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26.  Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control 
Cardiovascular Diabetology  2014;13(1):156.
Background and aims
Elevated plasma asymmetric dimethylarginine (ADMA) levels have been observed in patients with insulin resistance and diabetes, and have been reported to predict adverse cardiovascular events in type 2 diabetic patients. However, the relationship between ADMA and glycemic control in patients with type 2 diabetes remained controversial.
Methods and results
We evaluated 270 patients with type 2 diabetes and measured their plasma ADMA and hemoglobin A1c (HbA1c) levels by high performance liquid chromatography. The mean age was 67 ± 12 years. The mean plasma ADMA and HbA1c level were 0.46 ± 0.09 μmol/l and 7.8 ± 1.6%, respectively. There was no significant correlation between plasma ADMA level and HbA1c level (r = −0.09, p = 0.13). During the median follow-up period of 5.7 years (inter-quartile range: 5.0 − 7.3 years), major adverse cardiovascular event (MACE, including cardiovascular death, myocardial infarction and stroke) was observed in 55 patients (20.4%). Multivariate Cox regression analysis revealed that the ADMA tertile was an independent risk factor for MACE (ADMA tertile III versus ADMA tertile I: p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). The prognosis predictive power of ADMA disappeared in patients with well glycemic control (HbA1c ≤6.5%), and the ADMA-HbA1c interaction p value was 0.01.
In patients with type 2 diabetes, ADMA might be an independent risk factor for long-term adverse cardiovascular events. However, ADMA was not correlated with serum HbA1c level, and in diabetic patients with HbA1c ≤6.5%, elevated ADMA level was no longer associated with increased risk of long-term prognosis. Our findings suggested that the prognosis predictive value of ADMA in type 2 diabetes might be modified by the glycemic control.
PMCID: PMC4262144  PMID: 25467091
Asymmetric dimethylarginine; Diabetes; Hemoglobin A1c; Nitric oxide
27.  DPP-4 inhibitor linagliptin ameliorates cardiovascular injury in salt-sensitive hypertensive rats independently of blood glucose and blood pressure 
Cardiovascular Diabetology  2014;13(1):157.
It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats).
High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3 mg/kg/day) once a day for 4 weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated.
Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67phox and p22 phox, and angiotensin-converting enzyme (ACE).
Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.
PMCID: PMC4255443  PMID: 25471116
Salt-sensitive hypertension; Cardiovascular injury; Oxidative stress; Inflammation; ACE; Pleiotrophic effects
28.  Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice 
Cardiovascular Diabetology  2014;13(1):149.
Liver X receptor (LXR) plays a critical regulatory role in metabolism and inflammation, and has been demonstrated to be involved in cardiovascular physiology/pathology. In the present study, we investigated the effect of GW3965, a potent LXR agonist, on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice.
Methods and Results
Non-diabetic db/+ mice and diabetic db/db mice received either vehicle or LXR agonist GW3965 for 12 weeks. Systemic insulin resistance was evaluated by glucose tolerance test and homeostasis model assessment for insulin resistance. Endpoint cardiac function was assessed by echocardiography and catheterization. Ventricular tissue was collected for histology and gene/protein expression analysis. Untreated db/db diabetic mice exhibited diastolic dysfunction with adverse structural remodeling (including myocardial fibrosis and increased apoptosis). Treatment with GW3965 remarkably attenuated myocardial dysfunction and structural remodeling in diabetic db/db mice. Mechanistically, GW3965 restored Akt phosphorylation and inhibited MAP kinases phosphorylation, and reduced oxidative/nitrative stress and inflammation response in the diabetic myocardium.
Our data demonstrate that GW3965 exerts a cardioprotective effect against DCM by (at least in part) attenuating insulin resistance, modulating Akt and MAP kinases pathways, and reducing oxidative/nitrative stress and inflammatory response. These findings strongly suggest that LXR agonist may have therapeutic potential in treating DCM.
PMCID: PMC4245833  PMID: 25416469
Liver X receptor; Diabetic cardiomyopathy; Insulin resistance; Antioxidant
29.  The protective effect of the Mediterranean diet on endothelial resistance to GLP-1 in type 2 diabetes: a preliminary report 
Cardiovascular Diabetology  2014;13(1):140.
In type 2 diabetes, acute hyperglycemia worsens endothelial function and inflammation,while resistance to GLP-1 action occurs. All these phenomena seem to be related to the generation of oxidative stress. A Mediterranean diet, supplemented with olive oil, increases plasma antioxidant capacity, suggesting that its implementation can have a favorable effect on the aforementioned phenomena. In the present study, we test the hypothesis that a Mediterranean diet using olive oil can counteract the effects of acute hyperglycemia and can improve the resistance of the endothelium to GLP-1 action.
