波动性高血糖与心血管并发症关系

2型糖尿病是冠心病的等危症,内皮功能异常是糖尿病心血管并发症发生发展的重要病理生理基础。除高血糖可导致内皮功能损伤外,波动性高血糖具有更为明显的作用,包括促进内皮细胞凋亡,诱导氧化应激,增加细胞间黏附分子合成等。对血糖波动的正确认识、评价和治疗可能对糖尿病合并心血管并发症的研究具有重要意义。     

Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases

Carbonyl compounds such as methylglyoxal (MGO) seem to play an important role in complications resulting from diabetes mellitus, in aging and neurodegenerative disorders. In this study, we are showing, that MGO is able to suppress cell viability and induce apoptosis in the cerebral cortex and hippocampus of neonatal rats ex-vivo. These effects are partially related with ROS production, evaluated by DCFH-DA assay. Coincubation of MGO and reduced glutathione (GSH) or Trolox (vitamin E) totally prevented ROS production but only partially prevented the MGO-induced decreased cell viability in the two brain structures, as evaluated by the MTT assay. Otherwise, L-NAME, a nitric oxide (NO) inhibitor, partially prevented ROS production in the two structures but partially prevented cytotoxicity in the hippocampus. Pharmacological inhibition of Erk, has totally attenuated MGO-induced ROS production and cytotoxicity, suggesting that MEK/Erk pathway could be upstream of ROS generation and cell survival. Otherwise, p38MAPK and JNK failed to prevent ROS generation but induced decreased cell survival consistent with ROS-independent mechanisms. We can propose that Erk, p38MAPK and JNK are involved in the cytotoxicity induced by MGO through different signaling pathways. While Erk could be an upstream effector of ROS generation, p38MAPK and JNK seem to be associated with ROS-independent cytotoxicity in neonatal rat brain. The cytotoxic damage progressed to apoptotic cell death at MGO concentration higher than those described for adult brain, suggesting that the neonatal brain is resistant to MGO-induced cell death. The consequences of MGO-induced brain damage early in life, remains to be clarified. However, it is feasible that high MGO levels during cortical and hippocampal development could be, at least in part, responsible for the impairment of cognitive functions in adulthood.     

Effect of diabetes on alteration of metabolism in cardiac myocytes: therapeutic implications

Diabetic cardiomyopathy is a distinct entity in humans. It leads to ventricular dysfunction independent of and additive to coronary artery disease and hypertension. Clinical and experimental studies have pointed to the role of metabolic derangements in the development of diabetic cardiomyopathy. Altered insulin signaling in diabetes leads to decreased myocyte glucose uptake and utilization, associated with an increased concentration of free fatty acids. This results in decreased glucose oxidation and increased fatty acid oxidation. Fatty acids increase mitochondrial oxygen consumption for ATP production and stimulate the uncoupling proteins in mitochondria. These proteins decrease the mitochondrial protein gradient, leading to fall in ATP production. The resultant defect in myocardial energy production impairs myocyte contraction and diastolic function. This is the hallmark of diabetic cardiomyopathy at earlier stages. In later stages diabetes impairs the myocyte ischemic defense mechanism, leading to increased cardiovascular morbidity and mortality. Other factors contributing toward causation of diabetic cardiomyopathy are collagen accumulation leading to reduced myocardial compliance, accumulation of advanced glycation end product-modified extracellular matrix proteins with subsequent inelasticity of vessel walls and myocytes, abnormal myocardial calcium handling leading to altered mechanics, endothelial dysfunction, cardiac autonomic neuropathy, and impairment of ischemic preconditioning. Trimetazidine acts a metabolic switch, favoring glucose over free fatty acids as the substrate for metabolism in cardiac myocytes.     

Glucose intolerance: the hidden danger in hypertensives!

