Showing papers in "Cardiovascular Diabetology in 2016"
TL;DR: Biomarkers of inflammation and endothelial dysfunction add to the prediction of T2D beyond a common risk score beyond acommon risk score.
Abstract: Oxidative stress, inflammation and endothelial dysfunction are interrelated factors in the etiology of cardiovascular disease, but their linkage to type 2 diabetes is less clear. We examined the association of these biomarkers with incident type 2 diabetes (T2D). Analysis of 2339 participants in the community-based coronary artery risk development in young adults (CARDIA) study. Participants (age 40.1 ± 3.6 years, 44 % Black, 58 % women) were free of diabetes, and were followed 10 years. Cox regression was used to estimate hazard ratios (HRs) for incident T2D adjusting for the other biomarkers under study, demographic and lifestyle measures, dietary biomarkers, BMI (kg/m2) and metabolic syndrome components. F2-isoprostanes and oxidized LDL (oxidative stress) were positively associated with incident T2D, but the associations were attenuated by adjustment for BMI. C-reactive protein was positively associated with T2D even with full adjustment: HR (95 % CI) = 2.21 (1.26–3.88) for quartile 4 (Q4) v. quartile 1 (Q1). The HR (95 % CI) for T2D for biomarkers of endothelial dysfunction ICAM-1 and E-selectin for Q4 v. Q1 were 1.64 (0.96–2.81) and 1.68 (1.04–2.71) respectively, with full adjustment. Including these two markers in a common risk score incorporating BMI and clinical measures improved the prediction probability of T2D: relative risk for the average person classified up compared to the average person classified down: 1.09, (1.06–1.13), P < 0.0001. Biomarkers of inflammation and endothelial dysfunction were positively associated with incident T2D. ICAM-1 and E-selectin add to the prediction of T2D beyond a common risk score.
202 citations
TL;DR: The higher leptin levels and leptin to fat mass ratio among adults born with a low weight might be related to nutritional factors during childhood or to the development of leptin resistance and/or higher leptin production by body fat unit.
Abstract: Low birth weight is associated with increased rates of obesity, insulin resistance and type 2 diabetes, but the precise mechanisms for this association remain unclear. We aimed to assess the relationships between birth weight and markers of glucose homeostasis or obesity in adults. Cross-sectional population-based study on 1458 women and 1088 men aged 35–75 years living in Lausanne, Switzerland. Birth weight was self-reported and categorized into ≤2.5, 2.6–3.5, 3.6–4.0 and >4.0 kg. Body composition was assessed by bioimpedance. Leptin and adiponectin levels were measured by ELISA. Women with low birth weight (≤2.5 kg) had higher levels of fasting plasma glucose, insulin, HOMA, diabetes and metabolic syndrome; a non significant similar trend was seen in men. In both genders, height increased with birth weight, whereas a U-shaped association was found between birth weight and body mass index, waist circumference and body fat percentage. After adjusting for age, smoking status, physical activity and fat mass, an inverse association was found between leptin and birth weight categories: adjusted mean ± standard error 17.3 ± 0.7, 16.2 ± 0.3, 15.6 ± 0.5 and 14.0 ± 0.8 ng/dL for birth weight categories ≤2.5, 2.6–3.5, 3.6–4.0 and >4.0 kg, respectively, in women (p < 0.05) and 9.8 ± 0.8, 9.1 ± 03, 7.8 ± 0.4 and 7.7 ± 0.5 ng/dL in men (p < 0.05). An inverse association was also found between reported birth weight and leptin to fat mass ratio: mean ± standard error 0.77 ± 0.04, 0.73 ± 0.02, 0.69 ± 0.03 and 0.62 ± 0.04 in women (p < 0.05); 0.46 ± 0.05, 0.45 ± 0.02, 0.39 ± 0.02 and 0.38 ± 0.03 in men (p < 0.05). No differences in adiponectin levels were found between birth weight groups. Middle-aged adults born with a low weight present a higher prevalence of diabetes and obesity and also higher leptin levels and leptin to fat mass ratio than adults born with a normal weight. The higher leptin levels and leptin to fat mass ratio among adults born with a low weight might be related to nutritional factors during childhood or to the development of leptin resistance and/or higher leptin production by body fat unit. Subjects born with a low weight should be counselled regarding the risks of developing diabetes and/or cardiovascular disease.
199 citations
TL;DR: There was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated and the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium–glucose cotransporter-2 (SGLT2) inhibitors.