Two groups of type 2 diabetic patients, each consisting of twelve subjects, participated in a randomized trial for three months, following a Mediterranean diet using olive oil or a control low-fat diet. Plasma antioxidant capacity, endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels were evaluated at baseline and at the end of the study. The effect of GLP-1 during a hyperglycemic clamp, was also studied at baseline and at the end of the study.
Compared to the control diet, the Mediterranean diet increased plasma antioxidant capacity and improved basal endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. The Mediterranean diet also reduced the negative effects of acute hyperglycemia, induced by a hyperglycemic clamp, on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. Furthermore, the Mediterranean diet improved the protective action of GLP-1 on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels, also increasing GLP-1-induced insulin secretion.
These data suggest that the Mediterranean diet, using olive oil, prevents the acute hyperglycemia effect on endothelial function, inflammation and oxidative stress, and improves the action of GLP-1, which may have a favorable effect on the management of type 2 diabetes, particularly for the prevention of cardiovascular disease.
PMCID: PMC4240857  PMID: 25407792
Diabetes mellitus; Acute hyperglycemia; GLP-1; Oxidative stress; Mediterranean diet
30.  Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury 
Cardiovascular Diabetology  2014;13(1):154.
Recently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).
Six-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.
Linagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.
Linagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.
PMCID: PMC4240860  PMID: 25407968
DPP-4 inhibitor; Linagliptin; Neointima formation; VSMC proliferation
31.  Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway 
Cardiovascular Diabetology  2014;13(1):153.
Arterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined.
Calcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA).
Exenatide, an agonist of GLP-1 receptor, attenuated β-glycerol phosphate (β-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser276, p-Ser536) level was observed in cells treated with exenatide or exenatide + BAY11-7082.
GLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.
PMCID: PMC4241215  PMID: 25407893
Arterial calcification; Vascular smooth muscle cells; Osteoblastic differentiation; Glucagon-like peptide-1; Diabetes
32.  Association of secreted frizzled-related protein 4 (SFRP4) with type 2 diabetes in patients with stable coronary artery disease 
Cardiovascular Diabetology  2014;13(1):155.
Secreted frizzled-related proteins (SFRP) are regulators of Wnt-signalling. SFRP4 has been shown to regulate insulin exocytosis and is overexpressed in type 2 diabetes mellitus.
Here we characterized the relation of SFRP4 to glucose and triglyceride metabolism and outcomes in patients with stable coronary artery disease on statin treatment in the prospective Homburg Cream & Sugar Study (NCT00628524).
Fasting SFRP4 concentrations were measured by ELISA in 504 consecutive patients with stable CAD confirmed by angiography.
The median age was 68 years and 83% of patients were male. Oral glucose tolerance tests were performed in all patients without known diabetes for metabolic characterization. 24.4% of patients showed normal glucose tolerance, 29.4% impaired glucose tolerance and 46.2% diabetes mellitus. SFRP4 concentrations correlated with insulin (R = 0.153, p = 0.001), HbA1c (R = 0.166, p < 0.0001), fasting triglycerides (R = 0.113, p = 0.011) and higher triglycerides after lipid challenge (postprandial triglycerides R = 0.124, p = 0.005; AUC R = 0.134, p = 0.003). Higher SFRP4 concentrations were associated with type 2 diabetes, metabolic syndrome, and severity of diabetes.
The primary outcome was the composite of cardiovascular death and cardiovascular hospitalization within 48 months follow-up. Comparison of event-free survival between SFRP4 tertiles showed that SFRP4 concentrations were not predictive for cardiovascular outcome.
SFRP4 concentrations are associated with impaired glucose and triglyceride metabolism but do not predict cardiovascular outcome in patients with stable coronary artery disease on treatment.
PMCID: PMC4247677  PMID: 25408147
SFRP4; Type 2 diabetes mellitus; Coronary artery disease
33.  Immunization with advanced glycation end products modified low density lipoprotein inhibits atherosclerosis progression in diabetic apoE and LDLR null mice 
Cardiovascular Diabetology  2014;13(1):151.
Diabetes accelerates atherosclerosis through undefined molecular mechanisms. Hyperglycemia induces formation of advanced glycation end product (AGE)-modified low-density lipoprotein (LDL). Anti-AGE-LDL autoantibodies favor atherosclerosis (AS) progression in humans, while anti oxidized LDL immunization inhibits AS in hypercholesterolemic, non-diabetic mice. We here investigated if AGE-LDL immunization protects against AS in diabetic mice.