Both systemic hypertension and abnormalities of glucose metabolism are independent recognised risk factors for the development of cardiovascular morbidity and mortality, but their effects become additive when they coexist. Hypertension and glucose intolerance increase arterial stiffness and lead to cardiac structural and functional changes such as left ventricular hypertrophy and diastolic dysfunction of the left ventricle. Oral glucose tolerance tests have shown that 58% of patients with systemic hypertension who have no cardiac history and who are not known to have diabetes, suffer from unrecognised abnormalities of glucose metabolism i.e. either diabetes or impaired glucose tolerance. Using the fasting plasma glucose level and/or glycated haemoglobin concentration to diagnose glucose intolerance in patients with systemic hypertension is insufficient because of their low sensitivity for the diagnosis of diabetes and their inability to identify impaired glucose tolerance. It is important to recognise abnormalities of glucose metabolism early in patients with systemic hypertension in order to implement appropriate management and avoid further complications. Failure to identify glucose intolerance results in serious underestimation of the cardiovascular risk of these patients and denies patients primary preventative measures, which are based on risk assessment. All patients referred to Hypertension Clinics for the management of raised blood pressure should therefore be investigated by glucose tolerance test.     

Role of the rs9939609 gene variant of FTO on cardiovascular risk factors and adipokines levels in naive patients with diabetes mellitus type 2

One of the genetic variants (rs9939609) of FTO gene is related with obesity and type 2 diabetes mellitus. The aim of the present study was to analyze the relationship of the rs9939609 FTO gene polymorphism to body weight, insulin resistance, cardiovascular risk factors and serum adipokine levels in patients with diabetes. 123 naïve patients with diabetes mellitus type 2 were analyzed in a cross sectional design. Body weight, blood pressure, fast blood glucose, c-reactive protein (CRP), insulin, HbA1c, insulin resistance (homeostasis model assessment, HOMA-R), total cholesterol, HDL-cholesterol, HDL-cholesterol, triglycerides blood and adipocytokines levels were measured. Forty one patients (14 males/27 females) (33.3 %) had the genotype TT (wild type group), 51 (11 males/40 females) (41.5 %) TA and 31 (9 males/22 females) (25.2 %) AA (mutant type group). No association between the FTO variant and anthropometric parameters or blood pressure was found. Wild type group had higher HOMA-R (1.3 units:CI95% 0.51–5.8), insulin (3.3 mUI/L:CI95% 0.31–13.4) and triglyceride (12.6 mg/dl: CI95% 3.90–46.1) levels than mutant allelic group (TA and AA). Adipocytokines levels were similar in both genotype groups. The FTO gene polymorphism, rs9939609, was found to be associated with HOMA-R, insulin and triglyceride levels in naïve diabetic patients with TT variant.     

TNF-alpha-induced apoptosis in human naïve and memory CD8+ T cells in aged humans

Recently, human CD8+ T cells have been divided into naïve, central memory (T_CM), and two types of effector memory cells (T_EM and T_EMRA), which are phenotypically identified by a set of cell surface molecules. In this investigation, we have compared the relative sensitivity of these subsets to TNF-α-induced apoptosis in young and aged humans. Our data show increased sensitivity of naïve and T_CM CD8+ T cells from aged humans to TNF-α-induced apoptosis as compared to young subjects. Both T_EM and T_EMRA CD8+ T cells from young and aged subjects were relatively resistant to TNF-α-induced apoptosis and no significant difference was observed between young and aged subjects. Increased apoptosis of naïve and T_CM CD8+ T cells in aged humans was associated with increased activation of caspase-8 and caspase-3 as compared to young subjects. There was no difference in the expression of TNFR-I or TNFR-II on any of the four subpopulations of CD8+ T cells between young and aged subjects. These data suggest that increased TNF-α-induced apoptosis of naïve and T_CM CD8+ T cells may play a role in the deficiency of naïve and T_CM CD8+ T cells in human aging. However, apoptosis does not appear to play a major role in increased accumulation of effector memory CD8+ T cells during human aging.     

Epidemiology of the diabetic heart

Diabetes mellitus is a worldwide epidemic. Cardiovascular disease remains the major cause of morbidity and mortality in people with diabetes. Studies have suggested that increased risk of cardiovascular disease is not restricted to type II or type I diabetes mellitus, but extends to prediabetic stages such as impaired fasting glucose, impaired glucose tolerance, metabolic syndrome, and obesity. Insulin resistance, impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus form a continuous sequence of risk for cardiovascular disease. Therefore, cardiovascular disease mortality and morbidity within the diabetes epidemic grow into vast proportions. Evidence also exists that diabetic patients have a high prevalence of heart failure or impaired diastolic and systolic cardiac function subsequent to the combination of coronary artery disease, hypertension, and diabetic cardiomyopathy. In view of the proportions of this new epidemic, prevention of diabetes and its prediabetic states is likely to be the most effective strategy to prevent serious cardiovascular events.     

