Glycemic risk factors of diabetic vascular complications: the role of glycemic variability.
Zaccardi Francesco,Pitocco Dario,Ghirlanda Giovanni
Diabetes/metabolism research and reviews
Achieving adequate targets relatively to all risk factors is considered a standard of care for patients with diabetes mellitus. To date, current guidelines underline the importance of the 'glucose triad' (post-prandial glucose, fasting plasma glucose and glycated haemoglobin) as the three glycemic factors that should be controlled in diabetes care; however, several literature data show that optimizing glycemic control needs achieving a control of glycemic variations. The objective of the present work is reviewing biological and clinical data supporting the role of glycemic variability, its measurement and relationship with the three other well-known glycemic risk factors and evidencing the areas that need further investigation. At last, we propose a simple model that summarizes the 'glucose triad' plus the 'new' risk factor glycemic variability (the 'Pyramid of the Risk').
Advanced glycation end products and receptor-oxidative stress system in diabetic vascular complications.
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in patients with diabetes mellitus, thus being involved in the development and progression of diabetic micro- and macroangiopathy. Indeed, there is accumulating evidence that an interaction between an AGE and its receptor (RAGE) generates oxidative stress and subsequently evokes vascular inflammation and thrombosis, thereby playing a central role in diabetic vascular complications. In this paper, we review the pathophysiological role of AGE-RAGE-oxidative stress system and its therapeutic interventions in diabetic micro- and macroangiopathy.
Molecular mechanisms of diabetic vascular complications.
Kitada Munehiro,Zhang Zhaoyun,Mima Akira,King George L
Journal of diabetes investigation
Diabetic complications are the major causes of morbidity and mortality in patients with diabetes. Microvascular complications include retinopathy, nephropathy and neuropathy, which are leading causes of blindness, end-stage renal disease and various painful neuropathies; whereas macrovascular complications involve atherosclerosis related diseases, such as coronary artery disease, peripheral vascular disease and stroke. Diabetic complications are the result of interactions among systemic metabolic changes, such as hyperglycemia, local tissue responses to toxic metabolites from glucose metabolism, and genetic and epigenetic modulators. Chronic hyperglycemia is recognized as a major initiator of diabetic complications. Multiple molecular mechanisms have been proposed to mediate hyperglycemia's adverse effects on vascular tissues. These include increased polyol pathway, activation of the diacylglycerol/protein kinase C pathway, increased oxidative stress, overproduction and action of advanced glycation end products, and increased hexosamine pathway. In addition, the alterations of signal transduction pathways induced by hyperglycemia or toxic metabolites can also lead to cellular dysfunctions and damage vascular tissues by altering gene expression and protein function. Less studied than the toxic mechanisms, hyperglycemia might also inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, platelet-derived growth factor and activated protein C, which play important roles in maintaining vascular homeostasis. Thus, effective therapies for diabetic complications need to inhibit mechanisms induced by hyperglycemia's toxic effects and also enhance the endogenous protective factors. The present review summarizes these multiple biochemical pathways activated by hyperglycemia and the potential therapeutic interventions that might prevent diabetic complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00018.x, 2010).
The role of vascular endothelial growth factor in the progression of diabetic vascular complications.