After diabetes induction with streptozotocin and high fat diet, both low density lipoprotein receptor (LDLR)−/− and apoE female mice were randomized to: AGE-LDL immunization with aluminum hydroxide (Alum) adjuvant; Alum alone; or PBS.
AGE-LDL immunization: significantly reduced AS; induced specific plasma IgM and IgG antibodies; upregulated splenic Th2, Treg and IL-10 levels, without altering Th1 or Th17 cells; and increased serum high density lipoprotein(HDL) while numerically lowering HbA1c levels.
Subcutaneous immunization with AGE-LDL significantly inhibits atherosclerosis progression in hyperlipidemic diabetic mice possibly through activation of specific humoral and cell mediated immune responses and metabolic control improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0151-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4234834  PMID: 25391642
Immunization; Advanced glycation end products; Low density lipoprotein; Atherosclerosis; Diabetes
34.  Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis 
Cardiovascular Diabetology  2014;13(1):152.
The prevalence of type 2 diabetes (T2D) among adults worldwide is rapidly increasing, and in patients with diabetes the major cause of death is macrovascular disease. Endothelial cells play an important role in maintaining vascular homeostasis. Free fatty acids, which are elevated in T2D, have previously been shown to induce endothelial dysfunction and apoptosis of endothelial cells, which is considered as an important and early factor in the onset of atherosclerosis and cardiovascular disease. Metformin, which is used as first line treatment of T2D patients, is believed to exert its pharmacological effects through activation of AMP-activated protein kinase, which has emerged as a new potential target in reversing endothelial dysfunction.
Here we studied the protective effect of metformin against free fatty acid-induced apoptosis of human coronary artery endothelial cells (HCAECs) by assessing DNA fragmentation and cleaved caspase 3 levels. We also attempted to elucidate the underlying mechanisms by investigating the involvement of AMP-activated protein kinase, p38 MAPK and eNOS. Generation of reactive oxygen species by free fatty acid exposure was also examined.
Our results suggest that metformin protects HCAECs from lipoapoptosis, an effect that involves eNOS and p38 MAPK, downstream of AMPK signaling, but not as previously suggested through suppression of reactive oxygen species.
The protective effect of metformin against free fatty acid induced apoptosis is potentially clinically relevant as metformin is first line treatment for patients with T2D, a patient group which is rapidly increasing and carries a high burden of cardiovascular disease.
PMCID: PMC4234893  PMID: 25391818
Metformin; Endothelial cell; Free fatty acids; Apoptosis
35.  Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris 
Cardiovascular Diabetology  2014;13(1):145.
Recent evidence demonstrated that the circulating adipokines were associated with the onset of acute coronary syndrome (ACS) including unstable angina pectoris (UAP) and acute myocardial infarction (AMI). As a novel adipokine, chemerin has been related to atherosclerosis and the presence of coronary artery disease. However, the plasma levels of chemerin in patients with ACS have yet to be investigated.
Plasma levels of chemerin and adiponectin were measured by an enzyme-linked immunosorbent assay (ELISA) in 60 patients with stable angina pectoris (SAP), 60 patients with UAP, 60 patients with AMI and 40 control patients. Left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured using a GE ViVid E7 ultrasonography machine, and the severity of coronary stenosis in patients was estimated with a Gensini coronary score following coronary angiography.
Plasma chemerin levels were significantly higher in ACS patients than in the control and SAP groups, while plasma adiponectin levels were significantly lower in ACS patients than the control group. A correlation analysis revealed that plasma chemerin levels were positively correlated with the levels of C-reactive protein (CRP) (r = 0.29, P < 0.01) and LVEDD (r = 0.27, P < 0.01) but negatively correlated with LVEF (r = -0.45, P < 0.01) and that plasma adiponectin levels were positively correlated with LVEF (r = 0.53, P < 0.01) but negatively correlated with CRP (r = -0.33, P < 0.01) and LVEDD (r = -0.30, P < 0.01). Although significant correlations between chemerin, adiponectin and BMI or the Gensini coronary score were found in patients with SAP, neither chemerin nor adiponectin was correlated with BMI and the Gensini coronary score in patients with ACS. Furthermore, both chemerin (OR 1.103, 95% CI 1.065 to 1.142; P = 0.001) and adiponectin (OR 0.871, 95% CI 0.776 to 0.970; P = 0.018) were independently associated with the presence of ACS.
Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris.
PMCID: PMC4229596  PMID: 25367628
Chemerin; Adiponectin; Acute coronary syndrome; Inflammation; Left ventricular function
36.  Association of impaired fasting glucose, diabetes and their management with the presentation and outcome of peripheral artery disease: a cohort study 
Cardiovascular Diabetology  2014;13(1):147.