Comparison of incretin immunoassays with or without plasma extraction: Incretin secretion in Japanese patients with type 2 diabetes

Aims/Introduction: The effectiveness of incretin‐based therapies in Asian type 2 diabetes requires investigation of the secretion and metabolism of glucose‐dependent insulinotropic polypepide (GIP) and glucagon‐like peptide 1 (GLP‐1). Plasma extractions have been suggested to reduce variability in intact GLP‐1 levels among individuals by removing interference that affects immunoassays, although no direct demonstration of this method has been reported. We have evaluated the effects of ethanol and solid‐phase extractions on incretin immunoassays. We determined incretin levels during meal tolerance tests in Japanese patients with type 2 diabetes and characterized predictors for incretin secretion. Materials and Methods: Japanese patients with type 2 diabetes (23 anti‐diabetic drug‐naïve and 18 treated with sulfonylurea [SU] alone) were subjected to meal tolerance tests, and incretin levels were determined by immunoassays with or without extraction. Results: Intact GLP‐1 levels determined by an intact GLP‐1 immunoassay with ethanol and solid‐phase extractions were lower than those determined without extraction. Intact GLP‐1 levels determined by the extractions were highly correlated with each other, much more so than the levels with and without extraction. Total GLP‐1 was unaffected by extractions, showing that extractions remove interference only in the case of intact GLP‐1. Incretin secretion after meal ingestion was similar between drug‐naïve and SU‐treated patients. Fasting and postprandial GLP‐1 levels were correlated positively with fasting free fatty acids and negatively with dipeptidyl peptidase‐4 activity. Conclusions: Ethanol and solid‐phase extractions remove interference for intact GLP‐1 immunoassay. SU showed little effect on incretin secretion. GLP‐1 and GIP secretion were predicted by different factors. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00141.x, 2012)     

Effects of Folic Acid on Cardiac Myocyte Apoptosis in Rats with Streptozotocin-induced Diabetes Mellitus

BACKGROUNDS: The effect of folic acid on cardiac myocyte apoptosis secondary to diabetes is unknown. METHODS: Diabetic rats were divided into diabetic control (DC, n = 11), low-dose (LDF, 0.4 mg/kg/day, n = 12) and high-dose (HDF, 1.2 mg/kg/day, n = 12) folic acid groups. Non-diabetic rats (n = 11) were used as the normal control (NC). RESULTS: After 11 weeks of treatment, compared with the NC group, the DC group showed a reduced blood levels of reactive oxygen species (ROS, P < 0.01). The rate of cardiac myocyte apoptosis in the diabetic control group was also greater than in the non-diabetic control group (P < 0.01). In folic acid-treated rats, the blood levels of ROS was higher than in the diabetic control group (P < 0.05). There was a dose-dependent reduction in the rate of cardiac myocyte apoptosis in the folic acid groups (P < 0.01), and this was accompanied by an increased level of anti-apoptotic protein Bcl-2 and decreased level of pro-apoptotic protein Bax and Fas (P < 0.01). CONCLUSIONS: Dietary folic acid supplementation diminishes the cardiac myocyte apoptosis in streptozotocin-induced diabetes. The apoptosis suppression is accompanied by an increase in the expression of Bcl-2 and a decrease in Bax and Fas.     

Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats

Diabetes and oxidative stress concur to cardiac myocyte death in various experimental settings. We assessed whether N-acetyl-L-cysteine (NAC), an antioxidant and glutathione precursor, has a protective role in a rat model of streptozotocin (STZ)-induced diabetes and in isolated myocytes exposed to high glucose (HG). Diabetic rats were treated with NAC (0.5 g/kg per day) or vehicle for 3 months. At sacrifice left ventricle (LV) myocyte number and size, collagen deposition and reactive oxygen species (ROS) were measured by quantitative histological methods. Diabetes reduced LV myocyte number by 29% and increased myocyte volume by 20% compared to non-diabetic controls. NAC protected from myocyte loss (+25% vs. untreated diabetics, P < 0.05) and reduced reactive hypertrophy (-16% vs. untreated diabetics, P < 0.05). Perivascular fibrosis was high in diabetic rats (+88% vs. control, P < 0.001) but prevented by NAC. ROS production and fraction of ROS-positive cardiomyocyte nuclei were drastically raised in diabetic rats (2.4- and 5.1-fold vs. control, P < 0.001) and normalized by NAC. In separate experiments, isolated adult rat ventricular myocytes were incubated in a medium containing high concentrations of glucose (HG, 25 mM) +/- 0.01 mM NAC; myocyte survival (Trypan blue exclusion and apoptosis by TUNEL) and glutathione content were evaluated. The number of dead and apoptotic myocytes increased five and 6.7-fold in HG and glutathione decreased by 48% (P < 0.05). NAC normalized cell death and apoptosis and prevented glutathione loss. NAC effectively protects from hyperglycemia-induced myocyte cell death and compensatory hypertrophy through direct scavenging of ROS and replenishment of the intracellular glutathione content.     