Mahdy R A,Nada W M,Hadhoud K M,El-Tarhony S A
Eye (London, England)
PURPOSE:This study was planned to study the relationship between vascular endothelial growth factor (VEGF) as an angiogenic factor and different micro- and macrovascular complications in type II diabetic patients and look for a possible role of control on the serum level of VEGF. METHODS:The study included 55 type II diabetic patients, 10 of them were not complicated with any of the vascular complications of type II diabetes mellitus (DM) (group 1), 21 patients had microvascular complication either retinopathy, nephropathy, or neuropathy (group 2), 14 patients had macrovascular complications either coronary artery disease or peripheral vascular disease (group 3), and 10 patients with mixed micro- and microvascular complications (group 4), as well as 15 healthy subjects served as control group. All subjects were subjected to complete clinical examination, including fundus examination, proper investigations with stress on electrocardiography, electromyography, nerve conduction velocity, Doppler study of the peripheral arteries, and laboratory investigations such as complete blood count, liver function test, serum creatinine, 24-h urinary albumin excretion, lipid profile, fasting and 2-h postprandial blood glucose, glycosylated haemoglobin (HbA(1c)), and serum VEGF. RESULTS:The study revealed that there was a highly significant increase in the serum VEGF in the diabetic patients compared with the control group. The P-value (P<0.001) was detected and there was also a highly significant increase in the serum VEGF in the patients with different micro- and macrovascular diabetic complications compared with uncomplicated diabetic group (P<0.001). A highly significant increase in the serum VEGF in diabetic patients with proliferative diabetic retinopathy was detected compared with non-proliferative diabetic retinopathy (40.55±8.28 vs20.3±2.45, P<0.001) and in diabetic nephropathic patients with macroalbuminuria compared with those with microalbuminuria (36.14±6.99 vs19.42±2.44, P<0.001). The reduction of the serum VEGF in a group of diabetic patients with poor control when their diabetic state was corrected through 4 months follow-up was highly significant (17.29±1.61 before vs9.39±0.82 after control P<0.001), as well as the reduction of the serum VEGF, which was observed in a group of patients with proliferative diabetic retinopathy (PDR) when proper pan retinal photocoagulation (PRP) was applied to their retinae with 4 months follow-up (40.55±8.28 before vs21.15±1.76 after PRP, P<0.001). On the other hand, the impact of some clinical and laboratory parameters of our diabetic patients on the serum VEGF revealed significant positive correlations between serum VEGF and age of the patients, duration of diabetes, systolic and diastolic blood pressure, body mass index, fasting and 2-h postprandial blood glucose, HbA(1c), serum creatinine, degree of albuminuria and total cholesterol, LDL, and platelet count. CONCLUSION:Serum VEGF was significantly increased in diabetic patients especially with micro- and macrovascular complications and the proper control of diabetes reduced the elevation of serum VEGF in uncontrolled diabetic patients, and in patients with PDR with proper PRP, indicating that VEGF is an angiogenic factor that reflects the degree of neovascularization in diabetic complications.
New perspectives on diabetic vascular complications: the loss of endogenous protective factors induced by hyperglycemia.
Jeong In-Kyung,King George L
Diabetes & metabolism journal
Diabetic vascular complications are among the leading causes of morbidity and mortality in diabetic patients. In the past, many studies have focused on the mechanisms of hyperglycemia-induced chronic vascular complications via the formation of toxic metabolites such as oxidative stress, advanced glycosylated end products, persistent activation of protein kinase C, and increased sorbitol concentrations. However, vascular complications result from imbalances caused by increases in systemic toxic metabolites, such as those that occur under conditions of hyperglycemia and dyslipidemia, and by reductions in endogenous protective factors such as insulin, vascular endothelial growth factor, and platelet derived growth factor. This review outlines some of the evidence supporting the importance of enhancing endogenous regenerative factors.
Epigenetic mechanisms in diabetic vascular complications.
Reddy Marpadga A,Natarajan Rama
There has been a rapid increase in the incidence of diabetes as well the associated vascular complications. Both genetic and environmental factors have been implicated in these pathologies. Increasing evidence suggests that epigenetic factors play a key role in the complex interplay between genes and the environment. Actions of major pathological mediators of diabetes and its complications such as hyperglycaemia, oxidant stress, and inflammatory factors can lead to dysregulated epigenetic mechanisms that affect chromatin structure and gene expression. Furthermore, persistence of this altered state of the epigenome may be the underlying mechanism contributing to a 'metabolic memory' that results in chronic inflammation and vascular dysfunction in diabetes even after achieving glycaemic control. Further examination of epigenetic mechanisms by also taking advantage of recently developed next-generation sequencing technologies can provide novel insights into the pathology of diabetes and its complications and lead to the discovery of much needed new drug targets for these diseases. In this review, we highlight the role of epigenetics in diabetes and its vascular complications, and recent technological advances that have significantly accelerated the field.
Controlling the receptor for advanced glycation end-products to conquer diabetic vascular complications.
Yamamoto Yasuhiko,Yamamoto Hiroshi
Journal of diabetes investigation
Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long-term diabetes. Extensive intracellular and extracellular formation of advanced glycation end-products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00191.x, 2012).
Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications.