Pre-diabetes and untreated diabetes are common in patients with peripheral artery disease however their impact on outcome has not been evaluated. We examined the association of impaired fasting glucose, diabetes and their treatment with the presentation, mortality and requirement for intervention in peripheral artery disease patients.
We prospectively recruited 1637 patients with peripheral artery disease, measured fasting glucose, recorded medications for diabetes and categorised them by diabetes status. Patients were followed for a median of 1.7 years.
At entry 22.7% patients were receiving treatment for type 2 diabetes by oral hypoglycaemics alone (18.1%) or insulin (4.6%). 9.2% patients had non-medicated diabetes. 28.1% of patients had impaired fasting glucose (5.6-6.9 mM). Patients with non-medicated diabetes had increased mortality and requirement for peripheral artery intervention (hazards ratio 1.62 and 1.31 respectively). Patients with diabetes prescribed insulin had increased mortality (hazard ratio 1.97). Patients with impaired fasting glucose or diabetes prescribed oral hypoglycaemics only had similar outcomes to patients with no diabetes.
Non-medicated diabetes is common in peripheral artery disease patients and associated with poor outcomes. Impaired fasting glucose is also common but does not increase intermediate term complications. Peripheral artery disease patients with diabetes requiring insulin are at high risk of intermediate term mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0147-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4230372  PMID: 25361884
Peripheral artery disease; Diabetes; Mortality; Surgery; Patient management
37.  PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors 
Cardiovascular Diabetology  2014;13(1):150.
Peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPARγ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs).
PACs were isolated from bone marrow of 10–12 weeks old, wild type, db/db and PPARγ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 μmol/L) or GW9662 (10 μmol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model.
ECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPARγ activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells.
Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPARγ and changed expression of PPARγ-regulated genes. Using normoglycemic PPARγ+/− mice we demonstrated that reduced expression of PPARγ does not influence neovascularization either in wound healing or in hind limb ischemia models.
In summary, activation of PPARγ by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPARγ in diabetes does not impair angiogenesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0150-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4233236  PMID: 25361524
Diabetes; PPARγ; Therapeutic angiogenesis; Endothelial progenitor cells
38.  Association between carotid intima-media thickness and index of central fat distribution in middle-aged and elderly Chinese 
Cardiovascular Diabetology  2014;13(1):139.
Evidence has demonstrated that central fat distribution produces the most profound metabolic abnormalities and is associated with an increased risk of atherosclerotic cardiovascular diseases. We aimed to investigate whether the indexes of central fat distribution, including waist-to-height ratio (WHtR) and visceral fat area (VFA), were stronger risk factors of subclinical atherosclerosis than body mass index (BMI) in Chinese adults.
A total of 3381 participants aged 40 years or older without history of cardiovascular diseases (CVD) were enrolled in the present cross-sectional study from the Songnan community, Shanghai, China. Height, weight and waist circumference (WC) were measured by experienced physicians. High-resolution B-mode ultrasonography was performed to measure carotid intima-media thickness (CIMT). Regional adiposity was measured by a dual-source computed tomography (CT) scanner.
Normal weight but central obesity group (BMI < 23 kg/m2 and WHtR > 0.5) had higher levels of systolic blood pressure (SBP), fasting plasma glucose (FPG), 2 h post-load glucose (2 h PG), Hemoglobin A1c (HbA1c), and CIMT, as well as an elevated prevalence of hypertension and diabetes compared with overweight/obesity but not central obesity group (BMI ≥ 23 kg/m2 and WHtR ≤ 0.5). In logistic regression analysis, WHtR > 0.5 was significantly and independently associated with elevated CIMT (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.01-1.68, p value = 0.044). Similar association was noted for each standard deviation (SD) increase of WHtR (OR 1.25, 95% CI 1.07-1.47, p value = 0.006). Stepwise multiple linear regression analysis revealed that both WHtR and VFA were important determinants of CIMT, independent of other well-recognized risk factors (both p values < 0.01).
WHtR and VFA were associated with CIMT, independent of BMI and conventional CVD risk factors. Given the relatively high cost and complexness of VFA measurement, WHtR could be a more convenient and appropriate measure of abdominal obesity in clinical practice.
PMCID: PMC4219037  PMID: 25359238
Waist-to-height ratio; Visceral fat area; Carotid intima-media thickness
39.  Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice 
Cardiovascular Diabetology  2014;13(1):148.
There has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate cardiovascular injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes.
(1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on cardiovascular injury, vascular dysfunction, cognitive decline, and renal injury in db/db mice.
(1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular injury in db/db mice.
Glycemic control with empagliflozin significantly ameliorated cardiovascular injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.