Cardiovascular disease in cirrhosis--a point-prevalence study in relation to glucose tolerance

OBJECTIVE: Impaired glucose tolerance or diabetes are frequently observed in cirrhosis. Overt diabetes was reported to affect long term survival of cirrhotic patients by increasing the risk of hepatocellular failure, without increasing the risk of diabetes-associated cardiovascular events. METHODS: We evaluated the prevalence of cardiovascular disease in 122 patients with cirrhosis, subdivided according to their glucose tolerance. The following parameters were considered: arterial pressure, peripheral vascular disease (ankle to brachial pressure ratio), ischemic heart disease, microalbuminuria, retinopathy. The prevalence of abnormal findings was compared with that observed in 60 randomly selected patients with noninsulin-dependent diabetes and in 40 controls. RESULTS: Noninsulin-dependent diabetic patients and patients with cirrhosis and diabetes were comparable for age, metabolic control, and smoking habits; the duration of diabetes was 5 yr longer for noninsulin-dependent diabetes. In cirrhosis, the prevalence of micro- and peripheral macroangiopathy, as well as coronary heart disease, was not different in relation to glucose tolerance, it was comparable to that of controls, and significantly lower than that observed in non-insulin-dependent diabetes. CONCLUSIONS: Cirrhotic patients, even in the presence of overt diabetes, are at low risk of cardiovascular disease. The low prevalence may be related to shorter duration of diabetic disease, also in relation to reduced life expectancy, as well as to liver disease-induced abnormalities protecting the cardiovascular system from atherosclerosis.     

Alternative therapies for diabetes and its cardiac complications: role of vanadium

It is now well known that a cardiomyopathic state accompanies diabetes mellitus. Although insulin injections and conventional hypoglycemic drug therapy have been of invaluable help in reducing cardiac damage and dysfunction in diabetes, cardiac failure continues to be a common cause of death in the diabetic population. The use of alternative medicine to maintain health and treat a variety of diseases has achieved increasing popularity in recent years. The goal of alternative therapies in diabetic patients has been to lower circulating blood glucose levels and thereby treat diabetic complications. This paper will focus its discussion on the role of vanadium on diabetes and the associated cardiac dysfunction. Careful administration of a variety of forms of vanadium has produced impressive long-lasting control of blood glucose levels in both Type 1 and Type 2 diabetes in animals. This has been accompanied by, in many cases, a complete correction of the diabetic cardiomyopathy. The oral delivery of vanadium as a vanadate salt in the presence of tea has produced particularly impressive hypoglycemic effects and a restoration of cardiac function. This intriguing approach to the treatment of diabetes and its complications, however, deserves further intense investigation prior to its use as a conventional therapy for diabetic complications due to the unknown long-term effects of vanadium accumulation in the heart and other organs of the body.     

Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation

Cardiac glucose metabolism is critical to hypoxic cardiac function and hypoxia is known to stimulate glucose metabolism. This increases generation of ATP when mitochondrial respiration is inhibited. In diabetes, cardiac glucose metabolism declines and this may contribute to diabetic cardiomyopathy. The first step in committing glucose to metabolism is glucose phosphorylation catalyzed by hexokinase. But the potential role of hexokinase in the hypoxic or diabetic heart is uncertain. This study is designed to assess the ability of hexokinase and elevated ATP to protect cardiomyocyte contractility from hypoxia and diabetes. We used cardiomyocytes from the transgenic mouse Mh, which has cardiac specific expression of yeast hexokinase, to investigate the importance of glucose phosphorylation in the myocyte response to hypoxia and diabetes. Cardiomyocytes were isolated from FVB control and Mh hearts to assess the effects of 2h of hypoxia on myocyte contractility and ATP conent. The protective effect of hexokinase on diabetes was assessed in myocytes from the OVE26 Type I diabetic mouse and in OVE26Mh diabetic mice that carry the hexokinase gene. Overexpression of hexokinase had no effect during aerobic culture, but during hypoxia, hexokinase improved ATP content by 44% and this restored contractility almost to normal levels. In myocytes from diabetic mice, tested under both aerobic and hypoxic conditions, the hexokinase gene significantly improved ATP content and this significantly improved contractility. These results demonstrate that elevating hexokinase activity can be beneficial to hypoxic or diabetic cardiomyocytes secondary to improving myocyte ATP levels.     