Murea Mariana,Ma Lijun,Freedman Barry I
The review of diabetic studies : RDS
Faced with a global epidemic of type 2 diabetes (T2D), it is critical that researchers improve our understanding of the pathogenesis of T2D and related vascular complications. These findings may ultimately lead to novel treatment options for disease prevention or delaying progression. Two major paradigms jointly underlie the development of T2D and related coronary artery disease, diabetic nephropathy, and diabetic retinopathy. These paradigms include the genetic risk variants and behavioral/environmental factors. This article systematically reviews the literature supporting genetic determinants in the pathogenesis of T2D and diabetic vasculopathy, and the functional implications of these gene variants on the regulation of beta-cell function and glucose homeostasis. We update the discovery of diabetes and diabetic vasculopathy risk variants, and describe the genetic technologies that have uncovered them. Also, genomic linkage between obesity and T2D is discussed. There is a complementary role for behavioral and environmental factors modulating the genetic susceptibility and diabetes risk. Epidemiological and clinical data demonstrating the effects of behavioral and novel environmental exposures on disease expression are reviewed. Finally, a succinct overview of recent landmark clinical trials addressing glycemic control and its impact on rates of vascular complications is presented. It is expected that novel strategies to exploit the gene- and exposure-related underpinnings of T2D will soon result.
Is HbA1c a risk factor for type 2 diabetic subjects without macro and micro vascular complications?
Bhaktha Geetha,Nayak B Shivananda,Mayya Sreemathi,Shantaram Manjula
Archives of physiology and biochemistry
OBJECTIVE:Our study attempted to evaluate the diagnostic value of HbA1c in predicting diabetic dyslipidemia and cardiovascular diseases (CVD). METHODS:Study comprised 229 subjects (156 males and 73 females) with diabetic dyslipidemia without any micro and macro vascular disorders. Fasting blood samples were taken to analyse biochemical parameters like HbA1c, sugar and lipid profile. RESULTS:The HbA1c levels did not differ much between males (6.96 ± 1.11) and females (7.01 ± 1.19). HbA1c demonstrated a positive significant correlation with cholesterol, LDL and a negative significant correlation with HDL. Patients with HbA1c >7.0% had significantly higher value of cholesterol, LDL when compared with <7.0%. CONCLUSIONS:The findings of this study clearly suggest that HbA1c endures the ability of predicting CVD risk in the diabetic patients without any micro and macro vascular disorder. Therefore study recommends using HbA1c as a marker for predicting the risk of developing CVD.
Role of platelet indices, glycemic control and hs-CRP in pathogenesis of vascular complications in type-2 diabetic patients.
Jabeen Farah,Fawwad Asher,Rizvi Husan Afroz,Alvi Faraz
Pakistan journal of medical sciences
OBJECTIVES:Alteration in platelet morphology and functions are associated with pathological processes and increased risk of vascular complications in patients with diabetes. The purpose of the study was to find the correlation between platelet indices with fasting blood glucose, HbA1c and hs-CRP level in pathogenesis of vascular complications in type 2 diabetic patients. METHODOLOGY:The study has been carried out on 51 Type 2 Diabetics and 55 age and sex matched healthy control subjects. Fasting blood glucose (FBG), Glycosylated hemoglobin (HbA1c), high sensitivity C- reactive protein (hs-CRP) level and platelet indices including Platelet count (PLT), Plateletcrit (PCT), Mean platelet volume (MPV), Platelet distribution width (PDW) were estimated and compared with normal subjects. The results were evaluated statistically. RESULTS:The study demonstrated that FBG, HbA1c, MPV, PDW and hs-CRP were statistically higher in diabetics in comparison with control subjects (P is less than 0.05). Positive correlation of FBG with HbA1c (r is equal to 0.993, P is equal to 0.0001), PLT with PCT (r is equal to 0.922, P is equal to 0.0001) and MPV with PDW (r is equal to 0.332, P is equal to 0.024) was found in diabetics. CONCLUSION:The poor glycemic control is positively correlated with high HbA1c level. The increased values of MPV, PDW and elevated hs-CRP level may also serve as confirmatory test in finding risk of developing complications.
Vascular complications and changes in body mass index in Japanese type 2 diabetic patients with abdominal obesity.