Abstract: A pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterise the CV profile of dapagliflozin. This showed no increase in CV risk with dapagliflozin compared with control (placebo or comparator treatment) with or without background glucose-lowering therapies. The analysis reported here aimed to characterise the CV profile of dapagliflozin in subgroups of patients in these 21 studies grouped by degree of CV risk, based on both baseline and in-study risk factors (including hypoglycaemic events), with a focus on major adverse CV events (MACE). Patients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analysed. A further analysis compared CV risk in patients who experienced a hypoglycaemic event prior to MACE and those who did not. Analyses were based on time to first event using a Cox proportional hazards model stratified by study comparing dapagliflozin versus control. In total, 9339 patients were included in this meta-analysis; 5936 patients received dapagliflozin 2.5–10 mg (6668 patient–years) and 3403 received control (3882 patient–years). Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population [Hazard Ratio (HR) 0.77; 95 % CI (0.54, 1.10) for MACE] and in those with a history of CVD [HR 0.80 (0.53, 1.22)]. These findings were consistent in patients with varying degrees of CV risk, including age, number and type of CVD events in medical history and number of CV risk factors present. Furthermore, there was no increased risk of MACE in patients who experienced a hypoglycaemic event compared with those who did not. There was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated. In addition, the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium–glucose cotransporter-2 (SGLT2) inhibitors.
158 citations
TL;DR: The results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway.
Abstract: Endothelial dysfunction has been suggested as a possible causal link between hyperglycemia and microvascular complications in diabetes mellitus. The effect of metformin on endothelial progenitor cells (EPCs) is still unclear. This study was designed to test the hypothesis that metformin could accelerate wound healing by improving the impaired EPC functions in streptozotocin-induced diabetic mice. Streptozotocin (STZ, 60 mg/kg/d × 5 d, i.p.) was injected to induce type 1 diabetes in male C57BL/6 mice. Mice were treated with metformin (250 mg/kg/d, i.g.) for consecutive 14 days. Wound closure was evaluated by wound area and number of CD31 stained capillaries. Functions of bone marrow-endothelial progenitor cells (BM-EPCs) were assessed by tube formation and migration assays, and expression of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) was determined by western blot analysis. Metformin accelerated wound closure and stimulated angiogenesis in diabetic mice. The number of circulating EPCs was increased significantly in metformin treated diabetic mice. Abilities of tube formation and migration of BM-EPCs were impaired in diabetic mice, which were improved by metformin. Expression of both phosphorylated-AMPK and phosphorylated-eNOS was significantly increased, and nitric oxide (NO) production was enhanced by metformin in BM-EPCs of diabetic mice. In vitro, metformin improved impaired BM-EPC functions, and increased phosphorylated-eNOS expression and NO production in cultured BM-EPCs caused by high glucose, which was prevented by the AMPK inhibitor compound C. Our results suggest that metformin could improve BM-EPC functions in STZ-induced diabetic mice, which was possibly dependent on the AMPK/eNOS pathway.
121 citations
TL;DR: This longitudinal study demonstrated for the first time that baseline Angiopoietin-like protein 8 levels were associated with baseline and future changes in TG levels in Korean children.
Abstract: Previous studies have shown that angiopoietin-like protein 8 (ANGPTL8), also called as betatrophin, acts together with ANGPTL3 to regulate lipid metabolism, glucose metabolism, and energy homeostasis. Moreover, ANGPTL8 promotes proliferation of pancreatic β-cells and induces insulin secretion. However, there are no previous longitudinal studies in humans. We analyzed the age- and sex-matched data of 240 normal weight and overweight Korean children from the Korean Metabolic disorders and Obesity Study in Elementary School children (K-MOSES), a prospective observational cohort study. At baseline, ANGPTL8 concentrations were positively associated with triglycerides (TG) (r = 0.168, P = 0.010), whereas ANGPTL3 levels were associated with fasting insulin (r = 0.248, P < 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.197, P = 0.002). Although both ANGPTL8 and ANGPTL3 levels did not differ between children with normal weight and children with overweight, ANGPTL8 levels were increased in males compared to females (341.2 [267.4–436.5] vs. 270.2 [213.9–378.8] pg/ml, P = 0.001). In particular, there was no significant inter-relationship between circulating ANGPTL8 and ANGPTL3 concentrations in Korean boys and girls (r = −0.073, P = 0.265). Multivariate analysis showed that baseline ANGPTL8 concentrations were independently associated with future changes of serum TG levels in Korean children after adjusting for confounding factors after a 3 year follow-up period (r = −0.165, P = 0.016). This longitudinal study demonstrated for the first time that baseline ANGPTL8 levels were associated with baseline and future changes in TG levels in Korean children.
118 citations
TL;DR: The present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect.
