Prognostic value of endothelial dysfunction in type 1 diabetes mellitus

Patients with diabetes mellitus are at high risk of developing atherosclerosis, associated with higher rates of micro and macro vascular involvement such as coronary artery disease and renal disease. The role of hyperglycemia to induce synthesis of reactive oxygen species by the oxidation of glucose, leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction(ED). The interaction between C-peptide- the connecting segment of pro-insulin-and nitric oxide in vasodilation is also discussed. Therefore, endothelial dysfunction has been identified as an early marker of vascular disorder in type 1 and type 2 diabetes mellitus. In some other diseases, ED has been considered an independent predictor of vascular disease, regardless of the method used. Studies have demonstrated the importance of endothelial dysfunction as an useful tool for identifying the risk of vascular complications in patients with type 1 diabetes mellitus, particularly as regards to renal impairment. The aim of this review is to clarify the prognostic value of endothelial dysfunction as a marker of vascular disease in these subjects.     

Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes

Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET(A) receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance = mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P = NS, P = 0.018 comparing all groups). ET(A) blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects (P = 0.04), suggesting a combined effect of ET(A) blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes.     

2型糖尿病肾病营养不良原因探讨

2型糖尿病肾病（DN）患者常常表现为进行性营养不良。我们进行了以下研究，探讨终末期2型DN患者营养不良的原因。     

Chronic methylglyoxal infusion by minipump causes pancreatic beta-cell dysfunction and induces type 2 diabetes in Sprague-Dawley rats

OBJECTIVE

The incidence of high dietary carbohydrate-induced type 2 diabetes is increasing worldwide. Methylglyoxal (MG) is a reactive glucose metabolite and a major precursor of advanced glycation end products (AGEs). MG levels are elevated in diabetic patients. We investigated the effects of chronic administration of MG on glucose tolerance and β-cell insulin secreting mechanism in 12-week-old male Sprague-Dawley rats.

RESEARCH DESIGN AND METHODS

MG (60 mg/kg/day) or 0.9% saline was administered by continuous infusion with a minipump for 28 days. We performed glucose and insulin tolerance tests and measured adipose tissue glucose uptake and insulin secretion from isolated pancreatic islets. We also used cultured INS-1E cells, a pancreatic β-cell line, for molecular studies. Western blotting, quantitative PCR, immunohistochemistry, and transferase-mediated dUTP nick-end labeling (TUNEL) assay were performed.

RESULTS

In rats treated with MG and MG + l-buthionine sulfoximine (BSO), MG levels were significantly elevated in plasma, pancreas, adipose tissue, and skeletal muscle; fasting plasma glucose was elevated, whereas insulin and glutathione were reduced. These two groups also had impaired glucose tolerance, reduced GLUT-4, phosphoinositide-3-kinase activity, and insulin-stimulated glucose uptake in adipose tissue. In the pancreatic β-cells, MG and MG + BSO reduced insulin secretion, pancreatic duodenal homeobox-1, MafA, GLUT-2, and glucokinase expression; increased C/EBPβ, nuclear factor-κB, MG-induced AGE, N^ε-carboxymeythyllysine, and receptor for AGEs expression; and caused apoptosis. Alagebrium, an MG scavenger and an AGE-breaking compound, attenuated the effects of MG.