Nagao Hirofumi,Kashine Susumu,Nishizawa Hitoshi,Okada Takuya,Kimura Takekazu,Hirata Ayumu,Fukuda Shiro,Kozawa Junji,Maeda Norikazu,Kitamura Tetsuhiro,Yasuda Tetsuyuki,Okita Kohei,Hibuse Toshiyuki,Tsugawa Mamiko,Imagawa Akihisa,Funahashi Tohru,Shimomura Iichiro
BACKGROUND:Although many Asian type 2 diabetic patients have been considered to be not obese and have low capacity of insulin secretion, the proportion of obese patients with visceral fat accumulation has increased in recent years. We found previously considerable number of Japanese non-obese subjects (body mass index (BMI) < 25 kg/m²) with visceral fat accumulation and multiple cardiovascular risk factors. The aim of the study was to investigate the difference in clinical features of type 2 diabetic patients with and without visceral fat accumulation, focusing on vascular complications and changes in BMI. METHODS:We enrolled 88 Japanese hospitalized type 2 diabetic patients. Abdominal obesity represented waist circumference (WC) of ≥85 cm for males and ≥90 cm for females (corresponding to visceral fat area of 100 cm²). Subjects were divided into two groups; with or without abdominal obesity. RESULTS:Hypertension, dyslipidemia and cardiovascular diseases were significantly more in the patients with abdominal obesity. The prevalence of cardiovascular disease in the non-obese patients (BMI < 25 kg/m²) with abdominal obesity were similar in obese patients (BMI ≥25 kg/m²). The mean BMI of the patients with abdominal obesity was < 25 kg/m² at 20 years of age, but reached maximum to more than 30 kg/m² in the course. Furthermore, substantial portion of the type 2 diabetic patients (52% in males and 43% in females) were not obese at 20 year-old (BMI < 25 kg/m²), but developed abdominal obesity by the time of admission. CONCLUSION:These results emphasize the need to control multiple risk factors and prevent atherosclerotic disease in patients with abdominal obesity. The significant weight gain after 20 years of age in patients with abdominal obesity stresses the importance of lifestyle modification in younger generation, to prevent potential development of type 2 diabetes and future atherosclerotic cardiovascular disease.
Plasminogen activator inhibitor-1 (PAI-1) in children and adolescents with type 1 diabetes mellitus: relation to diabetic micro-vascular complications and carotid intima media thickness.
Adly Amira Abdel Moneam,Elbarbary Nancy Samir,Ismail Eman Abdel Rahman,Hassan Samar Reda
Journal of diabetes and its complications
BACKGROUND:Plasminogen activator inhibitor-1 (PAI-1) is a fast-acting inhibitor of fibrinolysis that has been linked to increase risk of thrombosis. We determined PAI-1 levels in 80 children and adolescents with type 1 diabetes (T1DM) compared with 40 healthy controls as a potential marker for micro-vascular complications and assessed the relation to carotid intima media thickness (CIMT) as a synergistic risk factor for development of atherosclerosis. METHODS:Patients were divided into 2 groups according to micro-vascular complications. Hemoglobin A1c (HbA1c), urinary albumin excretion, fasting serum lipid profile and PAI-1 levels were measured. CIMT of the common carotid artery was assessed using high resolution ultrasonography. RESULTS:PAI-1 levels were significantly elevated in the group with diabetes compared with control group (p<0.001). PAI-1 levels were also increased in patients with micro-vascular complications compared with those without (p<0.001). CIMT was significantly higher in patients, particularly those with micro-vascular complications than patients without complications or controls (p<0.001). Positive correlations were found between PAI-1 levels and random blood glucose, HbA1c, triglycerides, total cholesterol and CIMT (p<0.05). CONCLUSIONS:Increased plasma PAI-1 may be involved in the state of hypofibrinolysis in patients with T1DM leading to the occurrence of micro-vascular complications and increased risk of atherosclerosis.
Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications.