Abstract: The potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes. SHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system. Empagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis. Our present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.
115 citations
TL;DR: Diabetes mellitus significantly alters the expression of vascular endothelial miRs in circulating endothelial MPs with potential implications on vascular heath and in vitro experiments revealed that hyperglycemia reduces the packaging of miR-126 and mi-26a into EMPs.
Abstract: Circulating microRNAs (miRs) are differentially regulated and selectively packaged into microparticles (MPs). We evaluated whether diabetes mellitus alters circulating vascular and endothelial MP-incorporated miRs expression levels. Circulating MPs were isolated from 135 patients with or without diabetes mellitus type II and characterized using flow cytometer and electron microscope. Nine miRs involved in the regulation of vascular performance—miR-126, miR-222, miR-let7d, miR-21, miR-30, miR-92a, miR-139, miR-199a and miR-26a—were quantified in circulating MPs by reverse transcription polymerase chain reaction. Among those, miR-126 and miR-26a were significantly reduced in diabetic patients compared to non-diabetic patients. Patients with low miR-26a and miR-126 levels were at higher risk for a concomitant coronary artery disease. MP-sorting experiments showed that endothelial cells were the major cell sources of MPs containing miR-126 and miR-26a, respectively. Finally, in accordance with our clinical results, in vitro experiments revealed that hyperglycemia reduces the packaging of miR-126 and miR-26a into EMPs. Diabetes mellitus significantly alters the expression of vascular endothelial miRs in circulating endothelial MPs with potential implications on vascular heath.
114 citations
TL;DR: A history of GDM was identified as a risk factor of CVD, especially coronary vascular diseases, within the 7 years postpartum, and a lifestyle changes from post partum onwards can be recommended and supported.
Abstract: The effect of gestational diabetes mellitus (GDM) on cardiovascular diseases (CVD) is not assessed within the first 10 years postpartum, regardless of subsequent diabetes. The aim of this study was to determine the risk of CVD events related to GDM within 7 years of postpartum. This nationwide population-based study of deliveries in 2007 and 2008 with a follow-up of 7 years was based on data from the French medico-administrative database. Two groups were formed: women with a history of GDM and women without GDM or previous diabetes. CVD included angina pectoris, myocardial infarction, stroke, heart bypass surgery, coronary angioplasty, carotid endarterectomy and fibrinolysis. Hypertensive disease was assessed separately. Determinants studied included age, obesity, subsequent diabetes mellitus and hypertensive diseases during pregnancy. Adjusted odds ratios for outcomes were calculated using multiple logistic regressions. The hospital database recorded 1,518,990 deliveries in 2007 and 2008. Among these, 62,958 women had a history of GDM. After adjusting for age, DM, obesity and hypertensive disorders in pregnancy, GDM was significantly associated with a higher risk of CVD (adjusted Odds Ratio aOR = 1.25 [1.09–1.43]). Considering each variable in a separate model, GDM was associated with angina pectoris (aOR = 1.68 [1.29–2.20]), myocardial infarction (aOR = 1.92 [1.36–2.71]) and hypertension (aOR = 2.72 [2.58–2.88]) but not with stroke. A history of GDM was identified as a risk factor of CVD, especially coronary vascular diseases, within the 7 years postpartum. A lifestyle changes from postpartum onwards can be recommended and supported.
112 citations
TL;DR: Acute glucose fluctuation may cause significant oxidative stress and inflammation in endothelial cells, increase the adhesion of monocytes to endothelium cells, and elevate endothelial cell apoptosis, resulting in severe cardiovascular injury.
