WITHDRAWN: Expression of p53, p63, and p73 isoforms in squamous cell carcinoma and adenocarcinoma of esophagus☆,☆☆

Diabetic microangiopathy is often observed in diabetic patients, but there is little evidence regarding the relationship between post-prandial glycemia or insulinemia and the incidence of diabetic microangiopathy. In this study, to elucidate the relationship between post-prandial glycemia (or insulinemia) and diabetic microangiopathy, we performed a cross-sectional study of 232 subjects with type 2 diabetes mellitus who were not being treated with insulin injections. A multiple regression analysis showed that post-prandial hyperglycemia independently correlated with the incidence of diabetic retinopathy and neuropathy. Post-prandial hyperglycemia also correlated, although not independently, with the incidence of diabetic nephropathy. In addition, interestingly, post-prandial hypoinsulinemia independently correlated with the incidence of diabetic retinopathy, although not correlated with diabetic neuropathy or nephropathy. In conclusion, post-prandial hyperglycemia, rather than fasting glycemia or hemoglobin A1c levels, is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients.     

Alteration of endothelin-1 concentration in STZ-induced diabetic rat nephropathy. Effects of a PGI(2) derivative

BACKGROUND: Recently, an endothelin (ET-1) with a potent vasoconstrictive activity and stimulative activity of vascular muscular cell growth was discovered and blood ET-1 levels were higher in diabetic patients than in healthy subjects, suggesting that high ET-1 levels assist development and progression of diabetic microangiography. METHODS: We examined renal function, and serum and tissue ET-1 levels in streptozotocin (STZ)-induced diabetic rats treated with a prostaglandin (PG) I(2) derivative to investigate the effect of PGI(2) in diabetic vascular disturbance. RESULTS: Renal weight, urinary albumin, urinary N-acetyl-beta,D-glucosaminidase (NAG) and serum ET-1 levels increased in STZ-induced diabetic rats, and a tendency to increase in renal tissue ET-1 levels was observed. Furthermore, electron-microscopic findings in the kidneys showed mesangial cell proliferation and mesangial matrix expansion which might be caused by diabetic nephropathy. The PGI(2) derivative reduced urinary albumin and NAG levels in STZ-induced rats. It was considered, therefore, that the PGI(2) derivative is effective in diabetic nephropathy. As the PGI(2) derivative also reduced renal tissue ET-1 levels, improvement of diabetic nephropathy partially was considered to result from the reduction of renal tissue ET-1 levels. CONCLUSION: In STZ-induced rats, increased serum ET-1 levels and a tendency to increase in renal tissue ET-1 levels were associated with increases in urinary albumin and NAG levels, and these levels were decreased by a PGI(2) derivative. These findings suggested that increased ET-1 concentrations assist development and progression of diabetic nephropathy, especially diabetic microangiopathy, and the PGI(2) derivative may be effective for inhibition of diabetic microangiopathy mediated by reduction of ET-1 concentrations.     

Severe diabetic microangiopathy with normal glucose tolerance and pituitary infarction.

Blood glucose concentrations in a woman with severe retinopathy, nephropathy, and neuropathy were found to be within the normal range. A high random blood glucose concentration was recorded only once, six months before her initial presentation. At necropsy the anterior lobe of the pituitary gland showed old, extensive infarction. Occult pituitary hypofunction may explain severe diabetic microangiopathy in patients with normal glucose tolerance.     

The role of endothelin-1 and nitric oxide in the pathogenesis of hypertension in diabetic patients

The pathogenesis of renal hypertension has not yet been fully clarified. As the potential role of endothelin-1 (ET-1) and nitric oxide (NO) has been postulated, their concentrations were determined in plasma and urine of diabetic patients. The study included 30 diabetic patients (both IDDM and NIDDM) with initial or advanced diabetic nephropathy (decreased endogenous creatinine clearance, proteinuria) and 20 healthy control subjects. The correlation with blood pressure and other renal function parameters was monitored and compared with the control group. Also, the effect of ACE inhibitors (ACEI) on ET-1 and NO patterns was monitored in correlation with arterial hypertension. In diabetic patients that did not receive ACEI therapy, the increase in plasma ET-1 was associated with both systolic and diastolic blood pressure elevation, whereas in those administered ACEI the increase in plasma ET-1 was associated with a systolic blood pressure decline. In addition, the increase in plasma NO was accompanied by a statistically significant decline of both systolic and diastolic blood pressure in diabetic patients receiving ACEI.     

Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The pathogenesis of DPN is complex and involves an intertwined array of mechanisms. The purposes of this study were to evaluate the association of oxidative stress and vascular risk factors with the prevalence of DPN and to determine the role of these biochemical parameters in the prognosis of DPN. One hundred patients with type 2 diabetes mellitus and 40 clinically healthy individuals were evaluated. The patients were divided into two groups. Group 1 included 40 diabetic patients without peripheral neuropathy, and group 2 consisted of 60 patients with DPN. Erythrocytes glutathione (GSH) level, plasma malondialdehyde (MDA), nitrite/nitrate (NOx) and homocysteine (Hcy) levels as well as serum ceruloplasmin (Cp), total antioxidants (TAO), endothelin-1 (ET-1) levels and γ-glutamyl transferase (GGT) activity were estimated. A significant decrease of erythrocyte GSH was observed in groups 1 and 2 relative to the controls. An increase in glycosylated haemoglobin (HbA1c), MDA, NOx, GGT, Cp, TAO, Hcy and ET-1 was noted in patients with DPN. In conclusion, oxidative stress biomarkers and vascular risk factors could be important in the pathogenesis of DPN. The measurement of serum GGT and Hcy in addition to HbA1c and disease duration could facilitate the early detection of neuropathy in diabetic patients.     

Treatment of renal failure from diabetic nephropathy with cadaveric homograft

We report two patients with terminal renal failure secondary to diabetic nephropathy treated with cadaveric kidney transplantation. Neither of these patients had peripheral vascular disease or peripheral neuropathy. There was a proliferative diabetic retinopathy with hemorrhages and exudates in one patient and only background diabetic changes in the ocular fundi of the other; there have been no significant changes in visual acuity or retinopathy in either patient following the transplantation. Both have good kidney function after 8 and 15 months and are completely rehabilitated.The requirement for insulin decreased in both patients during the period of renal insufficiency and increased following transplantation; this seemed to be related to the large dose of steroids given because now that a maintenance level of steroids has been established, both patients require the same dosage of insulin as they did before the onset of renal insufficiency.     

Advanced glycation end-products and the progress of diabetic vascular complications

Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently.     

Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin

The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats.     

Elevated levels of endothelin-1 and prostaglandin E2 and their effect on nitric oxide generation in placental tissue from neonatal streptozotocin-induced diabetic rats

Endothelin-1 (ET-1), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) are regulators of feto-placental hemodynamics. In this study we explore the inter-regulatory pathways that modulate the levels of these vasoactive agents in control and neonatal streptozotocin-induced (n-stz) diabetic rat placenta. ET-1 levels are increased in diabetic placenta when compared to controls (P<0.001), and are strongly reduced by an NO synthase inhibitor (P<0.001). PGE(2) production is increased in diabetic placenta when compared to controls (P<0.01), but these levels are not modulated by ET-1. NO levels, similar in control and in diabetic placenta, are not influenced by PGE(2), but they are negatively modulated by ET-1 in both control (P<0.05) and diabetic (P<0.01) placenta. We conclude that rat placental ET-1 inhibits NO levels but does not modify PGE(2) concentrations. The elevated levels of ET-1 and PGE(2) in diabetic placenta, potent vasoconstrictors of placental vasculature, are probably related to the induction of placental insufficiency and fetal hypoxia in this pathology.     

Clinically apparent eating disorders in young diabetic women: associations with painful neuropathy and other complications.

Of 208 young women with insulin dependent diabetes, 15 (7%) had a clinically apparent eating disorder (anorexia nervosa or bulimia), a much higher prevalence than reported in non-diabetic women. Most, but not all, of these patients had a long history of poor glycaemic control. In contrast with previous suggestions, control did not deteriorate after the onset of the eating disorder. There was a high incidence and an early onset of diabetic complications. Eleven of the 15 patients had retinopathy, six with proliferative changes; six had nephropathy; and six neuropathy. Most strikingly, four patients with anorexia nervosa developed acute painful polyneuropathy. In each case pain started when the eating disorder developed, almost coinciding with the peak of weight reduction. Remission of pain occurred as weight was regained. The symptoms were accompanied by abnormalities in peripheral nerve electrophysiology and autonomic nerve function, some improvements in which accompanied weight recovery. It is suggested that nutritional factors may contribute to the high rate of early onset diabetic complications, particularly neuropathy.     