Chawla Diwesh,Bansal Savita,Banerjee Basu Dev,Madhu Sri Venkata,Kalra Om Prakash,Tripathi Ashok Kumar
AIMS:Vascular complications are the major causes of morbidity and mortality in diabetic subjects. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) induces signal transduction that culminates in vascular complications. Therefore, in the present study we investigated the dependence of RAGE expression on circulating AGEs and evaluated the outcome of AGE-RAGE interaction by the oxidative stress and nature of vascular complications in type 2 diabetes mellitus (T2DM) patients. METHODS:RAGE expression was determined by quantitative real-time PCR and western blotting, serum AGEs were estimated by ELISA and spectrofluorometry and oxidative stress markers namely protein carbonyl (PCO), advanced oxidation protein products (AOPP) and lipid peroxidation (MDA) were assayed spectrophotometerically in 75 T2DM patients (DM without vascular complication n=25; DM with microvascular complications n=25; DM with macrovascular complications n=25) and 25 healthy controls. RESULTS:Serum AGE level was significantly higher in diabetic patients having vascular complications as compared to T2DM without complications (p<0.01). RAGE m-RNA expression level in PBMCs assayed by quantitative real time PCR was four times higher in diabetic subjects without vascular complications while DM patients having microvascular and macrovascular complications showed 12 fold and 8 fold higher RAGE m-RNA expression respectively compared to healthy controls. Circulating AGE level showed significant positive correlation with RAGE m-RNA expression and oxidative stress markers. CONCLUSION:AGE-mediated exacerbation of RAGE expression may contribute to oxidative stress generation that plays a key role in pathogenesis of vascular complications in diabetes.
Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications.
Yamagishi Sho-ichi,Fukami Kei,Matsui Takanori
Advanced glycation end products (AGEs) consist of heterogenous group of macroprotein derivatives, which are formed by non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids, and whose process has progressed at an accelerated rate under diabetes. Non-enzymatic glycation and cross-linking of protein alter its structural integrity and function, contributing to the aging of macromolecules. Furthermore, engagement of receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes proliferative, inflammatory, and fibrotic reactions in a variety of cells. Indeed, accumulating evidence has suggested the active involvement of accumulation of AGEs in diabetes-associated disorders such as diabetic microangiopathy, atherosclerotic cardiovascular diseases, Alzheimer's disease and osteoporosis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, gut hormones secreted from the intestine in response to food intake, both of which augment glucose-induced insulin release, suppress glucagon secretion, and slow gastric emptying. Since GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4), inhibition of DPP-4 and/or DPP-4-resistant GLP-1 analogues have been proposed as a potential target for the treatment of diabetes. Recently, DPP-4 has been shown to cleave multiple peptides, and blockade of DPP-4 could exert diverse biological actions in GLP-1- or GIP-independent manner. This article summarizes the crosstalk between AGEs-RAGE axis and DPP-4-incretin system in the development and progression of diabetes-associated disorders and its therapeutic intervention, especially focusing on diabetic vascular complications.
Vascular endothelial growth factor polymorphisms are involved in the late vascular complications in Type II diabetic patients.
Bleda Silvia,De Haro Joaquin,Varela Cesar,Esparza Leticia,Ferruelo Antonio,Acin Francisco
Diabetes & vascular disease research
AIM:To determine the potential genotype differences in the vascular endothelial growth factor (VEGF) gene in diabetic patients, which might explain the difference in terms of the development of clinical vascular complications: great vessels atherosclerosis vs. retinopathy. METHODS:Genotyping of the VEFG gene insertion/deletion -2549, the C-2578A and the G+405C polymorphisms was done in 40 diabetic patients (26 with peripheral artery disease (PAD) and 14 with diabetic retinopathy (DR)). RESULTS:There was a significant increase in the frequency of the VEGF -2549 DD genotype in PAD patients compared with the DR group (34.6 vs. 0; p = 0.016), as well as in the distribution of the VEGF -2549 ID genotype in DR compared with PAD patients (85.7 vs. 38.4; p = 0.005). There was a significant increase in the frequency of the VEGF -2578 CC genotype in the PAD group compared with DR (34.6 vs. 0; p = 0.016), as well as in the VEGF -2578 CA genotype in DR patients compared with PAD (85.7 vs. 34.6; p = 0.002). The VEGF +405 genotype was not associated with diabetic vascular complications. CONCLUSION:This study provides preliminary evidence that VEGF polymorphisms are associated with a differential presentation of diabetic vascular complications.
Regulation of RAGE for attenuating progression of diabetic vascular complications.