Abstract: Complications of diabetes mellitus (DM) are related not only to elevated plasma glucose, but also plasma glucose fluctuations. However, the specific mechanism underlying the role of plasma glucose fluctuation in the pathogenesis of DM complications remains poorly understood. In the present study, the influence of acute fluctuant hyperglycemia and persistent hyperglycemia on vascular endothelial cell apoptosis, function, oxidative stress and inflammation was examined in vivo. Rats were assigned to three different groups (n = 10/group) that received 48-h infusions of saline (SAL group), continuous 50 % glucose (constant high glucose group [CHG]), or intermittent 50 % glucose (acute blood glucose fluctuation group [AFG]). Plasma 8-isoprostaglandin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) levels were quantified by using enzyme-linked immunosorbent assay (ELISA) commercial kits. Plasma insulin levels were measured by radioimmunoassays (RIAs) using kits. The aortic segment was collected. The levels of malondialdehyde (MDA) and activity of glutathione peroxidase (GSH-PX) were measured in endothelial homogenates prepared from endothelial cells harvested from the aorta using colorimetric kits. Apoptosis of vascular endothelial cells was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Endothelial dysfunction was assessed by isometric tension recording to evaluate the endothelial function. The expression of B cell lymphoma-2 (Bcl-2), Bcl-2 Associated X protein (Bax), pro caspase-3, caspase-3 p17, 3-nitrotyrosine (3-NT) and p47phox protein in rat aortic endothelial cells were tested with Western blot analysis. Endothelial cells reactive oxygen species (ROS) formation was determined using dihydroethidium-dependent fluorescence microtopography in aortic cryo-sections. Expression of IL-6, TNF-α and ICAM-1 mRNAs in vascular endothelial cells were determined by real-time quantitative PCR. Endothelial cells apoptosis and dysfunction were observed significantly in the aortas of the AFG group (P < 0.05). The AFG had reduced Bcl-2 and pro caspase-3 levels and enhanced Bax mitochondrial translocation and caspase-3 p17 protein levels in comparison with the CHG group (P < 0.05). Both AFG and CHG induced β-cell dysfunction and insulin resistance (P < 0.05). AFG increased MDA and 8-isoprostaglandin levels in plasma, oxidative stress in vascular endothelial cells, and inflammatory cytokines in plasma and vascular endothelial cells (P < 0.05). Acute glucose fluctuation may cause significant oxidative stress and inflammation in endothelial cells, increase the adhesion of monocytes to endothelial cells, and elevate endothelial cell apoptosis, resulting in severe cardiovascular injury.
102 citations
TL;DR: Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study and shows a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up.
Abstract: Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM. We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naive to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500–3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter. There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months. Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study. Trial Registration ClinicalTrials.gov: NCT01715428.
100 citations
TL;DR: This work reports for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T1D and Mediterranean diet intervention on these associations.
Abstract: Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes.
We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54–0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43–0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63–1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40–0.94; P = 0.024 versus CC) in the multivariable-adjusted model. In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.
TL;DR: In T2DM patients with no history of cardiovascular disease, impaired GLS was associated with cardiovascular events and provided incremental prognostic value and the presence of either a high E/E′ ratio or an impairment GLS provides an excellent negative predictive value of cardiovascular events in these patients.
Abstract: Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular events. The aim of the study was to assess whether global longitudinal strain (GLS) provides prognostic value in these patients. A total of 247 T2DM patients without history of cardiovascular complications and participated in the CDATS study were prospectively enrolled. Left ventricular (LV) systolic function was assessed by LV ejection fraction and speckle tracking derived LV systolic GLS. Diastolic function was assessed by E/E′ ratio defined as the passive trans-mitral LV inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus. Cardiovascular event included acute coronary syndrome, cerebrovascular stroke, hospitalization for heart failure and cardiovascular death. A total of 18 cardiovascular events occurred during a median follow-up duration of 33 months. Both E/E′ ratio [hazard ratio (HR) 1.15, P 13.6 or GLS > −17.9 % were associated with cardiovascular events. The presence of either a high E/E′ ratio or an impaired GLS provides an excellent negative predictive value of cardiovascular events in these patients. In T2DM patients with no history of cardiovascular disease, impaired GLS was associated with cardiovascular events and provided incremental prognostic value.
TL;DR: A pro-inflammatory stimulus like IL1β transforms excess glucose into a vascular deleterious agent by causing an increase in glucose uptake and its subsequent diversion into the PPP, promoting the pro-oxidant conditions required for the exacerbation of pro- oxidant and pro- inflammatory pathways.
