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Aims/hypothesis There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA 1c and the risks of vascular complications and death in such patients. Methods Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA 1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA 1c decile were estimated using Cox models. Possible differences in the association between HbA 1c and risks at different levels of HbA 1c were explored using linear spline models. Results There was a non-linear relationship between mean HbA 1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA 1c studied (5.5–10.5%), there was evidence of ‘thresholds’, such that below HbA 1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p  > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA 1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p  < 0.0001). Conclusions/interpretation In patients with type 2 diabetes, HbA 1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm. Trial Registration: ClinicalTrial.gov NCT00145925 Funding: Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281)

Studies have demonstrated the adverse effects of smoking on the risk of microvascular complications; however, few have also examined the potential mediating effects of glycemic control. Using data from the Diabetes Control and Complications Trial (DCCT 1983-1993), we describe the acute and long-term risks of smoking on glycemic control and microvascular complications in a well-characterized cohort of participants with type 1 diabetes. The DCCT recorded self-reported smoking behaviors, glycemic exposure based on HbA1c, and complications status. Generalized linear mixed models were used to assess whether time-dependent measurements of smoking predict HbA1c levels. Cox proportional hazard models were used to assess time-dependent smoking exposures as predictors of retinopathy and nephropathy. During a mean of 6.5 years of follow-up, current smokers had consistently higher HbA1c values and were at a higher risk of retinopathy and nephropathy compared with former and never smokers. These risk differences were attenuated after adjusting for HbA1c suggesting that the negative association of smoking on glycemic control is partially responsible for the adverse association of smoking on the risk of complications in type 1 diabetes. These findings support the potential for a beneficial effect of smoking cessation on complications in type 1 diabetes.

Aims/hypothesis Downregulation of levels of endothelial progenitor cells (EPCs) during in-vitro short-term exposure to high glucose concentrations relates to reduced activity of silent information regulator 1 (SIRT1) and increased synthesis of platelet-activating factor (PAF). We investigated the possible relationship between PAF and SIRT1 pathways in EPCs during altered glucose homeostasis. Methods SIRT1 and PAF receptor (PAF-R) levels were determined by western blot, RT-PCR and confocal laser-scanning microscopy. In-vivo experiments were performed on 48 type 2 diabetic patients (25 with poor glycaemic control and 23 with good glycaemic control) and 20 control individuals. In-vitro experiments with the PAF-R antagonist CV3988 were performed on EPCs isolated from leucocyte-rich buffy coat of healthy human donors. Results Decreased SIRT1 protein levels were observed in EPCs from type 2 diabetic patients compared with control individuals ( p  < 0.01). Notably, the SIRT1 level was consistently lower in patients with poor glycaemic control than in those with good glycaemic control ( p  < 0.01). Diabetic patients also showed an upregulation of PAF-Rs; this response occurred to a greater extent in individuals with poor glycaemic control than in those with good glycaemic control. In-vitro experiments confirmed that EPCs respond to PAF stimulation with decreased SIRT1 protein and SIRT1 mRNA levels. Moreover, reduction of SIRT1 levels and activity were abolished by CV3988. Conclusions/interpretation These findings unveil a link between PAF and SIRT1 pathways in EPCs that contributes to the deleterious effect of hyperglycaemia on the functional properties of EPCs, crucial in diabetes and peripheral vascular complications.