Cortical gray matter loss in treatment-naïve alcohol dependent individuals

Background: Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. Such samples represent a small proportion of alcoholics in the general population. Such samples may embody a bias (Berkson's fallacy) if the association between variables (for example, alcoholism and cortical gray matter loss) differs between the population of alcoholics in treatment and alcoholics in the general population. Our objective was to determine if treatment‐naïve alcoholics show structural brain changes versus controls and to compare our findings with reports evaluating alcoholic samples drawn from treatment populations. Methods: Structural MRI was used to assess whole brain and regional volumes of cortical gray matter and white matter in 24 young to middle‐aged treatment‐naïve alcohol‐dependent males versus 17 controls. Results: Cortical gray matter volumes in alcohol‐dependent individuals were negatively associated with age and lifetime duration of alcohol use (which were highly confounded). These subjects showed reduced whole brain (p < 0.05), prefrontal (p < 0.01), and parietal (p < 0.05) cortical gray matter compared with controls. White matter and temporal cortex, tissues that usually show volume reductions in samples drawn from treatment, did not differ between treatment‐naïve alcoholics and controls (all p > 0.40). Conclusions: Our findings are consistent with the hypothesis that structural brain changes in treatment‐naïve alcoholics are less severe than those reported in clinical samples of alcoholics, perhaps due to less concomitant psychopathology and a reduced severity of alcoholism in treatment‐naïve alcoholics. However, caution must be taken when comparing our findings with results from clinical samples, as we did not directly compare treatment‐naïve alcoholics with treated alcoholics and our treatment‐naïve sample tended to be younger than the (clinical) samples reported in the literature. Nevertheless, we suggest that most of the reports of the central nervous system consequences of alcoholism may not accurately describe the majority of alcoholic‐dependent individuals.     

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ )‐induced diabetic mice, but not in SIRT 1^?/? diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT 1 and PGC ‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT 1 or PGC ‐1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT 1/PGC ‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC ‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT 1‐PGC 1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.     

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV-1 infected patients

Objectives

Infection with HIV leads to progressive CD4 T‐cell loss, resulting in AIDS. Apoptosis is the main mechanism for the loss of infected and bystander cells, but the complex interacting factors inducing and inhibiting apoptosis are not fully understood. Mitochondrial dysfunction is a pivotal step of the apoptotic cascade and can result in reduced mitochondrial membrane potential.

Methods

The mitochondrial membrane potential of peripheral blood mononuclear cells (PBMC) was measured by flow cytometry using the dye JC‐1 (Molecular Probes Inc). Apoptotic cells were identified using the Annexin V assay (Becton Dickinson GmbH).

Results

The mitochondrial membrane potential of PBMC was significantly decreased and apoptotic cell rate was increased in HIV‐infected therapy‐naïve patients compared with HIV‐negative controls. There was a highly significant correlation between the mitochondrial membrane potential and the rate of apoptosis. CD4 cell count was correlated negatively to the apoptotic rate and positively to the mitochondrial membrane potential.

Conclusions

The JC‐1 assay is a sensitive tool to detect changes of mitochondrial membrane potential associated with apoptosis in HIV‐infected therapy‐naïve patients. We could show in vivo that a reduction of mitochondrial membrane potential is correlated to apoptosis of PBMC, CD4 cell count and HIV viral load during HIV infection.     

Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition

Dietary obesity is associated with type 2 diabetes and cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.     

