Diabetes-related Macrovascular Complications Research Articles

Blood immune cell profiling in adults with longstanding type 1 diabetes is associated with macrovascular complications.

There is increasing evidence for heterogeneity in type 1 diabetes mellitus (T1D): not only the age of onset and disease progression rate differ, but also the risk of complications varies markedly. Consequently, the presence of different disease endotypes has been suggested. Impaired T and B cell responses have been established in newly diagnosed diabetes patients. We hypothesized that deciphering the immune cell profile in peripheral blood of adults with longstanding T1D may help to understand disease heterogeneity. Adult patients with longstanding T1D and healthy controls (HC) were recruited, and their blood immune cell profile was determined using multicolour flow cytometry followed by a machine-learning based elastic-net (EN) classification model. Hierarchical clustering was performed to identify patient-specific immune cell profiles. Results were compared to those obtained in matched healthy control subjects. Hierarchical clustering analysis of flow cytometry data revealed three immune cell composition-based distinct subgroups of individuals: HCs, T1D-group-A and T1D-group-B. In general, T1D patients, as compared to healthy controls, showed a more active immune profile as demonstrated by a higher percentage and absolute number of neutrophils, monocytes, total B cells and activated CD4+CD25+ T cells, while the abundance of regulatory T cells (Treg) was reduced. Patients belonging to T1D-group-A, as compared to T1D-group-B, revealed a more proinflammatory phenotype characterized by a lower percentage of FOXP3+ Treg, higher proportions of CCR4 expressing CD4 and CD8 T cell subsets, monocyte subsets, a lower Treg/conventional Tcell (Tconv) ratio, an increased proinflammatory cytokine (TNFα, IFNγ) and a decreased anti-inflammatory (IL-10) producing potential. Clinically, patients in T1D-group-A had more frequent diabetes-related macrovascular complications. Machine-learning based classification of multiparameter flow cytometry data revealed two distinct immunological profiles in adults with longstanding type 1 diabetes; T1D-group-A and T1D-group-B. T1D-group-A is characterized by a stronger pro-inflammatory profile and is associated with a higher rate of diabetes-related (macro)vascular complications.

Diabetes-Related Macrovascular Complications Are Associated With an Increased Risk of Diabetic Microvascular Complications: A Prospective Study of 1518 Patients With Type 1 Diabetes and 20 802 Patients With Type 2 Diabetes in the UK Biobank.

Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.

Association Between Atrial Fibrillation and Diabetes-Related Complications: A Nationwide Cohort Study.

This study aimed to investigate the associations between concurrent atrial fibrillation and diabetes-related complications among patients with diabetes. This nationwide observational cohort study used the health checkup database from the Korean National Health Insurance Service. Patients diagnosed with diabetes who underwent health checkups between 2009 and 2012 were investigated. The patients with atrial fibrillation were matched in a 1:5 ratio with those without atrial fibrillation using propensity scores. Study outcomes included macrovascular, microvascular (diabetic retinopathy and diabetic nephropathy), and diabetic foot complications. The risks of clinical outcomes were measured using hazard ratios (HRs) with 95% CIs. A total of 65,760 patients with diabetes were analyzed (54,800 without atrial fibrillation and 10,960 with atrial fibrillation). After well-balanced propensity score matching, atrial fibrillation was associated with significantly higher risks of macrovascular complications (HR 1.12, 95% CI 1.09-1.16), diabetic nephropathy (HR 1.23, 95% CI 1.16-1.30), and diabetic foot complications (HR 1.13, 95% CI 1.09-1.17) compared with no atrial fibrillation, while the risk of diabetic retinopathy was comparable (HR 0.99, 95% CI 0.96-1.03). Patients with atrial fibrillation had a significantly higher risk of diabetic foot amputation (HR 4.12, 95% CI 1.98-8.56). Among patients with diabetes, concurrent atrial fibrillation was associated with increased risks for diabetes-related macrovascular complications, diabetic nephropathy, and diabetic foot. Such patients require holistic management to reduce the risk of adverse outcomes.