PMCID: PMC4219031  PMID: 25344694
Cardiovascular complications; Vascular dysfunction; Cognitive decline; Oxidative stress; Inflammation
40.  Aortic reservoir characteristics and brain structure in people with type 2 diabetes mellitus; a cross sectional study 
Cardiovascular Diabetology  2014;13(1):143.
Central hemodynamics help to maintain appropriate cerebral and other end-organ perfusion, and may be altered with ageing and type 2 diabetes mellitus (T2DM). We aimed to determine the associations between central hemodynamics and brain structure at rest and during exercise in people with and without T2DM.
In a sample of people with T2DM and healthy controls, resting and exercise measures of aortic reservoir characteristics (including excess pressure integral [Pexcess]) and other central hemodynamics (including augmentation index [AIx] and aortic pulse wave velocity [aPWV]) were recorded. Brain volumes (including gray matter volume [GMV] and white matter lesions [WML]) were derived from magnetic resonance imaging (MRI) scans. Multivariable linear regression was used to study the associations of hemodynamic variables with brain structure in the two groups adjusting for age, sex, daytime systolic BP (SBP) and heart rate.
There were 37 T2DM (63 ± 9 years; 47% male) and 37 healthy individuals (52 ± 8 years; 51% male). In T2DM, resting aPWV was inversely associated with GMV (standardized β = −0.47, p = 0.036). In healthy participants, resting Pexcess was inversely associated with GMV (β = −0.23, p = 0.043) and AIx was associated with WML volume (β = 0.52, p = 0.021). There were no associations between exercise hemodynamics and brain volumes in either group.
Brain atrophy is associated with resting aortic stiffness in T2DM, and resting Pexcess in healthy individuals. Central vascular mechanisms underlying structural brain changes may differ between healthy individuals and T2DM.
PMCID: PMC4221700  PMID: 25338824
Type 2 diabetes mellitus; Central hemodynamics; Aortic stiffness; Magnetic resonance imaging; Vascular cognitive impairment
41.  Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists 
Cardiovascular Diabetology  2014;13(1):142.
Patients with type 2 diabetes have a several-fold increased risk of developing cardiovascular disease when compared with nondiabetic controls. Myocardial infarction and stroke are responsible for 75% of all death in patients with diabetes, who present a 2-4× increased incidence of death from coronary artery disease. Patients with diabetes are considered for cardiovascular disease secondary prevention because their risk level is similar to that reported in patients without diabetes who have already suffered a myocardial infarction. More recently, with a better risk factors control, mainly in intensive LDL cholesterol targets with statins, a significant decrease in acute cardiovascular events was observed in population with diabetes. Together with other major risk factors, type 2 diabetes must be considered as an important cause of cardiovascular disease.
Glucagon like peptide-1 receptor agonists represent a novel class of anti-hyperglycemic agents that have a cardiac-friendly profile, preserve neuronal cells and inhibit neuronal degeneration, an anti-inflammatory effect in liver protecting it against steatosis, increase insulin sensitivity, promote weight loss, and increase satiety or anorexia.
This review is intended to rationally compile the multifactorial cardiovascular effects of glucagon-like peptide-1 receptor agonists available for the treatment of patients with type 2 diabetes.
PMCID: PMC4216654  PMID: 25338737
42.  Normal weight diabetic patients versus obese diabetics: relation of overall and abdominal adiposity to vascular health 
Cardiovascular Diabetology  2014;13(1):141.
The present study investigated the impact of overall obesity defined by BMI and abdominal obesity defined by WC on vascular atherosclerotic changes in obese and normal weight diabetic subjects.
Design and methods
285 subjects were divided according to presence diabetes mellitus (DM) and obesity: Group 1 included 144 nonobese subjects without DM; Group 2 consisted of 141 type 2 diabetic patients. Then diabetic patients were divided into two groups according to presence of overall obesity, defined by BMI and furthermore, abdominal obesity, defined by waist circumference (WC). Pulse wave velocity (PWV) and augmentation index (AI) were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia).
Between Group Comparisons by BMI: Diabetic subjects with and without overall obesity did not differ from one another in terms of AI and PWV.
Between Group Comparisons by WC: AI as well as PWV increased consistently from Group 1 to Group 3, AI and PWV were significantly higher in abdominally obese diabetic subjects than in the diabetics without abdominal obesity (p = 0.008 and p = 0.013, respectively). Significant by-group differences in PWV and AI persisted after adjustment for age, sex, blood pressure, fasting glucose and BMI.