Comparison of twice-daily injections of biphasic insulin lispro and basal-bolus therapy: glycaemic control and quality-of-life of insulin-naïve type 2 diabetic patients

Objective: The aim of this study was to evaluate twice‐daily injections of biphasic insulin lispro vs. basal–bolus (BB) therapy with regard to quality‐of‐life (QOL) and glycaemic control in insulin‐naïve type 2 diabetic patients. Methods: Twenty‐eight patients with type 2 diabetes were randomized to receive either twice‐daily 50/50 premixed insulin lispro (Mix50 group) or BB (NPH insulin at bedtime and preprandial insulin lispro) therapy (BB group) for 12 weeks. Glycated haemoglobin (HbA1C), 1,5‐anhydroglucitol (1,5‐AG), blood plasma glucose level, body mass index (BMI), daily total insulin dosage and insulin therapy–related QOL (ITR‐QOL) were studied. Results: ITR‐QOL was significantly better in the Mix50 than in the BB group (103.1 ± 9.8 vs. 90.6 ± 19.4; p < 0.05). HbA_1c improved in both groups (from 11.1 ± 2.1 to 6.9 ± 1.0% with Mix50 vs. from 11.0 ± 2.3 to 6.6 ± 0.8% with BB therapy). Conclusion: These results might suggest that twice‐daily injections of premixed rapid‐acting insulin analogue therapy could achieve good glycaemic control and better QOL compared with BB therapy in insulin‐naïve type 2 diabetes.     

高血压大鼠心肌内质网应激时GRP78和CHOP的表达及其与心肌细胞凋亡的关系

目的:探讨心肌组织内质网应激相关因子葡萄糖调节蛋白78(glucose-regulated protein78,GRP78)和C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白(C/EBP homologous protein,CHOP)在高血压大鼠心肌中的表达及其与心肌细胞凋亡的关系。方法:将48只SD大鼠随机等分为两个组,一组采用腹主动脉缩窄术(TAC)建立高血压模型,称为TAC组;另一组只进行相应的假手术,称为Sham组。按术后饲养时间(3 d、7 d、14 d和28 d)的不同,TAC组又分为4个组,即TAC3d组、TAC7d组、TAC14d组和TAC28d组,每组6只(n=6);Sham组也又分为4个组,即Sham3d组、Sham7d组、Sham14d组和Sham28d组,每组6例(n=6)。用颈动脉插管法测定各组大鼠的平均动脉压(MAP);用Western blot法检测GRP78蛋白和CHOP蛋白表达的水平;用TUNNEL法检测心肌细胞的凋亡。结果:①TAC3d组、TAC7d组、TAC14d组和TAC28d组的MAP均显著高于相应的各Sham组(P0.05),且TAC各组的MAP随着术后时间的延长,血压值呈逐渐递增的趋势。②GRP78蛋白在TAC术后3 d即发现表达(0.20±0.02),明显高于Sham3d组(0.10±0.02)(P0.05);但明显低于其他各TAC组(P0.05)。随着术后时间的延长,TAC7d组GRP78蛋白的表达达到最高(0.94±0.03),其后各组呈递减趋势;但TAC7d组、TAC14d组和TAC28d组GRP78蛋白表达的水平均明显高于相应的各Sham组(P0.05)。③随着TAC术后时间的延长,心肌组织中CHOP蛋白的表达呈递増趋势;TAC7d组、TAC14d组和TAC28d组CHOP蛋白表达的水平,分别为(0.17±0.01)、(0.36±0.03)和(0.61±0.02),均明显高于相应的各Sham组(P0.05)。TAC3d组CHOP蛋白的表达与Sham3d组比较,无明显差异。④Sham3d组和TAC3d组中仅有极少数凋亡细胞;Sham7d组和TAC7d组可见较多的凋亡细胞,且随着时间的延长细胞凋亡率逐渐增加,TAC28d组的凋亡率达最高(30.23±0.17)%;TAC7d组、TAC14d组和TAC28d组细胞凋亡率显著高于相应的各Sham组(P0.05)。⑤相关性分析显示,从TAC7d组、14d组及28d组的MAP与心肌组织中GRP78蛋白的表达呈显著的负相关(r=-0.882,P0.01),与CHOP蛋白的表达呈显著正相关(r=0.933,P0.01);CHOP蛋白的表达与GRP78蛋白的表达呈显著负相关(r=-0.980,P0.01),与心肌细胞的凋亡率呈显著的正相关(r=0.997,P0.01)。结论:高血压诱导心肌组织内质网应激反应在血压升高早期以GRP78的表达占优势,随着血压持续性升高可导致CHOP在心肌中超表达,参与心肌细胞凋亡的病理过程,并使心肌内质网应激稳态调节发生失衡。