Plasma endothelin-1 levels and albumin excretion rate in normotensive,microalbuminuric type 2 diabetic patients

BACKGROUND: Endothelin-1 (ET-1) is able to determine functional and structural renal alterations and plasma levels of this vasoconstrictor peptide are increased in diabetic patients. In a selected group of type 2 normotensive diabetic patients with microalbuminuria, we investigated circulating ET-1 levels compared to a control group and verified whether there is a relationship between ET-1 levels and albumin excretion rate in diabetics. SUBJECTS AND METHODS: Thirty-two microalbuminuric type 2 diabetic patients (12 males and 20 females; mean age 57 +/- 8 years) without hypertension, renal failure, hypercholesterolemia or atherosclerotic damage were selected. The control group was made up of 28 healthy subjects matched for sex and age. Blood pressure, creatinine clearance, serum cholesterol and plasma ET-1 values were determined in diabetic and control group. In diabetic patients, glycosilated hemoglobin and urinary albumin excretion rate were also assayed. Mean ET-1 values in diabetics and controls were compared using Student's t-test. Linear regression test was done to relate two variables. Statistical significance was set at p<0.05. RESULTS: Mean ET-1 values were significantly higher in the diabetic group than in controls (11.77 +/- 1.16 pg/ml vs 8.9 +/- 2.1 pg/ml; p<0.05). No relationship (p>0.05) was found between circulating ET-1 and blood pressure, creatinine clearance, serum cholesterol and metabolic control in diabetics. There was a significant positive correlation (r=0.403; p=0.03) between plasma ET-1 levels and albumin excretion rate in diabetic patients. CONCLUSIONS: Our results showed that circulating ET-1 values were increased in microalbuminuric, normotensive, type 2 diabetic patients and correlated with albumin excretion rate. These findings confirm that endothelial dysfunction, as expressed by ET-1 levels, occurs early in these patients and support the hypothesis of a potential role for this peptide in development of microalbuminuria in diabetic nephropathy.     

Plasma inactive renin in patients with diabetes mellitus: effects of standing and the relation to serum protease inhibitor

In order to investigate the mechanisms of increased plasma inactive renin in diabetics with microvascular complications, changes in active and inactive renin with the progress of diabetes mellitus were studied, and effects of standing on inactive renin release and the relationship between plasma inactive renin and serum trypsin or protease inhibitors wee also studied. Inactive renin increased with the aggravation of diabetes mellitus, but active renin didn't show significant changes with the aggravation of diabetes mellitus. Active renin was significantly increased both in the healthy subjects and in the diabetic patients when they were in an upright position, but no significant change was observed in inactive renin. Serum trypsin in diabetics with retinopathy and nephropathy was lower than that in those with no clinical sign of microangiopathy, but the correlation between plasma inactive renin and serum trypsin was not significant. There was a significant correlation between plasma inactive renin and serum alpha 2-globulin (r = 0.52, p less than 0.01). Although plasma inactive renin was not significantly correlated with serum alpha 1-antitrypsin, there was a significant correlation between plasma inactive renin and serum alpha 2-macroglobulin (r = 0.61, p less than 0.01). These results show that the increased levels of plasma inactive renin observed with the development of diabetic microangiopathy are probably related to the altered plasma protein metabolism observed in patients with diabetes mellitus. However, it is not clear whether this altered protein metabolism is related to the conversion from inactive to active renin.     

前列地尔联合中药治疗糖尿病周围神经病变疼痛临床观察

目的:评价前列地尔E1(PGE1)与营养补充剂甲钴胺(mecbl)联合我院自拟成药首乌保元颗粒治疗糖尿病周围神经病变疼痛(DPN)的临床疗效与安全性。方法:将309例DPN疼痛患者随机分为3组(A、B与C组),每组各103例患者。对所有患者给予静脉注射Me Cbl,给予A组患者静脉滴注PGE1治疗,B组患者在A组患者治疗基础上加服我院自拟中成药首乌保元颗粒(制首乌、黄精、女贞子、黄芪、淫羊藿、茯苓、枳壳、甘草、山茱萸)治疗,连续治疗3周。观察各组患者疗效及不良反应情况。结果:B组总有效率为89.3%,明显高于A组和C组(分别为79.6%和55.3%;P0.05)。在治疗期间,三组均没有发生严重的不良反应。结论:用前列地尔联合中药治疗糖尿病周围神经病变疼痛疗效好,安全性高。     