Win Myat Thu Thu,Yamamoto Yasuhiko,Munesue Seiichi,Saito Hidehito,Han Dong,Motoyoshi So,Kamal Tarek,Ohara Takuro,Watanabe Takuo,Yamamoto Hiroshi
Experimental diabetes research
Diabetic angiopathy including micro- and macroangiopathy is concerned with high rate of morbidity and mortality in patients with long-standing diabetes. Receptor for advanced glycation end products (RAGE) and its ligands have been considered as important pathogenic triggers for the progression of the vascular injuries in diabetes. The deleterious link between RAGE and diabetic angiopathy has been demonstrated in animal studies. Preventive and therapeutic strategies focusing on RAGE and its ligand axis may be of great importance in relieving diabetic vascular complications and reducing the burden of disease.
Association of endothelial and vascular smooth muscle dysfunction with cardiovascular risk factors, vascular complications, and subclinical carotid atherosclerosis in type 2 diabetic patients.
Kawano Naoya,Emoto Masanori,Mori Katsuhito,Yamazaki Yuko,Urata Hiromi,Tsuchikura Shoko,Motoyama Koka,Morioka Tomoaki,Fukumoto Shinya,Shoji Tetsuo,Koyama Hidenori,Okuno Yasuhisa,Nishizawa Yoshiki,Inaba Masaaki
Journal of atherosclerosis and thrombosis
AIM:Atherosclerosis and arteriosclerosis are mainly caused by the dysfunction of arterial components, namely, vascular endothelial cells, smooth muscle cells, and the extracellular matrix. Endothelial dysfunction is well established as a predictive surrogate marker of cardiovascular events; however, little is known regarding the clinical implications of vascular smooth muscle dysfunction for cardiovascular disease and microangiopathy. In the present study, we aimed to clarify the association of arterial dysfunction with micro-/macroangiopathy and conventional cardiovascular risk factors in 181 type 2 diabetic patients (T2DM; age ± SD, 64 ± 10 years; duration of diabetes, 12 ± 10 years). METHODS:Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) were assessed to evaluate endothelial dysfunction and vascular smooth muscle dysfunction, respectively, by using a novel ultrasound device, UNEXEF18G (Unex Co. Ltd., Japan). RESULTS:The FMD and NMD were 6.4 ± 3.9% and 13.4 ± 6.6%, respectively. No significant differences in FMD were noted between T2DM with and without micro- or macroangiopathy; however, NMD in T2DM patients with micro- and macroangiopathy was significantly lower than that in T2DM patients without angiopathy. NMD decreased with the progression of chronic kidney disease (CKD) stage (p = 0.005), but not FMD (p = 0.071). On multiple regression analysis, significant independent contributors to FMD were age, smoking, systolic blood pressure, glycosylated hemoglobin, and serum total cholesterol, while those for NMD were age, systolic blood pressure, and waist circumference. CONCLUSION:The relationship of vascular complications and cardiovascular risk factors with NMD is different from that with FMD in type 2 diabetic patients.
Association between Fluorescent Advanced Glycation End-Products and Vascular Complications in Type 2 Diabetic Patients.
Guerin-Dubourg Alexis,Cournot Maxime,Planesse Cynthia,Debussche Xavier,Meilhac Olivier,Rondeau Philippe,Bourdon Emmanuel
BioMed research international
Objectives:Diabetes is a major health problem associated with hyperglycemia and chronically increased oxidative stress and enhanced formation of advanced glycation end-products (AGEs). The aim of this study was to determine whether oxidative plasma biomarkers in diabetic patients could be evidenced and associated with vascular complications. Methods:Oxidative stress biomarkers such as thiols, ischemia-modified albumin (IMA), glycated albumin (GA), fructosamine, and AGEs were measured in 75 patients with poorly controlled type 2 diabetes (HbA1c > 7.5%) with (44) or without (31) vascular disease and in 31 nondiabetic controls. Results:Most biomarkers of oxidation and glycation were significantly increased in diabetic patients in comparison with nondiabetics. Fructosamines, GA, IMA, and AGEs were positively correlated and levels of fluorescent AGEs were significantly increased in the plasma from patients presenting vascular complication. Conclusions:These results bring new evidence for the potential interest of glycated albumin, oxidative stress, and glycoxidation parameters in the monitoring of type 2 diabetic patients. Furthermore, it emphasizes fluorescent AGEs as a putative indicator for vascular event prediction in diabetic patients.
Novel insights into DNA methylation and its critical implications in diabetic vascular complications.