Associations Between Mean HbA1c, HbA1c Variability, and Both Mortality and Macrovascular Complications in Patients with Diabetes Mellitus: A Registry-Based Cohort Study.

We investigate the association between mean HbA1c, HbA1c variability, and all-cause mortality and diabetes-related macrovascular complications in patients with diabetes. We performed a retrospective cohort study using patients present in the Singapore Health Services diabetes registry (SDR) during 2013 to 2014. We assessed mean HbA1c using three models: a baseline mean HbA1c for 2013-14, the mean across the whole follow-up period, and a time-varying yearly updated mean. We assessed HbA1c variability at baseline using the patient's HbA1c variability score (HVS) for 2013-14. The association between mean HbA1c, HVS, and 6 outcomes were assessed using Cox proportional hazard models. We included 43,837-53,934 individuals in the analysis; 99.3% had type 2 diabetes mellitus. The data showed a J-shaped distribution in adjusted hazard ratios (HRs) for all-cause mortality, ischemic heart disease, acute myocardial infarction, peripheral arterial disease, and ischemic stroke, with an increased risk of developing these outcomes at HbA1c <6% (42 mmol/mol) and ≥8% (64 mmol/mol). With the addition of HVS, the J-shaped distribution was maintained for the above outcomes, but HRs were greater at HbA1c <6.0% (42 mmol/mol) and reduced at HbA1c ≥8.0% (64 mmol/mol) when compared to models without HVS. The risk for all outcomes increased substantially with increasing glycaemic variability. Both low (<6.0% [42 mmol/mol]) and high (≥8.0% [64 mmol/mol]) levels of glycaemic control are associated with increased all-cause mortality and diabetes-related macrovascular complications. Glycaemic variability is independently associated with increased risk for these outcomes. Therefore, patients with stable glycaemic level of 6-8% (42-64mmol/mol) are at lowest risk of all-cause mortality and diabetes-related macrovascular complications.

A 48-month Prospective Study of the Effects of Multifactorial Interventions on Cardiovascular Risk Factors in Patients with Type 2 Diabetes Mellitus in an Urban Community: The Beijing Communities Diabetes Study 12

Objective: To assess whether multifactorial interventions have long-term effects on the risk of diabetes-related macrovascular complications in patients with type 2 diabetes mellitus living in urban communities of Beijing. Design, setting and participants: A total of 2926 patients with type 2 diabetes from 15 community health centers were divided into a diabetes mellitus (DM) group (n=824), a hypertension (HTN) group (n=1267), and a cardiovascular disease (CVD) group (n=835). By applying Framingham risk scores (FRS), patients in the 3 groups were subdivided into low (FRS 20%) Framingham risk strata. After 48 months, patients were followed-up to assess the long-term effects of the multifactorial interventions. Results: At baseline, the patients’ mean neck circumference (NC) was significantly higher in the HTN and CVD groups than in the DM group (P<0.05). After 48 months of follow-up, the CVD and HTN groups both had higher blood pressures and lipid levels than the DM group (both P<0.01). Although there was no significant change in the FRS versus baseline in the low and medium Framingham risk strata, a significant reduction in FRS was noted in the high Framingham risk strata. In Cox multivariate analyses, the HTN and CVD groups had higher incidences of endpoint events than the DM group. Conclusions: This study has demonstrated for the first time a relationship between NC and CVD in diabetic patients. Multifactorial interventions for CVD risk factors over 48 months lowered the estimated 10-year risk for CVD events in diabetes. FRS score influences the incidence of CVD events in diabetic patients. Aggressive risk reduction should be focused on these individuals who had high FRS score.

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore

AimsThis study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). MethodsPlasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). ResultsHigher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid–femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle–brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=−7.925, p=0.009), and ABI (B=−142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103−3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175−0.919). However, SPARC was not independently associated with chronic kidney disease. ConclusionsThe anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.