Abstract: Hyperglycemia is acknowledged as a pro-inflammatory condition and a major cause of vascular damage. Nevertheless, we have previously described that high glucose only promotes inflammation in human vascular cells previously primed with pro-inflammatory stimuli, such as the cytokine interleukin (IL)1β. Here, we aimed to identify the cellular mechanisms by which high glucose exacerbates the vascular inflammation induced by IL1β. Cultured human aortic smooth muscle cells (HASMC) and isolated rat mesenteric microvessels were treated with IL1β in medium containing 5.5–22 mmol/L glucose. Glucose uptake and consumption, lactate production, GLUT1 levels, NADPH oxidase activity and inflammatory signalling (nuclear factor-κB activation and inducible nitric oxide synthase expression) were measured in HASMC, while endothelium-dependent relaxations to acetylcholine were determined in rat microvessels. Pharmacological inhibition of IL1 receptors, NADPH oxidase and glucose-6-phosphate dehydrogenase (G6PD), as well as silencing of G6PD, were also performed. Moreover, the pentose phosphate pathway (PPP) activity and the levels of reduced glutathione were determined. We found that excess glucose uptake in HASMC cultured in 22 mM glucose only occurred following activation with IL1β. However, the simple entry of glucose was not enough to be deleterious since over-expression of the glucose transporter GLUT1 or increased glucose uptake following inhibition of mitochondrial respiration by sodium azide was not sufficient to trigger inflammatory mechanisms. In fact, besides allowing glucose entry, IL1β activated the PPP, thus permitting some of the excess glucose to be metabolized via this route. This in turn led to an over-activation NADPH oxidase, resulting in increased generation of free radicals and the subsequent downstream pro-inflammatory signalling. Moreover, in rat mesenteric microvessels high glucose incubation enhanced the endothelial dysfunction induced by IL1β by a mechanism which was abrogated by the inhibition of the PPP. A pro-inflammatory stimulus like IL1β transforms excess glucose into a vascular deleterious agent by causing an increase in glucose uptake and its subsequent diversion into the PPP, promoting the pro-oxidant conditions required for the exacerbation of pro-oxidant and pro-inflammatory pathways. We propose that over-activation of the PPP is a crucial mechanism for the vascular damage associated to hyperglycemia.
TL;DR: The German Diabetes Study is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease and aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities.
Abstract: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.
TL;DR: Among patients with CAD, omentin-1 expression was lower in EAT surrounding coronary segments with stenosis than those without stenosis, in terms of mRNA and protein, whereas adiponectin mRNA level in E AT did not seem to differ between stenotic and non-stenotic coronary segments in CAD patients.
Abstract: Omentin-1, a novel adipocytokine mainly expressed in visceral adipose tissue, has been found to inhibit the inflammatory response and improve insulin resistance as well as other obesity-related disorders. This study investigated the association between omentin-1 expression in human epicardial adipose tissue (EAT) and coronary atherosclerosis. Serum samples, and paired biopsies from EAT and subcutaneous adipose tissue (SAT), were obtained from patients with and without coronary artery disease (CAD, n = 28 and NCAD, n = 12, respectively) during elective cardiac surgery. Coronary angiography was performed to identify CAD presence. Serum omentin-1 and adiponectin levels were measured by ELISA. mRNA expression of omentin-1 and adiponectin was detected in adipose tissue by quantitative real-time PCR, and omentin-1 protein expression was evaluated by immunohistochemistry. Correlation and multivariate linear regression analyses were performed to determine the association between omentin-1 expression and clinical risk factors. mRNA and protein expression of omentin-1 were higher in EAT than paired SAT in patients with CAD and NCAD. Compared with NCAD patients, CAD patients had lower omentin-1 and adiponectin mRNA levels in EAT and serum levels as well as lower omentin-1 protein levels. Among patients with CAD, omentin-1 expression was lower in EAT surrounding coronary segments with stenosis than those without stenosis, in terms of mRNA and protein, whereas adiponectin mRNA level in EAT did not seem to differ between stenotic and non-stenotic coronary segments in CAD patients. In multivariate linear regression analysis, CAD was an independent predictor of EAT omentin-1 mRNA expression (beta = −0.57, 95 % CI −0.89 to −0.24; P = 0.001) and serum omentin-1 levels (beta = −0.35, 95 % CI −0.67 to −0.03; P = 0.036). Circulating and EAT-derived omentin-1 levels were reduced in patients with CAD. Omentin-1 expression in patients with CAD was lower in EAT adjacent to coronary stenotic segments than non-stenotic segments.
TL;DR: ApoE gene polymorphisms associate with CVD and affect the lipid profile, with E3/E4 genotype associated with significantly higher levels of TC and non HDL-C in all groups and in both T2DM and CVD patients.