Zheng Jia,Cheng Jing,Zhang Qian,Xiao Xinhua
Recent epidemiological and clinical studies have shown that type 2 diabetic patients can develop diabetic vascular complications even after intensive glycaemic control. It has been suggested that this phenomenon could be explained by the hypothesis of 'metabolic memory'. The underlying mechanisms between these enduring effects and the prior hyperglycaemic state are still not well understood. Preliminary studies demonstrate that hyperglycaemia can regulate gene expression by epigenetic modifications, such as DNA methylation, which can persistently exist even after glucose normalization. Increasing evidence shows that epigenetic mechanisms may play a substantial role in the pathophysiology of diabetes and its associated vascular complications, including atherosclerosis, diabetic cardiomyopathy (DCM), nephropathy and retinopathy. In this review, we will examine the growing role of DNA methylation in diabetes and its vascular complications, thus it can provide critical implications for the early prevention of diabetes and its vascular complications.
Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective.
Bellini Stefania,Barutta Federica,Mastrocola Raffaella,Imperatore Luigi,Bruno Graziella,Gruden Gabriella
International journal of molecular sciences
Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective.
The Role of Advanced Glycation End Products in Diabetic Vascular Complications.
Rhee Sang Youl,Kim Young Seol
Diabetes & metabolism journal
In cases of chronic hyperglycemia, advanced glycation end-products (AGEs) are actively produced and accumulated in the circulating blood and various tissues. AGEs also accelerate the expression of receptors for AGEs, and they play an important role in the development of diabetic vascular complications through various mechanisms. Active interventions for glucose and related risk factors may help improve the clinical course of patients by reducing AGEs. This review summarizes recent updates on AGEs that have a significant impact on diabetic vascular complications.
Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden).
Nordwall Maria,Abrahamsson Mariann,Dhir Meryl,Fredrikson Mats,Ludvigsson Johnny,Arnqvist Hans J
OBJECTIVE:HbA1c is strongly related to the development of diabetes complications, but it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of the current study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. RESEARCH DESIGN AND METHODS:A longitudinal observation study followed an unselected population of 451 patients diagnosed with type 1 diabetes during 1983-1987 before the age of 35 years in a region of Southeast Sweden. Retinopathy was evaluated by fundus photography and nephropathy data collected from medical records. HbA1c was measured starting from diagnosis and during the whole follow-up period of 20-24 years. Long-term weighted mean HbA1c was then calculated. Complications were analyzed in relation to HbA1c levels. RESULTS:The incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. CONCLUSIONS:Long-term weighted mean HbA1c, measured from diagnosis, is closely associated with the development of severe complications in type 1 diabetes. Keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years.
Endothelial Glycocalyx as a Shield Against Diabetic Vascular Complications: Involvement of Hyaluronan and Hyaluronidases.
Dogné Sophie,Flamion Bruno,Caron Nathalie
Arteriosclerosis, thrombosis, and vascular biology
The endothelial glycocalyx (EG), which covers the apical surface of the endothelial cells and floats into the lumen of the vessels, is a key player in vascular integrity and cardiovascular homeostasis. The EG is composed of PGs (proteoglycans), glycoproteins, glycolipids, and glycosaminoglycans, in particular hyaluronan (HA). HA seems to be implicated in most of the functions described for EG such as creating a space between blood and the endothelium, controlling vessel permeability, restricting leukocyte and platelet adhesion, and allowing an appropriate endothelial response to flow variation through mechanosensing. The amount of HA in the EG may be regulated by HYAL (hyaluronidase) 1, the most active somatic hyaluronidase. HYAL1 seems enriched in endothelial cells through endocytosis from the bloodstream. The role of the other main somatic hyaluronidase, HYAL2, in the EG is uncertain. Damage to the EG, accompanied by shedding of one or more of its components, is an early sign of various pathologies including diabetes mellitus. Shedding increases the blood or plasma concentration of several EG components, such as HA, heparan sulfate, and syndecan. The plasma levels of these molecules can then be used as sensitive markers of EG degradation. This has been shown in type 1 and type 2 diabetic patients. Recent experimental studies suggest that preserving the size and amount of EG HA in the face of diabetic insults could be a useful novel therapeutic strategy to slow diabetic complications. One way to achieve this goal, as suggested by a murine model of HYAL1 deficiency, may be to inhibit the function of HYAL1. The same approach may succeed in other pathological situations involving endothelial dysfunction and EG damage.