The effects of glycemic control on malondialdehyde modified low-density-lipoprotein-immunglobulin G levels in type 2 diabetics

Objective: The aim of this study is investigation of effect of glycemic control on the levels of malondialdehyde-low-density-lipoprotein-immunglobulin G (MDA-LDL-IgG) which is supposed to be positively correlated with myocardial infarction risk in subjects with type 2 diabetes mellitus (DM). Material and Method: We evaluated the levels of glucose, triglyceride, total cholesterol, high-density-lipoprotein-cholesterol (HDL-C), low-density-lipoprotein-cholesterol (LDL-C), hemoglobin A1c (A1C) and MDA-LDL-IgG in subjects with well-controlled DM (W-DM, 7% HbA1c, n=22) and in non-diabetics (Non-DM, n=15). Results: There were no significant differences between P-DM and W-DM groups for triglyceride, total cholesterol and LDL-C levels but these tests were significantly low in the Non-DM group compared to other groups (respectively, p=0.002, p<0.001 and p=0.001). There was no significant difference between W-DM and Non-DM groups for MDA-LDL-IgG levels, but in P-DM group they were significantly higher compared to W-DM and Non-DM (p=0.002). There was a positive correlation between A1C andMDA-LDL-IgG levels (r=0.463, p= p=0.001). Conclusion: These findings suggest that the normalization of blood glucose levels in type 2 diabetics may persuade the reduced rate of the formation of new antigenic epitopes on the LDL via non-enzymatic glycosylation. The regulation of diabetes may be improved by reducing antibody formation against the MDA-LDL although there is no effect on lipid levels. A1C may not only be a good indicator of blood glucose control but also a good predictor for diabetes-related macro vascular complications.

Improvement of β-cell function ameliorated glycemic variability in patients with newly diagnosed type 2 diabetes after short-term continuous subcutaneous insulin infusion or in combination with sitagliptin treatment: a randomized control trial.

Glycemic variability (GV) has been proposed as contributor to diabetes-related macrovascular complications. This randomized control trial evaluated a new combination therapy with continuous subcutaneous insulin infusion (CSII) plus sitagliptin (CSII + sitagliptin) vs. CSII only in terms of metabolic control, GV and β-cell function in patients with newly diagnosed type 2 diabetes (T2DM). 217 patients were randomized to two weeks of CSII (n = 108) or CSII + sitagliptin (n = 109) therapy. As a measure of GV, the coefficient of variation (CV) was computed from capillary blood glucose during the first and second week, respectively. β-cell function before and after treatment was determined with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). Good metabolic controls were established with both therapies. CSII + sitagliptin therapy resulted in greater improvements in CV and ISSI-2 than CSII alone (all P = 0.000). For each group, change in CV was inversely correlated with change in ISSI-2 (r = -0.529, P = 0.000 and r = -0.433, P = 0.000, respectively). The multivariate regression analysis demonstrated that improved ISSI-2 was the only independent contributor to reduced CV in both groups (standardized β = -0.388, P = 0.004 and standardized β = -0.472, P = 0.000, respectively). Correction of β-cell function in newly diagnosed T2DM patients via use of either CSII or CSII + sitagliptin therapy was feasible in controlling GV to prevent secondary complications of T2DM. Moreover, CSII + sitagliptin therapy was superior to CSII monotherapy in terms of GV.

Exploring Mechanisms of Diabetes-Related Macrovascular Complications: Role of Methylglyoxal, a Metabolite of Glucose on Regulation of Vascular Contractility

Methylglyoxal (MGO) is a metabolite of glucose. MGO binds to and modifies arginine, lysine, and cysteine residues in proteins, which leads to formation of a variety of advanced glycation end-products (AGEs) such as argpyrimidine and Nε-(carboxyethyl)lysine. The concentration of MGO significantly increases in plasma from diabetic patients. Increased plasma MGO level seems to be associated with diabetic microvascular complications. In addition, MGO accumulates in large vascular tissues from spontaneous hypertensive rats, which is associated with increased blood pressure. Although it is logical to hypothesize that MGO could directly affect vascular reactivity, available reports are very limited. Our group has examined effects of MGO on vascular reactivity (contraction and relaxation) and explored underlying mechanisms. In this review article, we summarized our recent findings on 1) short-term effects of MGO, 2) long-term effects of MGO, and 3) effects of MGO accumulation in arterial walls on vascular reactivity. These findings may provide further mechanistic insights into the pathogenesis of diabetes-related macrovascular complications including hypertension.