Abstract: Lipoprotein-related mechanisms have been associated with damage to the cardiovascular system in diabetic patients. Apolipoprotein E gene which affects the clearance of lipoproteins and consequently the lipid profile in our body is one of the most studied candidate genes and recently has been reported to be associated with T2DM and CAD. In this work, we studied the association of apoE gene polymorphism with T2DM and CVD and its effect on plasma lipids profile. Our study was conducted on 284 subjects categorized into 100 patients with T2DM, 100 patients with T2DM complicated with CVD and 84 normal control subjects. ApoE gene polymorphism was genotyped by real-time PCR using TaqMan® SNP Genotyping Assay. ApoE E3/E3 genotype was the most common in our subjects. The frequencies of E3/E4 genotype and e4 allele were increased in both T2DM patients and CVD patients as compared with controls, but were significant only in CVD patients (p = 0.004 and 0.007, respectively). Diabetic patients who carried E3/E4 genotype were at 2.4-fold increased risk to develop CVD (95 % CI 1.14–5.19, P = 0.02) and the e4 allele associated with 2.23-fold higher CVD risk (95 % CI 1.09–4.59, P = 0.02). After adjustment for other established risk factors, E3/E4 genotype was an independent risk factor for CVD (OR = 2.3, p = 0.009) but not for T2DM (OR = 1.7, p = 0.28), while e4 allele was an independent risk factor for both T2DM (OR = 2.2, p = 0.04) and CVD (OR = 3.0, p = 0.018) with 5.9-fold increased risk to develop CVD in T2DM patients (p = 0.019). E3/E4 genotype associated with significantly higher levels of TC and non HDL-C in all groups and with significantly higher levels of LDL-C in both T2DM and CVD patients. ApoE gene polymorphisms associate with CVD and affect the lipid profile. The e4 allele is an independent risk factor for both T2DM and CVD. Further genetic studies to add information beyond the traditional cardiovascular risk factors in T2DM and to identify risk genotypes will help in early prediction and identification of at risk patients.
TL;DR: Greater mitochondrial DNA damage was found in patients with diabetes mellitus and clinical atherosclerosis, which may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.
Abstract: Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease. We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function. We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.
TL;DR: EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability and was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD.
Abstract: Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD). We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group. EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD. Clinical Trial Registration UMIN Registry number: UMIN000011265 (
https://www.upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013200&language=E
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TL;DR: Glucose-related hyperosmolarity seems to be able to promote angiogenesis and retinopathy through activation of TonEBP and possibly increasing expression of AQP1 and COX-2.
Abstract: We tested the hypothesis that glucose-induced hyperosmolarity, occurring in diabetic hyperglycemia, promotes retinal angiogenesis, and that interference with osmolarity signaling ameliorates excessive angiogenesis and retinopathy in vitro and in vivo. We incubated human aortic (HAECs) and dermal microvascular endothelial cells (HMVECs) with glucose or mannitol for 24 h and tested them for protein levels and in vitro angiogenesis. We used the Ins2 Akita mice as a model of type 1 diabetes to test the in vivo relevance of in vitro observations. Compared to incubations with normal (5 mmol/L) glucose concentrations, cells exposed to both high glucose and high mannitol (at 30.5 or 50.5 mmol/L) increased expression of the water channel aquaporin-1 (AQP1) and cyclooxygenase (COX)-2. This was preceded by increased activity of the osmolarity-sensitive transcription factor Tonicity enhancer binding protein (TonEBP), and enhanced endothelial migration and tubulization in Matrigel, reverted by treatment with AQP1 and TonEBP siRNA. Retinas of Ins2 Akita mice showed increased levels of AQP1 and COX-2, as well as angiogenesis, all reverted by AQP1 siRNA intravitreal injections. Glucose-related hyperosmolarity seems to be able to promote angiogenesis and retinopathy through activation of TonEBP and possibly increasing expression of AQP1 and COX-2. Osmolarity signaling may be a target for therapy.
TL;DR: The findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease.
Abstract: Aims/hypothesis: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. Methods: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. Results: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32–1.93, p < 0.001 and OR 1.54, 95 % CI 1.21– 1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29–2.174, p < 0.001 and HR 1.47, 95 % CI 1.13–1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. Conclusions/Interpretations: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.
The George Institute for Global Health1, Johns Hopkins University2, Monash University, Clayton campus3, University of Sydney4, Université de Montréal5, University of Melbourne6, National Institutes of Health7, National Institute for Health Research8, French Institute of Health and Medical Research9, Paris Diderot University10
TL;DR: Lower-extremeity ulceration or amputation, and peripheral revascularization both increased the risks of death and cardiovascular events, but only lower-extremity ulcers or amputations increased the risk of severe retinopathy in patients with type 2 diabetes.