The effects of adiponectin and inflammatory cytokines on diabetic vascular complications in obese and non-obese patients with type 2 diabetes mellitus.
Hong Seong Bin,Lee Jung Jin,Kim So Hun,Suh Young Ju,Han Ju Young,Kim Yong Seong,Nam Moonsuk
Diabetes research and clinical practice
AIMS:To evaluate the associations between inflammatory cytokines and adiponectin and various vascular complications in type 2 diabetes mellitus (T2DM). METHODS:A total of 761 patients with T2DM were divided into a non-obese group and an obese group to enable the effects of obesity and T2DM on vascular complications to be differentiated. The serum levels of circulating inflammatory cytokines, that is, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, total adiponectin, and high molecular weight (HMW) adiponectin were measured, and carotid intima media thickness (IMT), the presence of carotid plaque, and the severities of retinopathy and nephropathy, were assessed. RESULTS:The obese group had significantly lower serum total and HMW adiponectin levels than the non-obese group. In the obese group, serum levels of total and HMW adiponectin, and TNF-α were significantly higher in patients with proliferative retinopathy than in those without retinopathy after adjusting for covariates. In the non-obese group, only IL-6 levels were significantly higher in patients with proliferative retinopathy than in those without. Serum levels of total and HMW adiponectin were significantly higher in patients with macroalbuminuria than in those with normoalbuminuria. No significant difference of three cytokines levels were observed depending on the carotid IMT or the presence of plaque. Logistic regression analysis revealed that serum total adiponectin (OR=1.209, P=0.038), diabetes duration (OR=1.230, P=0.014), and HbA1c (OR=2.359, P=0.006) were significantly associated with proliferative retinopathy in the obese group. CONCLUSION:The study shows total adiponectin may influence proliferative retinopathy in obese patient with T2DM.
Association of serum high-sensitivity C-reactive protein with metabolic control and diabetic chronic vascular complications in patients with type 2 diabetes.
Chuengsamarn Somlak,Rattanamongkolgul Suthee,Sittithumcharee Gunya,Jirawatnotai Siwanon
Diabetes & metabolic syndrome
AIMS:To determine an association between hs-CRP and metabolic control/diabetic chronic vascular complications (DCVCCxs) in the patients with type 2 diabetes (DM). In addition, the possibility of using hs-CRP levels to predict risk of DCVCCxs will also be validated. METHODS:This cohort study randomly enrolled 608 patients with DM during the 2007-2008 study period. We also recorded basic laboratory findings at baseline and at one year, to include fasting plasma glucose, HbA1c, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and hs-CRP. RESULTS:Logistic regressions of odds ratios between hs-CRP and DCVCCxs (coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy) showed significant correlations, except for cerebrovascular disease, as follows 0.2 (0.11-0.38), 0.09 (0.01-0.77), 0.06 (0.02-0.16), 0.31 (0.12-0.82), and 0.17 (0.07-0.43), respectively. Linear regression for changes in hs-CRP were significantly correlated with HbA1c (r=0.38), fasting plasma glucose (r=0.40), triglyceride (r=0.20), low-density lipoprotein cholesterol (r=0.12), and high-density lipoprotein cholesterol (r=-0.12). No correlation was found for total cholesterol (r=0.06). Based on receiver operating characteristic (ROC) analysis, the cut-off points for hs-CRP levels for prediction of DCVCCxs were 2.89, 2.25, 2.10, 2.25, and 2.82mg/L, for coronary arterial disease, cerebrovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy, respectively. CONCLUSIONS:Our data showed that DCVCCxs were associated with hs-CRP in patients with DM. The cut-off point for hs-CRP can be used to predict association with DCVCCxs. Well-controlled metabolic components in diabetic patients, especially HbA1c, fasting plasma glucose, and triglyceride may reduce the level of hs-CRP.
Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.
Moh Mei Chung,Sum Chee Fang,Tavintharan Subramaniam,Pek Sharon Li Ting,Yeoh Lee Ying,Ng Xiaowei,Lee Simon Biing Ming,Tang Wern Ee,Lim Su Chi
Journal of diabetes and its complications
AIMS:This 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). METHODS:Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). RESULTS:Higher 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. CONCLUSIONS:The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.