective approach to reduce future cardiovascular complications in people with diabetes.
Clinical trial registry: NCT02034695, http://www.ClinicalTrials.gov
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0267-3) contains supplementary material, which is available to authorized users.
Diabetes mellitus; Risk stratification; Multidisciplinary; Cardiovascular complications
Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients.
We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization.
Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04–1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45–11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95–0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23–1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43–2.24; p = 0.98).
The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed.
Endothelial dysfunction; Diabetes mellitus; Coronary microcirculation
The global prevalence of diabetes has risen to epidemic proportions and the trend is predicted to continue. The consequent burden of cardiovascular morbidity and mortality is a major public health concern and new treatments are required to mitigate the deleterious effects of cardiovascular disease in diabetic patients. Ischaemia–reperfusion injury is well known to exacerbate the harmful effects of acute myocardial infarction and subsequent therapeutic reperfusion, and several mechanical and pharmacological approaches to mitigating this injury have been investigated. Metformin, which is cheap, relatively safe and widely used in type 2 diabetes, is one such pharmacotherapy with considerable pre-clinical evidence for cardioprotective utility beyond its glucose-lowering effect. However, despite convincing basic evidence its translation to clinical application has largely been limited to studies of cardiovascular risk. There are several barriers to prospective randomized assessment in the context of acute myocardial infarction, not least the accessibility and already widespread use of metformin among patients with type 2 diabetes at high risk of cardiovascular events. In the place of class 1 evidence, well-designed prospective cohort studies of the potential pleiotropic utility of metformin in cardiovascular disease, and particularly its benefit in ischaemia–reperfusion injury, are needed. Given the availability of metformin worldwide, this is particularly true in low- and middle-income countries where the optimal therapy for acute myocardial infarction, primary percutaneous coronary intervention, may not be available, and instead patients are managed with thrombolysis. As this is less effective, metformin as an adjunct to thrombolysis (or PPCI) could represent an effective, cheap means of cardioprotection with global relevance.
Metformin; Cardioprotection; Ischaemia–reperfusion injury; STEMI; Type 2 diabetes; PCI; Thrombolysis
Vascular calcification is an independent risk factor for cardiovascular disease. Diabetes mellitus increases the incidence of vascular calcification; however, detailed molecular mechanisms of vascular calcification in diabetes mellitus remain unknown. We recently reported that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) regulates osteoblast-like trans-differentiation of human coronary artery smooth muscle cells (HCASMCs).
We investigated the effect of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), commonly used in patients with atherosclerotic diseases and diabetes mellitus, on alkaline phosphatase (ALP) mRNA expression in aortas of streptozotocin-induced diabetic mice. We also investigated the effects of the statin, Rho-associated protein kinase (ROCK) inhibitors and BMPER knockdown on ALP mRNA expression and activity in HCASMCs cultured in high glucose-containing media.
Alkaline phosphatase mRNA expression was increased in aortas of streptozotocin-induced diabetic mice, and the increase was inhibited by rosuvastatin. ALP mRNA expression and activity were increased in HCASMCs cultured in high glucose-containing media, and the increases were suppressed by rosuvastatin. This suppression was reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate. High glucose-increased ALP mRNA expression and activity were suppressed by ROCK inhibitors. Moreover, BMPER mRNA expression was increased in diabetic mouse aortas and in HCASMCs cultured in high glucose-containing media, but was not inhibited by rosuvastatin or ROCK inhibitors. Knockdown of BMPER suppressed high glucose-increased ALP activity, but not ROCK activity in HCASMCs.
There are at least two independent pathways in high glucose-induced ALP activation in HCASMCs: the Rho–ROCK signaling pathway and the BMPER-dependent pathway.
ALP; BMPER; High glucose; ROCK; Statin; Vascular smooth muscle cells
Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart.
Methods and results
Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins
in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1–Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1–Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor.
The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0264-6) contains supplementary material, which is available to authorized users.
Type 2 diabetes; Autophagy; DPP-4 inhibitor; Myocardial infarction; Mortality
Enhancement of myocardial
glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM).
In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)—one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments.
In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain −18.1 ± 6.6 versus −15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia.
In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM.
Trial Registration: http://www.isrctn.org. Unique identifier ISRCTN69686930
Hyperglycemia; Coronary disease; Diabetes mellitus; Glucagon-like peptide; Stress echocardiography
Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.
Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments.
Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice.
HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0262-8) contains supplementary material, which is available to authorized users.
HDAC; Diabetes; Myocardium; Heart failure; Apoptosis; GLUT
The aim of the study was to evaluate the effect of delay in treatment intensification (IT; clinical inertia) in conjunction with glycaemic burden on the risk of macrovascular events (CVE) in type 2 diabetes (T2DM) patients.
A retrospective cohort study was carried out using United Kingdom Clinical Practice Research Datalink, including T2DM patients diagnosed from 1990 with follow-up data available until 2012.
In the cohort of 105,477 patients mean HbA1c was 8.1% (65 mmol/mol) at diagnosis, 11% had a history of cardiovascular disease, and 7.1% experienced at least one CVE during 5.3 years of median follow-up. In patients with HbA1c consistently above 7/7.5% (53/58 mmol/mol, n = 23,101/11,281) during 2 years post diagnosis, 26/22% never received any IT. Compared to patients with HbA1c <7% (<53 mmol/mol), in patients with HbA1c ≥7% (≥53 mmol/mol), a 1 year delay in receiving IT was associated with significantly increased risk of MI, stroke, HF and composite CVE by 67% (HR CI: 1.39, 2.01), 51% (HR CI: 1.25, 1.83), 64% (HR CI: 1.40, 1.91) and 62% (HR CI: 1.46, 1.80) respectively. One year delay in IT in interaction with HbA1c above 7.5% (58 mmol/mol) was also associated with similar increased risk of CVE.
Among patients with newly diagnosed T2DM, 22% remained under poor glycaemic control over 2 years, and 26% never received IT. Delay in IT by 1 year in conjunction with poor glycaemic control significantly increased the risk of MI, HF, stroke and composite CVE.
Type 2 diabetes; Delay in treatment intensification; Cardiovascular risk; Longitudinal analysis; Clinical inertia