Abstract: Peripheral arterial disease (PAD) is known to be associated with high cardiovascular risk, but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes. We aimed to evaluate the impact of major PAD, and its different presentations, on the 10-year risk of death, major macrovascular events, and major clinical microvascular events in these patients. Participants in the action in diabetes and vascular disease: PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery. Among 11,140 participants, 516 (4.6 %) had major PAD at baseline: 300 (2.7 %) had lower-extremity ulceration or amputation alone, 190 (1.7 %) had peripheral revascularization alone, and 26 (0.2 %) had both presentations. All-cause mortality, major macrovascular events, and major clinical microvascular events occurred in 2265 (20.3 %), 2166 (19.4 %), and 807 (7.2 %) participants, respectively. Compared to those without PAD, patients with major PAD had increased rates of all-cause mortality (HR 1.35, 95 % CI 1.15–1.60, p = 0.0004), and major macrovascular events (1.47 [1.23–1.75], p < 0.0001), after multiple adjustments for region of origin, cardiovascular risk factors and treatments, peripheral neuropathy markers, and randomized treatments. We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [1.31 (0.96–1.78), p = 0.09]. These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization. Furthermore, the risk of retinal photocoagulation or blindness, but not renal events, increased in patients with lower-extremity ulceration or amputation [1.53 (1.01–2.30), p = 0.04]. Lower-extremity ulceration or amputation, and peripheral revascularization both increased the risks of death and cardiovascular events, but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes. Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes (ClinicalTrials.gov number, NCT00949286).
TL;DR: Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet.
Abstract: We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study. In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m2; diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records. Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen’s d = −1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), −2.3 (−5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed. Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet. Trial registration: ClinicalTrials.gov NCT00435240
TL;DR: Glucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185.
Abstract: Intracellular antioxidant response to high glucose is mediated by Cu/Mn-superoxide dismutases (SOD-1/SOD-2), catalase (CAT) and glutathione peroxidases (GPx), particularly glutathione peroxidase-1 (GPx-1). Although oscillating glucose can induce a more deleterious effect than high glucose on endothelial cells, the mechanism by which oscillating glucose exerts its dangerous effects is incompletely understood; however, the involvement of oxidative damage has been generally accepted. In this study we sought to determine whether oscillating glucose differentially modulates antioxidant response, and to elucidate the potential regulatory mechanisms exerted by the microRNA-185 (miR-185). Human endothelial cells were exposed for 1 week to constant and oscillating high glucose. SOD-1, SOD-2, CAT and GPx-1, as well as two markers of oxidative stress [8-hydroxy-2′-deoxyguanosine (8-OHdG) and the phosphorylated form of H2AX (γ-H2AX)] were measured at the end of the experiment. Intracellular miR-185 was measured and loss-of function assays were performed in HUVEC. Bioinformatic tool was used to predict the link between miR-185 on 3′UTR of GPx-1 gene. Luciferase assay was performed to confirm the binding on HUVEC. After exposure to constant high glucose SOD-1 and GPx-1 increased, while in oscillating glucose SOD-1 increased and GPx-1 did not. SOD-2 and CAT remained unchanged under both conditions. A critical involvement of oscillating glucose-induced miR-185 in the dysregulation of endogenous GPx-1 was found. Computational analyses predict GPx-1 as miR-185′s target. HUVEC cultures were used to confirm glucose’s causal role on the expression of miR-185, its target mRNA and protein and finally the activation of antioxidant response. In vitro luciferase assays confirmed computational predictions targeting of miR-185 on 3′-UTR of GPx-1 mRNA. Knockdown of miR-185, using anti-miR-185 inhibitor, was accompanied by a significant upregulation of GPx-1 in oscillating glucose. 8-OHdG and γ-H2AX increased more in oscillating glucose than in constant high glucose. Glucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185.
TL;DR: These findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.
Abstract: High fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined. Mesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction. Vasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice. TNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.
TL;DR: It is suggested that dulaglutide does not increase the risk of major CV events in T2D patients.
Abstract: Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D. This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata. The analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all). These results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide.
TL;DR: This review focuses on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.
Abstract: Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.
TL;DR: Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening, and longitudinal follow-up in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension.
Abstract: Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease. We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters. 199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0–12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging. Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls. Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different. Mitral valve lateral e’ (17.6 ± 2.6 vs. 18.6 ± 2.6 cm/s; p < 0.001) and a’ (5.4 ± 1.1 vs. 5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e’ (7.3 ± 1.2 vs. 6.7 ± 1.3; p = 0.0003) increased in T1D. Left ventricular mid circumferential strain (−20.4 ± 2.3 vs. −19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (−19.0 ± 1.9 vs. −19.8 ± 1.5 % p < 0.001) in T1D. Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening. Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.
TL;DR: The role and potential mechanisms of CCL4 and one of its major receptors, fifth CC chemokine receptor (CCR5), in DM and cardiovascular diseases are provided.
Abstract: Chemokines are critical components in pathology. The roles of chemokine CC motif ligand 4 (CCL4) and its receptor are associated with diabetes mellitus (DM) and atherosclerosis cardiovascular diseases. However, due to the complexity of these diseases, the specific effects of CCL4 remain unclear, although recent reports have suggested that multiple pathways are related to CCL4. In this review, we provide an overview of the role and potential mechanisms of CCL4 and one of its major receptors, fifth CC chemokine receptor (CCR5), in DM and cardiovascular diseases. CCL4-related mechanisms, including CCL4 and CCR5, might provide potential therapeutic targets in DM and/or atherosclerosis cardiovascular diseases.