Diabetic patients with acute myocardial infarction (MI) have higher mortality than nondiabetic patients. The purpose of this study was to examine if larger infarct size explains the higher mortality in diabetic patients with acute ST-segment-elevation MI. In the CORE trial (n = 2948), subsets of patients underwent quantitative radionuclide measurement of technetium Tc 99m sestamibi infarct size (n = 1164) or gated equilibrium left ventricular ejection fraction (LVEF) (n = 1137) at days 6 to 16 after thrombolytic therapy. Clinical follow-up was 96.7% complete at 6 months. The prevalence of diabetes in these patient imaging subsets was 16% to 17%. Higher risk clinical characteristics including older age and a greater prevalence of prior MI were more common in diabetic patients. Median infarct size was larger in diabetic patients (22% vs 17% of the left ventricle, P = .04), a difference that remained significant after adjustment for clinical variables ( P = .048). Patients with diabetes also had lower median LVEF (48% vs 51%, unadjusted P = .002, adjusted P = .007). Six-month mortality was higher in diabetic patients: infarct size subset, 5.9% vs 1.6% ( P = .0016); LVEF subset, 6.1% vs 1.0% ( P < .0001). Multivariable models demonstrated that diabetes and each imaging variable were independent predictors of mortality. Infarct size is modestly larger and LVEF modestly lower in diabetic patients with ST-segment-elevation MI. The substantially higher (4- to 6-fold) mortality rate in diabetic vs nondiabetic patients is only partially explained by relatively small differences in infarct size and LVEF.

The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. The randomized cohort was 63.1 ± 9.1 years old and 29% female, with a median diabetes duration of 10.2 ± 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 ± 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 ± 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 ± 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD.

Chronic vascular inflammation may play a role in the development of macrovascular complications in diabetic patients. In this study, we examine the association of endothelial expression of two inflammatory mediators, receptor for advanced glycation end product (RAGE) and monocyte chemoattractant protein-1 (MCP-1), with type 2 diabetes using novel endothelial biopsy and RT-PCR techniques. Endothelial samples are obtained from the aorta of 12 patients with type 2 diabetes and 23 control subjects who underwent cardiac catheterization for chest pain syndrome or heart transplant follow-up. Endothelial cells are purified using magnetic beads with adsorbed CD146 antibody and subjected to RT-PCR analysis of RAGE and MCP-1 transcripts. The association of RAGE and MCP-1 expression with type 2 diabetes is assessed with chi(2) test and confirmed with in vitro experiments on human aorta endothelial cells. RT-PCR reveals gene expression patterns in patient-derived endothelial cells. Strong associations are observed between induction of RAGE mRNA and diabetes (P < 0.01) and between induction of RAGE and MCP-1 transcripts (P < 0.05). Treatment of cultured human aortic endothelial cells with S100b induces the expression of MCP-1 and RAGE transcripts. Endothelial cells can be harvested during cardiac catheterization and can be characterized with respect to molecular phenotypes under the influence of both genetic and environmental factors. Induction of RAGE and MCP-1 transcripts in patients with diabetes supports a role of chronic vascular inflammation in macrovascular complications.

Recommendations Commence screening for microvascular complications at age 11 years (formerly 10 years) Screening for microvascular disease should be performed preconception and during each trimester of pregnancy Screen for lipid abnormalities in the non-fasting state Screen for renal disease by first morning albumin creatinine ratio as the preferred method Recommendations—Screening for and prevention of complications Prevention Intensive education and treatment should be used in children and adolescents to prevent or delay the onset and progression of vascular complications. E Because of potential worsening of retinopathy for patients with longstanding poor glycemic control when control is rapidly improved, ophthalmological monitoring is recommended before initiation of intensive treatment and at three monthly intervals for 6 to 12 months thereafter, particularly if retinopathy is moderate non-proliferative stage or worse at the time of intensification. Screening methods Risk factors Nephropathy 11 years with 2-5 years diabetes duration Urinary albumin/creatinine ratio Hyperglycaemia High BP Lipid abnormalities Smoking Retinopathy 11 years with 2-5 years diabetes duration Fundal photography or mydriatic ophthalmoscopy Hyperglycemia High BP Lipid abnormalities Higher BMI Neuropathy 11 years with 2-5 years diabetes duration History Physical examination Clinical tests Hyperglycemia Higher BMI Age Diabetes duration Genetics Macrovascular disease 11 years with 2-5 years diabetes duration Lipid profile every 2 years, BP annually Hyperglycemia High BP Lipid abnormalities Higher BMI Smoking Other ocular conditions A comprehensive initial eye examination should also be considered to detect cataracts, major refractive errors, or other ocular disorders. B Recommended threshold values for different parameters for intervention and primary prevention of microvascular and CVD in children and adolescents with type 1 diabetes Threshold value Type of intervention BP >90th percentile for age, gender and height Lifestyle intervention: exercise, less screen time and diet BP >90th percentile despite lifestyle intervention ACE inhibitor or other BP lowering agent If microalbuminuria is present: ACE inhibitor or ARB BP >95th percentile for age, gender and height Lifestyle intervention and ACE inhibitor or other BP lowering agent If microalbuminuria is present: ACE inhibitor or ARB LDL cholesterol >2.6 mmol/L (100 mg/dL) Dietary and lifestyle intervention LDL cholesterol >3.4 mmol/L (130 mg/dL) Statins Lipids Screening for dyslipidemia should be performed soon after diagnosis (when diabetes stabilized) in all children with type 1 diabetes from age 11 years E. If normal results are obtained, this should be repeated every 5 years.