Methylglyoxal Accumulation in Arterial Walls Causes Vascular Contractile Dysfunction in Spontaneously Hypertensive Rats

Methylglyoxal (MGO) is a metabolite of glucose and perhaps mediates diabetes-related macrovascular complications including hypertension. In the present study, we examined if MGO accumulation affects vascular reactivity of isolated mesenteric artery from spontaneously hypertensive rats (SHR). Five-week-old SHR were treated with an MGO scavenger, aminoguanidine (AG), for 5 weeks. AG partially normalized increased blood pressure in SHR. In mesenteric artery from SHR treated with AG, increased accumulation of MGO-derived advanced glycation end-products was reversed. In mesenteric artery from SHR, AG normalized impaired acetylcholine (ACh)-induced relaxation and increased angiotensin (Ang) II-induced contraction. Reactive oxygen species (ROS) production increased in SHR mesenteric artery, and acute treatment with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor augmented ACh-induced relaxation. Protein expression of NOX1 and Ang II type 2 receptor (AT2R) increased in SHR mesenteric artery, which was normalized by AG. Acute treatment with an AT2R blocker but not a NOX inhibitor normalized the increased Ang II-induced contraction in SHR mesenteric artery. The present results demonstrate that MGO accumulation in mesenteric artery may mediate development of hypertension in SHR at least in part via increased ROS-mediated impairment of endothelium-dependent relaxation and AT2R-mediated increased Ang II contraction.

C-reactive protein, its role in inflammation, Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones.

Increased concentrations of the marker of inflammation, C-reactive protein (CRP), are associated with insulin resistance, Type 2 diabetes and the development of cardiovascular disease. In particular, inflammation is closely associated with endothelial dysfunction and is recognized as one of the cardiovascular risk factors clustering in the Insulin Resistance Syndrome or Metabolic Syndrome. The exact mechanisms linking insulin resistance and inflammation remain unclear. However, the close association between insulin resistance and inflammation in atherogenesis suggests that therapies that address both parameters may have benefits in reducing diabetes-related macrovascular complications. The thiazolidinedione class of oral anti-diabetic agents are powerful insulin sensitizers that also have anti-inflammatory properties. Treatment with these agents has a range of anti-atherogenic effects, including reduced levels of CRP, plasminogen activator inhibitor-1 (PAI-1), TNF-alpha and reactive oxygen species. Additionally, the insulin-sensitizing effect of thiazolidinediones improves other factors of the Insulin Resistance Syndrome, including dyslipidaemia and hypertension. Outcome studies are underway to determine if the effects of improving insulin sensitivity and reducing inflammation will translate into clinical benefits and reduce the cardiovascular morbidity and mortality associated with insulin resistance and Type 2 diabetes.

Reduction of cardiovascular morbidity and mortality in type 2 diabetes. A rational approach to hypoglycemic therapy.

Type 2 diabetes mellitus is the single most important risk factor for the development of coronary artery disease. Unfortunately, the traditional therapeutic strategies for the treatment of hyperglycemia have proven to be ineffective in preventing cardiovascular complications. In recent years the number of available hypoglycemic agents has increased and considerable progress has been made regarding the comprehension of the pathophysiology of diabetes and its vascular complications. In the present article we firstly present benefits and risks of intensive vs standard hypoglycemic intervention, and the pros and cons of therapy targeted to postprandial hyperglycemia. Secondly, we discuss the cardiovascular effects of sulfonylurea agents and insulin, focusing on the role of intensive insulin treatment in the context of acute coronary syndromes. Thirdly, we review the epidemiological, clinical and experimental evidence linking insulin resistance and cardiovascular disease. Finally, we present the rationale and the role of metformin and thiazolidinedionetherapy in the prevention of cardiovascular complications. We conclude that the optimal use of the full spectrum of hypoglycemic agents has the potential to play a key role in the prevention of diabetes-related macrovascular complications.