TL;DR: Non-smokers have a statistically significant lower HbA1c and more favourable lipid profile compared to smokers and smoking cessation does not lead to an increase in Hb a1c in long-term and may reduce vascular complications in diabetes by its favourable impact on lipid profile.
Abstract: Smoking is associated with increased macrovascular and microvascular complications in people with diabetes. In addition to other concomitant vascular perturbations, it also seems to influence the cardiometabolic parameters, which may partly explain the accelerated rate of vascular complications in smokers with diabetes. While smoking cessation is advocated as a universal component of the management of diabetes, there is some anecdotal evidence that HbA1c could increase following smoking cessation. The aim of this review is to explore the relationship between smoking and its cessation on cardiometabolic parameters in diabetes. Searches were conducted on Medline, EMBASE and CINAHL up to March 2016. After screening 6866 studies (Additional file 1), 14 observational studies with a total of 98,978 participants’ with either type 1 or type 2 diabetes were selected for review. Narrative synthesis and meta-analyses were carried out to explore the relationship between smoking and its cessation. Meta-analysis showed that the pooled mean difference of HbA1c between non-smokers and smokers was −0.61% (95% CI −0.88 to −0.33, p < 0.0001). The difference in LDL cholesterol between non-smokers and smokers was −0.11 mmol/l (95% CI −0.21 to −0.01, p = 0.04). The difference in HDL cholesterol between non-smokers and smokers was 0.12 mmol/l (95% CI 0.08–0.15, p < 0.001). However, there was no statistically significant difference in blood pressure between the two groups. The difference in HbA1c between quitters and continued smokers was not statistically significant −0.10% (95% CI −0.42 to 0.21, p = 0.53). However, a narrative synthesis revealed that over a period of 10 years, the HbA1c was comparable between non-smokers and quitters. Non-smokers have a statistically significant lower HbA1c and more favourable lipid profile compared to smokers. Smoking cessation does not lead to an increase in HbA1c in long-term and may reduce vascular complications in diabetes by its favourable impact on lipid profile.
TL;DR: Data from this study suggest a greater association of CAVI and baPWV values with MetS components in males than in females and indicate greater arterial stiffness in the event of simultaneously elevated blood pressure, fasting plasma glucose, and waist circumference.
Abstract: The cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV) can reflect both central and peripheral arterial stiffness. Metabolic syndrome (MetS) and its components may increase arterial stiffness and the risk of cardiovascular diseases. However, the correlation of MetS and its components with arterial stiffness is still not clear. The primary aim of this study is thus the relationship using baPWV and CAVI in Caucasian adults with intermediate cardiovascular risk. The secondary aim is to analyze sex differences. This study analyzed 2351 subjects aged 35–74 years (mean, 61.4 ± 7.7 years) comprising 61.7 % males and enrolled in the improving interMediAte Risk management (MARK) study. CAVI was measured using a VaSera VS-1500
®
device, and baPWV was calculated using a validated equation. MetS was defined based on the Joint Scientific Statement National Cholesterol Education Program III. Waist circumference, blood pressure, fasting plasma glucose, and lipid profile were measured. MetS was found in 51.9 % of the subjects. All MetS components except reduced HDL-cholesterol (p = 0.578) were associated with CAVI. High density lipoprotein cholesterol (p = 0.075) and waist circumference (p = 0.315) were associated with baPWV. The different MetS components that assess dyslipidemia using the stiffness measures show different associations according to patient sex. The high blood pressure component had a greater odds ratio (OR) for both baPWV ≥ 17.5 m/sec (OR = 6.90, 95 % CI 3.52–13.519) and CAVI ≥ 9 (OR = 2.20, 95 % CI 1.63–1.90). MetS and all its components (except HDL-cholesterol with baPWV and CAVI and WC with baPWV) were associated with baPWV and CAVI. However, there were sex differences in the association of MetS and its components with baPWV and CAVI. Data from this study suggest a greater association of CAVI and baPWV values with MetS components in males than in females and indicate greater arterial stiffness in the event of simultaneously elevated blood pressure, fasting plasma glucose, and waist circumference. Trial Registration Clinical Trials.gov Identifier: https://clinicaltrials.gov/ct2/show/
NCT01428934. Registered 2 September 2011. Last updated September 8, 2016