Hyperglycemia triggers abnormal signaling and proliferative responses in Schwann cells

Peripheral neuropathy is a serious diabetic complication. Delayed nerve regeneration in diabetic animal models suggests abnormalities in proliferation/differentiation of Schwann cells (SC). We recently reported that endothelins (ETs) regulate proliferation and phenotype in primary and immortalized SC (iSC). We now investigated changes in the effects of ETs on SC proliferation and signaling in nerve segments from streptozotocin-induced diabetic rats and in iSC exposed to high glucose. Cultured explants from diabetic rats displayed a delay in the time-course of [³H]-thymidine incorporation as well as enhanced sensitivity to endothelin-1 (ET-1) or insulin. iSC cultured in high (25 mM) glucose-containing media also exhibited higher [³H]-thymidine incorporation, along with an enhanced activation of p38 mitogen-activated protein kinase and phospholipase C in response to ET-1 or platelet-derived growth factor as compared to controls (5.5 mM glucose). These studies support an extra-vascular role of ETs in peripheral nerves and SC. The increased sensitivity to ET-1 in nerves and iSC exposed to high glucose may contribute to abnormal SC proliferation characterizing diabetic neuropathy.     

前列地尔联合尿激酶治疗糖尿病肾病尿蛋白的临床观察

目的:观察短期应用注前列地尔注射液、前列地尔注射液联合小剂量尿激酶对Ⅳ期糖尿病肾病患者尿蛋白的影响。方法:选取我院2005年1月～2009年12月的Ⅳ期糖尿病肾病住院患者548例,均采取强化控制血糖、血压,低蛋白饮食等基础治疗,分为前列地尔治疗组216例、前列地尔联合尿激酶治疗组332例,给予14天短期输液治疗,测定治疗前后24小时尿蛋白。结果:两组患者治疗前年龄、性别组成、糖尿病病程、血糖、血压、血脂、尿蛋白、肾功能等各项指标无显著差异。两组治疗前后各自比较,单独应用注前列地尔注射液、前列地尔注射液联合小剂量尿激酶,均可有效减少糖尿病肾病24小时尿蛋白排泄,但前列地尔注射液联合小剂量尿激酶改善尿蛋白排泄的效果较单独应用注前列地尔更显著(p<0.05),有效率更高(88.2%vs.75.4%,p<0.05);应用小剂量尿激酶未见眼底、皮肤、黏膜出血等不良反应,无凝血功能异常发生。结论:短期静脉应用前列地尔联合小剂量尿激酶治疗Ⅳ期糖尿病肾病,较单独使用前列地尔可更有效减少尿蛋白排泄,不增加眼底出血、皮肤出血、黏膜出血的风险,是一种降低糖尿病肾病尿蛋白水平的安全有效的治疗方法。     

Chemotactic cytokine receptor 5 gene polymorphism: relevance to microvascular complications in type 2 diabetes

We investigated the involvement of chemotactic cytokine receptor 5 (CCR5) gene polymorphism in microvascular complications of T2DM. All subjects were genotyped with the 59029 SNP in the CCR5 gene. The genotype/allele frequencies did not differ between T2DM patients and controls. Genotype distribution was compared in patients with and without complications (nephropathy, retinopathy and neuropathy). The frequency of A allele was significantly higher in patients with complications (OR for A allele 3.07, 95% CI 2.49-3.77). The A allele carriage was associated with diabetic nephropathy (OR 6.17, 95% CI 3.28-11.6). An association was observed between 59029 polymorphism and age at T2DM onset. The A allele was more frequent in early onset than in late onset patients. For AA homozygotes OR was 2.38 (1.19-4.76) and 2.26 (1.12-4.58) in complicated and uncomplicated subgroups, respectively. These results suggest that CCR5 gene polymorphism is associated with diabetic nephropathy in T2DM.     