Abdominal obesity defined by WC was associated with significantly higher AI and PWV in in both diabetic men and women; whereas overall obesity defined by BMI did not predict adverse vascular changes in this study population. Abdominal obesity was associated with an adverse effect on blood vessels, independently of age, sex, blood pressure, fasting glucose and BMI.
PMCID: PMC4226853  PMID: 25331525
43.  Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance 
Cardiovascular Diabetology  2014;13(1):146.
To directly compare traditional lipid ratios (total cholesterol [TC]/high density lipoprotein cholesterol [HDL-C], non-HDL-C/HDL-C, low density lipoprotein cholesterol [LDL-C]/HDL-C, and triglycerides [TG]/HDL-C), apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP), and the product of TG and fasting glucose (TyG) for strength and independence as risk factors for insulin resistance (IR).
We conducted a cross-sectional analysis of 7629 Chinese adults using data from the China Health and Nutrition Survey 2009.
For all lipid ratios (traditional lipid ratios and apoB/apoA-I), among both sexes, TG/HDL-C explained the most additional percentage of variation in HOMA-IR (2.9% in men, and 2.3% in women); for all variables of interest, the variability in HOMA-IR explained by VAI and TG/HDL-C were comparable; TyG had the most significant association with HOMA-IR, which explained 9.1% for men and 7.8% for women of the variability in HOMA-IR. Logistic regression analysis showed the similar patterns. Receiver operating characteristic (ROC) curve analysis showed that, among both sexes, TG/HDL-C was a better discriminator of IR than apoB/apoA-I; the area under the ROC curve (AUC) for VAI (0.695 in men and 0.682 in women) was greater than that for TG/HDL-C (AUC 0.665 in men and 0.664 in women); TyG presented the greatest value of AUC (0.709 in men and 0.711 in women).
The apoB/apoA-I performs no better than any of the traditional lipid ratios in correlating with IR. The TG/HDL-C, VAI and TyG are better markers for early identification of IR individuals.
PMCID: PMC4209231  PMID: 25326814
Insulin resistance; Apolipoprotein B; Apolipoprotein A-I; Visceral adiposity index; Lipid accumulation product; TyG index
44.  Obesity attenuates gender differences in cardiovascular mortality 
Cardiovascular Diabetology  2014;13(1):144.
To estimate cardiovascular disease (CVD) mortality in relation to obesity and gender.
Data from 11 prospective cohorts from four European countries including 23 629 men and 21 965 women, aged 24 to 99 years, with a median follow-up of 7.9 years were analyzed. Hazards ratios (HR) for CVD mortality in relation to baseline body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated using Cox proportional hazards models with age as the timescale.
Men had higher CVD mortality than women in all four BMI categories (<25.0, 25.0-29.9, 30.0-34.9 and ≥35.0 kg/m2). Compared with the lowest BMI category in women, multivariable adjusted HRs (95% confidence intervals) for higher BMI categories are 1.0 (0.8-1.4), 1.6 (1.1-2.1) and 2.8 (2.0-3.8) in women and 2.8 (2.2-3.6), 3.1 (2.5-3.9), 3.8 (2.9-4.9) and 5.4 (3.8-7.7) in men, respectively. Similar findings were observed for abdominal obesity defined by WC, WHR or WHtR. The gender difference was slightly smaller in obese than in non-obese individuals; but the interaction was statistically significant only between gender and WC (p = 0.02), and WHtR (p = 0.01). None of the interaction terms was significant among non-diabetic individuals.
Men had higher CVD mortality than women across categories of anthropometric measures of obesity. The gender difference was attenuated in obese individuals, which warrants further investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0144-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4212094
Obesity; Gender; Cardiovascular disease mortality
45.  Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study 
Cardiovascular Diabetology  2014;13(1):137.
Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups.
55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months.
HbA1c at baseline was, 7.3+/−0.7% in the oral group, 7.3+/−0.9% and 7.5+/−0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/−0.8%, 6.6+/−0.7% and 6.7+/−0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/−6.4 and 29.4+/− 6.7 units respectively) compared to the group on oral medication (23.2+/−6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/−0.14) at baseline to 0.76mm (+/−0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74).
The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus.
Trial registration
(Clinical Trials Identifier: NCT00523393).
PMCID: PMC4195950  PMID: 25300286
Insulin glargine; Type 2 diabetes; Endothelial progenitor cells
46.  Plasma triglycerides predict ten-years all-cause mortality in outpatients with type 2 diabetes mellitus: a longitudinal observational study 
Cardiovascular Diabetology  2014;13(1):135.
Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes mellitus (T2DM). American Diabetes Association standards of care set a series of targets recommended for the CVD prevention: blood pressure, LDL and HDL cholesterol (LDL-C and HDL-C), triglycerides and HbA1c goals. The aim of this study was to evaluate cardiovascular risk factors in a T2DM outpatient population in order to estimate their specific clinical value in predicting long-term overall mortality.