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic db/db mice (db/db SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic db/m⁺ mice. The exosomal proteins, rather than RNAs, mostly account for db/db SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in db/db SExos. Silence or overexpression of arginase 1 confirmed its essential role in db/db SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of bloodborne substances that monitor vascular homeostasis.

Background It has been suggested that the use of adjunctive hyperbaric oxygen therapy improves the healing of diabetic foot ulcers, and decreases the risk of lower extremity amputations. A limited number of studies have used a double blind approach to evaluate the efficacy of hyperbaric oxygen therapy in the treatment of diabetic ulcers. The primary aim of this study is to assess the efficacy of hyperbaric oxygen therapy plus standard wound care compared with standard wound care alone in preventing the need for major amputation in patients with diabetes mellitus and chronic ulcers of the lower limb. Methods/Design One hundred and eighteen (59 patients per arm) patients with non-healing diabetic ulcers of the lower limb, referred to the Judy Dan Research and Treatment Centre are being recruited if they are at least 18 years of age, have either Type 1 or 2 diabetes with a Wagner grading of foot lesions 2, 3 or 4 on lower limb not healing for at least 4 weeks. Patients receive hyperbaric oxygen therapy every day for 6 weeks during the treatment phase and are provided ongoing wound care and weekly assessments. Patients are required to return to the study centre every week for an additional 6 weeks of follow-up for wound evaluation and management. The primary outcome is freedom from having, or meeting the criteria for, a major amputation (below knee amputation, or metatarsal level) up to 12 weeks after randomization. The decision to amputate is made by a vascular surgeon. Other outcomes include wound healing, effectiveness, safety, healthcare resource utilization, quality of life, and cost-effectiveness. The study will run for a total of about 3 years. Discussion The results of this study will provide detailed information on the efficacy of hyperbaric oxygen therapy for the treatment of non-healing ulcers of the lower limb. This will be the first double-blind randomized controlled trial for this health technology which evaluates the efficacy of hyperbaric oxygen therapy in prevention of amputations in diabetic patients. Trial registration ClinicalTrials.gov Identifier: NCT00621608

Epidemiologic and clinical data from the last 2 decades have shown that the prevalence of heart failure in diabetes is very high, and the prognosis for patients with heart failure is worse in those with diabetes than in those without diabetes. Experimental data suggest that various mechanisms contribute to the impairment in systolic and diastolic function in patients with diabetes, and there is an increased recognition that these patients develop heart failure independent of the presence of coronary artery disease or its associated risk factors. In addition, current clinical data demonstrated that treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin reduced hospitalization for heart failure in patients with type 2 diabetes mellitus and high cardiovascular risk. This review article summarizes recent data on the prevalence, prognosis, pathophysiology, and therapeutic strategies to treat patients with diabetes and heart failure.