CONCLUSIONS

Chronic MG induces biochemical and molecular abnormalities characteristic of type 2 diabetes and is a possible mediator of high carbohydrate-induced type 2 diabetes.Type 2 diabetes is characterized by hyperglycemia, insulin resistance, and progressive decrease in insulin secretion from the pancreas (1). A genetic predisposition has been found in many patients. More recently there has been a staggering increasing in the incidence of type 2 diabetes, many of the cases being reported in children. This explosive increase is attributed to a diet high in carbohydrates, fat, and a sedentary lifestyle (2–6). Oxidative stress is associated with diabetes and has been proposed as one of the causative factors (7,8). An increase in oxidative stress caused the insulin resistance of Zucker obese rats to progress to type 2 diabetes in 1 week (9).Methylglyoxal (MG) is a reactive dicarbonyl metabolite of mainly glucose metabolism (10). MG reacts with proteins to form advanced glycation end products (AGEs) (10,11), which are implicated in the pathogenesis of vascular complications of diabetes (11,12). Plasma MG levels in healthy humans are 1 μmol/L or less and are elevated two- to fourfold in diabetic patients (13,14). Under physiological conditions, the glyoxalase system degrades MG into d-lactate with the help of reduced glutathione (GSH) (10,14) and keeps plasma MG levels at approximately 1 μmol/L or less (13,14). Incubation of vascular smooth muscle cells with 25 mmol/L glucose or fructose for 3 h significantly increases MG production and oxidative stress (15). In vitro incubation of MG with insulin modifies the insulin molecule and impairs insulin-mediated glucose uptake in adipocytes (16). Incubation of cultured L6 muscle cells with MG (2.5 mmol/L) for 30 min impaired insulin signaling (17). However, the in vitro studies cannot establish whether MG is the cause of diabetes or an effect of diabetes.The molecular mechanisms of high dietary carbohydrate-induced type 2 diabetes are not clear. It is possible that high carbohydrate-induced chronic elevation of MG causes cumulative pathologic changes that contribute to the development of insulin resistance and type 2 diabetes. We have recently shown that acute MG (50 mg/kg iv) administered to 12-week-old male Sprague-Dawley (SD) rats caused glucose intolerance and reduced adipose tissue insulin-stimulated glucose uptake (18). Here we report the results of a comprehensive study on the effects of chronically administered MG on in vivo glucose tolerance, adipose tissue glucose uptake and insulin secretion from isolated pancreatic islets, and the underlying molecular mechanisms. We administered MG by continuous infusion with minipump for 28 days, a method used for the first time to administer MG.     

Linkage of calpain 10 to type 2 diabetes: the biological rationale

The follow-up studies to the original report of association of variation at calpain 10 (CAPN10) with type 2 diabetes in the Mexican-American population of Starr County, Texas, encompass a broad range of science. There are association studies on genetic variation at CAPN10 in different human populations over a range of phenotypes related to type 2 diabetes, physiological studies on the biological functions of calpain proteases, and evolutionary studies on CAPN10 and the NIDDM1 region. We review here the studies published to date on CAPN10, as well as the latest findings from positional cloning studies on a number of other complex disorders. Collectively, these studies provide perspective on the challenges of moving from the linkage mapping and positional cloning studies on which we have been focused to an understanding of the biology shaping the relationship of genotype to phenotype at loci influencing susceptibility to complex disorders like type 2 diabetes.     

Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study

Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.     

HIV protease inhibitor ritonavir induces endothelial dysfunction in porcine arteries

Introduction: Although HIV Protease inhibitors significantly reduce the viral load, they may be associated with increased risk of cardiovascular disease. The aim of this study was to investigate the effects of HIV protease inhibitor ritonavir on endothelial cell function. Methods: Porcine carotid arteries were perfusion cultured for 24 hours without or with a clinically relevant dose of 15 μM of ritonavir. Subsequently, vessels were pre-contracted with norepinephrine followed by relaxation with graded doses of acetylcholine. Vessel diameters were determined with video imaging. Rings of vessels were cultured without or with ritonavir for 24 hours and subsequently basal and NADPH induced superoxide levels were determined using lucigenin enhanced chemiluminescence. Immunohistochemical staining for nitrotyrosine was also used to demonstrate oxidative stress. Results: Vessel contraction was reduced from 19 ± 3 % in control vessels (n = 12) to 9.9 ± 2.7% in ritonavir treated vessels (n = 11, P < 0.05). Endothelial dependent relaxation was also significantly reduced by 72%, 62%, and 65% in response to 10⁻⁹, 10⁻⁷, and 10⁻⁵ M concentrations of acetylcholine, respectively, in ritonavir treated vessels compared to controls (P < 0.005). There was a significant 56% increase in basal superoxide production (n = 7, P < 0.02) and a significant 40% increase in superoxide production (n = 8, P < 0.01) with addition of NADPH in vessel rings treated with ritonavir compared to control vessels. Diphenyleneiodonium Chloride (NAD(P)H oxidase inhibitor) and Tiron (cell permeable superoxide scavenger) significantly reduced superoxide production in ritonavir treated vessels. Nitrotyrosine immunoreactivity was increased in ritonavir treated vessels compared to controls. Conclusions: These data demonstrate that HIV protease inhibitor ritonavir causes a significant reduction in endothelium-dependent vasorelaxation in cultured porcine carotid arteries. Ritonavir also significantly increases superoxide levels, which may be resulted from increased NAD(P)H oxidase activity.     

beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms

Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial defect in early or first-phase insulin secretion, followed by a decreasing maximal capacity of glucose to potentiate all nonglucose signals. Last, a defective steady-state and basal insulin secretion develops, leading to complete beta-cell failure requiring insulin treatment. This functional loss exceeds the expected impact of a 20-50% loss of beta-cells reported at autopsy, which has been associated with amyloid deposits. This review summarizes the nature of the amyloid deposition process and its association with disproportionate hyperproinsulinemia. It reviews recent studies in IAPP (islet-amyloid polypeptide, or amylin) transgenic mice developing islet amyloid deposits and hyperglycemia to suggest that the process of amyloid fibril formation impairs function early and leads to beta-cell failure and eventual death. Based on the known association of amyloid deposits and relative hyperproinsulinemia, it is hypothesized that fibril formation begins during impaired glucose tolerance after other factors cause the initial defects in early insulin secretion and insulin action. Thus, the process that leads to beta-cell loss is implicated in the deposition of amyloid and the late unrelenting progressive hyperglycemia now found in all patients despite current therapies.     

Progressive axonal dysfunction precedes development of neuropathy in type 2 diabetes

To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA(1c) levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0-1 [n = 35]), grade 1 (TNS 2-8 [n = 42]), and grade 2/3 (TNS 9-24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA(1c) level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction.     

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

BACKGROUNDType 2 diabetes mellitus (T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia. The mechanisms of diabetes-associated cognitive dysfunction (DACD) have not been fully elucidated to date. Some studies proved lower cerebral blood flow (CBF) in the hippocampus was associated with poor executive function and memory in T2DM. Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor (VEGF) expression and CBF changes in humans and animal models. In this study, we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional (3D) arterial spin labeling (3D-ASL) and VEGF expression in the hippocampus.AIMTo assess the correlation between CBF (measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.METHODSForty Sprague-Dawley male rats were divided into control and T2DM groups. The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM. Cognitive function was assessed using the Morris water maze experiment. The CBF changes were measured by 3D-ASL magnetic resonance imaging. VEGF expression was determined using immunofluorescence. RESULTSThe escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group. The total distance traveled was longer in the T2DM group; also, the platform was crossed fewer times. The percentage of distance in the target zone significantly decreased. CBF decreased in the bilateral hippocampus in the T2DM group. No difference was found between the right CBF value and the left CBF value in the T2DM group. The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value. The escape latency negatively correlated with the CBF value. The number of rats crossing the platform positively correlated with the CBF value. CONCLUSIONLow CBF in the hippocampus and decreased VEGF expression might be crucial in DACD. CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.     

Autoimmune-mediated oxidative stress and endothelial dysfunction: implications of accelerated vascular injury in type I diabetes

The pathogenesis of cardiovascular disease in the setting of type 1 diabetes is not well-defined. The hypothesis that hyperglycemia is largely responsible for vascular endothelial dysfunction, and ultimately atherosclerosis, continues to evolve. However, despite tight glucose control, a subset of patients still develop clinically significant occlusive disease. While the specific mechanisms of persistent vascular injury are not clear, an increasing body of evidence suggests a dysregulated autoimmune response may contribute to the development of vascular injury. That is, the same inflammatory response that is responsible for pancreatic beta-cell destruction may facilitate chronic vascular endothelial injury prior to the onset of hyperglycemia. Herein, we discuss (1) the clinical experience with tight glycemic control and the risk of cardiovascular disease in patients with type 1 diabetes; (2) the cellular mechanisms involved in vascular endothelial injury; and (3) the long-term clinical implications of autoimmune-mediated vascular disease and current treatment strategies.     