Our study population was composed of 1917 T2DM outpatients attending the hospital-based Diabetes Clinic of Ferrara for a mean follow-up period of 10 years; recorded information included personal, clinical and biochemical data, and pharmacological treatment.
A Cox proportional hazard analysis was performed, pointing out as age (HR:1.08; IC95%: 1.06-1.11), sex (males: HR:1.97; IC95%: 1.26-3.07), mean triglycerides levels during follow-up (III vs I tertile: HR:1.87; IC95%: 1.12-3.12) and lipid-lowering treatment (HR:0.56; IC95%: 0.35-0.90) were significantly associated with all-cause mortality, independent of confounding factors such as mean values of LDL-C, HDL-C, HbA1c, blood pressure, BMI, fasting glucose, and antihypertensive and antidiabetic treatment.
This finding suggests that more attention should be given to the management of cardiovascular risk in type 2 diabetic patients with high triglycerides levels.
PMCID: PMC4198794  PMID: 25301574
47.  Diabetic hyperglycemia attenuates sympathetic dysfunction and oxidative stress after myocardial infarction in rats 
Cardiovascular Diabetology  2014;13(1):131.
Previous research has demonstrated that hyperglycemia may protect the heart against ischemic injury. The aim of the present study was to investigate the association between hyperglycemia and myocardial infarction on cardiovascular autonomic modulation and cardiac oxidative stress profile in rats. Male Wistar rats were divided into: control (C), diabetic (D), myocardial infarcted (MI) and diabetic infarcted rats (DMI).
Diabetes was induced by streptozotocin (STZ, 50 mg/Kg) at the beginning of the protocol and MI was induced by left coronary occlusion 15 days after STZ. Thirty days after streptozocin-induced diabetes, cardiovascular autonomic modulation was evaluated by spectral analysis, and oxidative stress profile was determined by antioxidant enzyme activities and superoxide anion, together with protein carbonylation and redox balance of glutathione (GSH/GSSG).
The diabetic and infarcted groups showed decreased heart rate variability and vagal modulation (p < 0.05); however, sympathetic modulation decreased only in diabetic groups (p < 0.05). Sympatho/vagal balance and vascular sympathetic modulation were increased only in the MI group (p < 0.05). Diabetes promoted an increase in catalase concentration (p < 0.05). Glutathione peroxidase activity was increased only in DMI when compared to the other groups (p < 0.05). Superoxide anion and protein carbonylation were increased only in MI group (p < 0.05). Cardiac redox balance, as evaluated by GSH/GSSG, was lower in the MI group (p < 0.05).
These data suggest that hyperglycemia promotes compensatory mechanisms that may offer protection against ischemia, as demonstrated by increased antioxidants, decreased pro-oxidants and protein damage, possibly related to the improvements in both redox balance and sympathetic modulation to the heart.
PMCID: PMC4198704  PMID: 25301475
Autonomic modulation; Oxidative stress; Diabetic hyperglycemia; Myocardial infarction
48.  Visceral adiposity index and risks of cardiovascular events and mortality in prevalent hemodialysis patients 
Cardiovascular Diabetology  2014;13(1):136.
The visceral adiposity index (VAI) is a newly-derived measure of visceral adiposity with well-validated predictive power for cardiovascular (CV) outcomes in the general population. However, this predictability has not been investigated in hemodialysis patients, and whether VAI is superior to waist circumference (WC) and waist-to-height ratio (WHtR) in predicting CV outcomes and survival in hemodialysis patients remains unknown.
We performed a prospective study including 464 prevalent hemodialysis patients. The composite outcome was the occurrence of death and CV events during follow-up. Using multivariate Cox regression analysis, VAI, WC and WHtR were tested for the predictive power of outcomes. To evaluate the predictive performance of the VAI, WC and WHtR, time-dependent receiver operating characteristic curve (ROC) analysis was performed.
VAI, WC and WHtR positively correlated with each other. Patients with a higher VAI (tertile 3 vs. tertile 1, adjusted hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.12-2.42; tertile 2 vs. tertile 1, adjusted HR, 1.52; 95% CI, 1.1-2.18) had more composite outcomes. VAI had a similar predictive power of all-cause mortality to WC and WHtR, but superior predictive power of composite and CV outcomes to WC when analyzed by a stepwise forward likelihood ratio test. In time-dependent ROC analysis, VAI, WC and WHtR showed similar predictive performance for outcomes.
VAI is an optimal method to measure visceral adiposity to assess long-term CV outcomes and all-cause mortality in prevalent hemodialysis patients. VAI may provide a superior predictive power of CV outcomes to WC and WHtR.