Roles of endothelin-1 and selected proinflammatory cytokines in the pathogenesis of proliferative diabetic retinopathy: Analysis of vitreous samples

PurposeTo investigate the roles of endothelin-1(ET-1), TNF-α, IL-6 in the pathogenesis of proliferative diabetic retinopathy (PDR) in type 2 diabetes.MethodsVitreous and blood serum samples were collected during vitrectomy from 19 patients with PDR and 15 patients who underwent vitrectomy for other reasons. The concentrations of ET-1, TNF-α, IL-6, vWF, sE-selectin were determined by ELISA.ResultsIntraocular and serous concentrations of ET-1, TNF-α, IL-6, vWF, sE-selectin were higher in patients with PDR than in the control group. The vitreous ET-1/plasma ET-1 ratios the group of diabetic patients and in the control group were similar. Also TNF-α, IL-6 vitreous/plasma ratio were not statistically different between the analysed groups. Correlation between intraocular ET-1 and TNF-α concentrations in patients with PDR and between the increases in both factors in the vitreous and HbA₁c concentration were shown. In the vitreous the increase in vWF depended on elevated levels of vWF in the serum. E-selectin concentration correlated with diastolic blood pressure.ConclusionThese data provide evidence of the activation of the local synthesis of ET-1, TNF-α, IL-6 in PDR. The relationship between the increase in vitreous ET-1, TNF-α concentrations and HbA₁c concentration is a important confirmation of the necessity to optimise diabetes treatment.     

Screening for vascular complications in children and adolescents with type 1 diabetes mellitus

Type 1 diabetes mellitus poses a significant health burden, particularly as a result of its microvascular complications. Clinically evident diabetes-related microvascular complications are extremely rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. Therefore, regular screening for diabetic microvascular disease, particularly retinopathy and nephropathy, are of foremost importance in paediatric diabetes care. Early detection of diabetic microangiopathy and timely treatment of early signs of these complications have a pivotal role in prevention of blindness and end-stage renal failure in children and adolescents with diabetes.     

Role of growth factors in the development of diabetic complications

The structural changes characterising diabetic microangiopathy, which may be referred to as 'abnormal growth' and 'impaired regeneration', strongly suggest a role for a number of aberrantly expressed growth factors, possibly acting in combination, in the development of these complications. This initial speculation has been supported by the detection of increased concentrations of several growth factors in the target tissues of diabetic long-term complications, and by enhanced expression of these growth factors consequent to the activation of the biochemical pathways linking hyperglycaemia to microvascular changes: the polyol pathway; non-enzymatic glycation of proteins; vasoactive hormones; oxidative stress, and hyperglycaemic pseudohypoxia. As to nephropathy, insulin-like growth factor I (IGF-I) seems to be implicated in the earlier stages of the disease, while transforming growth factor beta (TGF beta) is involved both in the early and later stages, being responsible, at least in part, for extracellular matrix (ECM) accumulation. Vascular endothelial growth factor (VEGF) plays a pivotal role both in non-proliferative and proliferative retinopathy. Finally, deficiency of several neurotrophic factors, namely nerve growth factor (NGF) and IGF-I has been related to the degeneration or impaired regeneration occurring in diabetic neuropathy. Knowledge of the involvement of growth factors in diabetic microangiopathy opens the way to new therapeutic interventions aimed at blocking the deleterious actions of several growth factors.     

Alterations in circulating angiogenic and anti‐angiogenic factors in type 2 diabetic patients with neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. There is an increased attention directed towards the role of angiogenic factors including vascular endothelial growth factor (VEGF) and anti‐angiogenic factors including soluble endoglin (sEng) as contributors to diabetic microvascular complications including neuropathy. The purposes of this study were to determine the role of these angiogenesis regulators in the prognosis of DPN. The study group included 60 patients with type 2 diabetes mellitus (T2DM) and 20 clinically healthy individuals. The patients were divided into two groups. Group I included 20 T2DM patients without peripheral neuropathy, and Group II consisted of 40 T2DM patients with DPN. In all groups, plasma VEGF, sEng and endothelin‐1 (ET‐1), nitric oxide and ET‐1 mRNA were estimated. Plasma levels of VEGF, sEng, ET‐1 and nitric oxide were significantly elevated in diabetic patients (Groups I and II) compared with healthy control subjects, with a higher increase in their levels in patients with DPN compared with diabetic patients without peripheral neuropathy. Measurement of plasma levels of angiogenesis‐related biomarkers in high‐risk diabetic patients might identify who later develop DPN, thus providing opportunities for early detection and targets for novel treatments. Copyright © 2013 John Wiley & Sons, Ltd.