2型糖尿病伴勃起功能障碍的相关发病因素探讨

目的:探讨中青年2型糖尿病(T2DM)患者伴发勃起功能障碍(ED)与血管、神经和雄激素等因素的关系,为ED早期防治提供临床依据。方法:53例50岁以下男性T2DM患者按国际勃起功能指数-5(IIEF-5)评分分为ED组(IIEF评分≤21,n=28)和非ED组(NED组)(IIEF评分≥22,n=28),测定两组血脂、血糖、血清总睾酮(TT)、性激素结合蛋白(SHBG)、硫酸脱氢表雄酮(DHEA-S)、计算法游离睾酮(cFT)等指标,检查两组视网膜病变(DR)、大血管病变和周围神经病变(DPN)等并发症,比较两组各指标及并发症的差异。结果:两组年龄、糖尿病病程、体重指数、血压、血脂、血糖水平具有可比性(P>0.05),ED组DR发生率(39.3%)高于NED组(4.0%)(P<0.05),两组TT、DHEA-S、cFT水平及大血管病变和DPN发生率差异均无统计学意义(P>0.05)。结论:T2DM患者伴ED发生与DR关系密切,对合并DR的T2DM患者尤应早期关注其勃起功能。     

Neutrophil antimicrobial peptide alpha-defensin causes endothelial dysfunction in porcine coronary arteries

BACKGROUND: Defensins are cysteine-rich cationic polypeptides released from neutrophils that exhibit powerful antimicrobial activities. Because inflammation, including neutrophil infiltration and release of defensins, may play an important role in atherosclerosis and other vascular diseases, we determined whether alpha-defensin could cause endothelial dysfunction, a major initial event of atherosclerosis, in porcine coronary arteries. METHODS: Porcine coronary arteries were sliced into 5-mm rings and treated with different concentrations of human recombinant alpha-defensin for 24 hours. Vasomotor reactivity was studied by using a myograph system. Levels of superoxide anion were detected by the lucigenin-enhanced chemiluminescence method. Endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein levels were determined by real-time polymerase chain reaction and immunohistochemistry analysis, respectively. RESULTS: Endothelium-dependent relaxation in response to bradykinin was significantly reduced by 40% for the rings treated with 1500 nM of alpha-defensin compared with controls (P< .05). Vessel contractility in response to the thromboxane A2 analogue U46619 and endothelium-independent relaxation in response to sodium nitroprusside were not affected with defensin treatment. In addition, the superoxide anion level at the endothelial layer of porcine coronary artery rings was significantly increased by 80% in the defensin-treated (1500 nM) vessels compared with controls (P< .05). Furthermore, the eNOS mRNA levels in endothelial cells isolated from the cultured rings treated with defensin (1500 nM) were significantly decreased by 27% compared with controls (P< .05). Immunoreactivity of eNOS in the defensin-treated vessel rings was also substantially reduced. CONCLUSIONS: Defensin reduces the endothelium-dependent vasorelaxation. This effect is associated with increased superoxide radical production and decreased eNOS expression in porcine coronary arteries. CLINICAL RELEVANCE: Inflammation is an important mechanism of atherosclerosis and other vascular diseases. The roles and interactions of biomediators released from inflammatory cells are not fully understood, however. This study provides new information about effects and potential molecular mechanisms of a major neutrophil releasing factor, alpha-defensin, on endothelial dysfunction of porcine coronary arteries. Thus, targeting alpha-defensin and its associated molecular mechanisms may become a new strategy to prevent vascular diseases.     

Glutathione supplementation to University of Wisconsin solution causes endothelial dysfunction