Trial registration NCT01457625
PMCID: PMC4189758  PMID: 25280960
Visceral adiposity index; Cardiovascular complication; Abdominal obesity; Survival
49.  Biomarkers of endothelial dysfunction in relation to impaired carbohydrate metabolism following pregnancy with gestational diabetes mellitus 
Cardiovascular Diabetology  2014;13(1):138.
History of gestational diabetes mellitus (GDM) identifies a very young population of females predisposed for type 2 diabetes and cardiovascular disease. Endothelial dysfunction might represent a shared precursor of both disorders. Hence, this study aimed to characterize endothelial biomarkers in relation to impaired insulin sensitivity and progression to overt diabetes early after index pregnancy.
108 women with previous GDM and 40 controls were included three to six months after delivery and underwent specific metabolic assessments including a frequently sampled intravenous glucose tolerance test and an oral glucose tolerance test. Diabetes progression was assessed in females with pGDM over 10 years of follow-up. Circulating sICAM-1 (intracellular-adhesion-molecule-1), sVCAM-1 (vascular-cell-adhesion-molecule-1) and sE-selectin, representing biomarkers of endothelial dysfunction were assessed at baseline and annually over five years.
Endothelial biomarkers were significantly associated with insulin sensitivity (sICAM-1: r = -0.23, p = 0.009; sVCAM-1: r = -0.22, p = 0.011; sE-selectin: r = -0.21, p = 0.018) as well as with GDM status and parameters of subtle inflammation. Analysis of long-term trajectories revealed constantly elevated sICAM-1 (p = 0.033) and sE-selectin (p = 0.007) in 25 subjects with diabetes progression. Accordingly, sE-selectin levels at the early post partum visit predicted a later development of the disease (HR =1.02 95%CI 1.01 to 1.04, p = 0.013), however, this was attenuated after adjustment for BMI.
Elevated circulating markers of endothelial dysfunction in young females with GDM history might reflect an early stage on the pathway to the manifestation of future cardiometabolic disorders. Timely identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression.
PMCID: PMC4197268  PMID: 25281032
Endothelial dysfunction; Insulin resistance; Gestational diabetes mellitus
50.  Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal 
Cardiovascular Diabetology  2014;13(1):134.
Excessive levels of methylglyoxal (MG) encountered in diabetes foster enhanced leukocyte-endothelial cell interactions, mechanisms of which are incompletely understood. MG genomically upregulates endothelial serum- and glucocorticoid-inducible kinase 1 (SGK1) which orchestrates leukocyte recruitment by regulating the activation and expression of transcription factors and adhesion molecules. SGK1 regulates a myriad of ion channels and carriers including the Na+/H+ exchanger NHE1. Here, we explored the effect of MG on SGK1-dependent NHE1 activation and the putative role of NHE1 activation in MG-induced leukocyte recruitment and microvascular hyperpermeability.
Using RT-PCR and immunoblotting, we analyzed NHE1 mRNA and protein levels in murine microvascular SVEC4-10EE2 endothelial cells (EE2 ECs). NHE1 phosphorylation was detected using a specific antibody against the 14-3-3 binding motif at phospho-Ser703. SGK in EE2 ECs was silenced using targeted siRNA. ROS production was determined using DCF-dependent fluorescence. Leukocyte recruitment and microvascular permeability in murine cremasteric microvasculature were measured using intravital microscopy. The expression of endothelial adhesion molecules was determined by immunoblotting and confocal imaging analysis.
MG treatment significantly upregulated NHE1 mRNA and dose-dependently increased total- and phospho-NHE1. Treatment with SGK1 inhibitor GSK650394, antioxidant Tempol and silencing SGK all blunted MG-triggered phospho-NHE1 upregulation in EE2 ECs. NHE1 inhibitor cariporide attenuated MG-triggered ROS production, leukocyte adhesion and emigration and microvascular hyperpermeability, without affecting leukocyte rolling. Cariporide treatment did not alter MG-triggered upregulation of P- and E-selectins, but reduced endothelial ICAM-1 expression.
MG elicits SGK1-dependent activation of endothelial Na+/H+ exchanger NHE1 which participates in MG-induced ROS production, upregulation of endothelial ICAM-1, leukocyte recruitment and microvascular hyperpermeability. Pharmacological inhibition of NHE1 attenuates the proinflammatory effects of excessive MG and may, thus, be beneficial in diabetes-associated inflammation.
PMCID: PMC4193979  PMID: 25270604
Methylglyoxal; NHE1; Oxidative stress; SGK1; Leukocyte recruitment

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