INTRODUCTION: Glutathione (GSH) is added to University of Wisconsin (UW) organ preservation solution to protect against oxidative stress. This study assesses the effect of GSH-supplementation on endothelial function in tissues subjected to cold ischaemia and compares its effects to a mono-ethyl ester equivalent (GSH-MEE) and S-nitrosated GSH (GSNO). METHODS: Rat aortic rings were stored for 1 h or 48 h in cold, hypoxic UW solution with or without GSH (3 mM), GSH-MEE (3 mM) or GSNO (100 mciroM) supplementation. Aortic rings were reoxygenated in warm Krebs solution; smooth muscle function was assessed by responses to phenylephrine (PE), and endothelial function by vasodilatation to the endothelium-dependent dilator, acetylcholine (ACh). The protective effects against oxidant-induced endothelial cell death were assessed in cultured human umbilical vein endothelial cells (HUVEC). RESULTS: Supplementation of UW with either GSH or GSH-MEE had no effect on vascular responses to PE, but smooth muscle contraction was significantly attenuated in rings incubated for 48 h with GSNO. Endothelium-dependent relaxation was significantly impaired in tissues stored under hypoxic conditions in GSH, GSH-MEE and GSNO supplemented UW solution for 1 h. However, impairment at 48 h was significantly more pronounced in GSH-treated vessels. Cultured HUVEC death was exacerbated by GSH and GSH-MEE in unstressed cells and in those stressed with a superoxide anion generator. CONCLUSIONS: GSH supplementation of UW solution exacerbates cold-ischaemia induced endothelial dysfunction. GSNO did not share the detrimental effects of GSH and promoted NO-mediated vasodilatation.     

Adipocyte-derived cytokine resistin causes endothelial dysfunction of porcine coronary arteries

OBJECTIVE: Resistin, a novel adipocyte-derived cytokine, is involved in the development of insulin resistance and diabetes mellitus. In this study, we determined whether resistin could affect vasomotor function, oxidative stress, and endothelial nitric oxide synthase (eNOS) expression in porcine coronary arteries. METHODS: Porcine coronary arteries were treated with resistin or antioxidant seleno-L-methionine (SeMet). Vasomotor function was studied by using a myograph system. Levels of superoxide anion (O 2 - ) were detected by the lucigenin-enhanced chemiluminescence method. The eNOS mRNA and protein levels were determined by real-time polymerase chain reaction and immunohistochemistry, respectively. Culture of isolated porcine coronary artery endothelial cells (PCAECs) was also included. RESULTS: Endothelium-dependent relaxation in response to bradykinin was reduced by 15% and 30% for the rings treated with 10 and 40 ng/mL of resistin, respectively, as compared with controls ( P < .05). Endothelium-independent relaxation in response to sodium nitroprusside (SNP) was also reduced by 11% after treatment with 40 ng/mL of resistin ( P < .05). The O 2 - level was increased in the 40 ng/mL resistin-treated vessels by 88% as compared with controls ( P < .05). SeMet reversed these effects. The eNOS mRNA levels in PCAEC cultures treated with resistin (10 and 40 ng/mL) were decreased by 27% and 55%, respectively ( P < .05) and by 39% in the endothelial cells purified from porcine coronary artery rings after treatment with 40 ng/mL of resistin ( P < .05). Immunoreactivity of eNOS in the resistin-treated vessel rings was also substantially reduced. CONCLUSIONS: Resistin reduces the endothelium-dependent and endothelium-independent vasorelaxation. This effect is associated with increased superoxide radical production, decreased eNOS expression, and is effectively reversed by the antioxidant SeMet. CLINICAL RELEVANCE: Obesity has been considered to be an independent risk factor for coronary artery disease and other vascular lesions. Resistin is a newly discovered adipocyte-derived cytokine, and its plasma levels are increased in obese individuals. However, it is not clear whether resistin could directly contribute to vascular disease formation. This study showed that resistin can cause endothelial dysfunction in porcine coronary arteries through oxidative stress and down-regulation of eNOS. Thus, this study may suggest a new mechanism of obesity-associated vascular disease and that antioxidants may effectively prevent vascular disease in obese individuals.     

Vascular dysfunction in diabetes: The endothelial progenitor cells as new therapeutic strategy

The vascular endothelium is a critical determinant of dia- betes-associated vascular complications, and improving endothelial function is an important target for therapy. Diabetes mellitus contributes to endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) play a critical role in maintaining endothelial function and might affect the progression of vascular disease. EPCs are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In diabetes, the circulating EPC count is low and their functionality is impaired. The me- chanisms that underlie this reduced count and impaired functionality are poorly understood. Knowledge of the status of EPCs is critical for assessing the health of the vascular system, and interventions that increase the number of EPCs and restore their angiogenic activity in diabetes may prove to be particularly beneficial. The pre-sent review outlines current thinking on EPCs’ therapeutic potential in endothelial dysfunction in diabetes, as well as evidence-based perspectives regarding their use for vascular regenerative medicine.