褪黑素对糖尿病应激状态垂体-肾上腺轴功能的影响

目的 :探讨褪黑素对糖尿病应激状态垂体 肾上腺轴功能影响及改善糖代谢紊乱作用的神经内分泌机制。方法 :采用随机、单盲、安慰剂平行对照的方法 ,连续观察 3天外源性褪黑素及安慰剂对 37例糖尿病急性并发症患者垂体 肾上腺轴及糖尿病急性代谢紊乱相关指标的影响 ;并观察给药两周后患者糖代谢控制情况。结果 :①患者下丘脑 垂体 肾上腺 (HPA)轴处于激活状态 ,于药物干预前血浆ACTH和皮质醇水平均高于正常值 ,两组间血浆ACTH和皮质醇水平的差异无显著意义 (P >0 .0 5 ) ;②药物干预后第 1天两组间血浆ACTH和皮质醇水平均有所下降 ,但差异无显著意义 (P >0 .0 5 ) ;药物干预后第 2天和第 3天褪黑素组血浆ACTH和皮质醇下降程度均明显高于安慰剂组 ,两组间差异具显著意义 (P <0 .0 5 ) ;③药物预后 3d内褪黑素对血浆血糖、HCO3 -、阴离子间隙及血浆渗透压等糖尿病急性代谢紊乱相关指标无明显影响。给药两周后褪黑素组患者血浆空腹血糖、餐后血糖及果糖胺水平均较安慰剂组明显下降 ,两组间差异具显著意义 (P <0 .0 5 )。结论 :褪黑素对糖尿病应激状态垂体 肾上腺功能有一定抑制作用 ,适度的抑制糖尿病急性并发症患者HPA轴功能可能对糖代谢的控制及疾病预后转归有利。     

2型糖尿病患者褪黑素水平与下丘脑-垂体-肾上腺轴激素关系的研究

目的 探讨不同血糖平均水平T2DM患者下丘脑-垂体-肾上腺（HPA）轴激素与褪黑素（MLT）的关系. 方法 将90例T2DM患者根据HbA1 c水平分为HbA1 c＜7％组28例、7％≤HbA1 c≤10％组32例和HbA1 c＞ 10％组30例,另选取健康对照（NC）组30名,分析不同HbA1c水平内源性MLT与HPA轴激素的关系. 结果 （1）HbA1c＜7％组和NC组HPA轴激素、MLT水平相对较低,而7％≤HbA1 c≤10％组和HbA1 c＞ 10％组相对较高.（2）多元相关分析显示,在HbA1 c＜7％组和NC组中,MLT与促肾上腺皮质激素（CRH）呈正相关（r=0.476、0.487,P均＜0.05）;在7％≤HbA1 c≤10％组和HbA1 c＞10％组MLT与血清皮质醇（CORS）呈正相关（r=0.318、0.047,P均＜0.05）.（3）多元逐步回归分析表明,T2DM患者血清CRH、促肾上腺皮质激素释放激素（ACTH）、CORS是MLT升高的独立影响因素. 结论 不同血糖水平的T2DM患者MLT与HPA轴的关系及作用机制不同.过高的CORS可刺激MLT分泌,HPA轴与MLT相互影响,协同作用影响糖尿病的发生发展.     

松果腺褪黑素对下丘脑-垂体-肾上腺轴的调节作用

松果腺褪黑素对多种不同功能状态下的下丘脑 垂体 肾上腺轴都有一定调节作用。其机制不仅在于直接与下丘脑 垂体 肾上腺轴上的褪黑素受体结合刺激激素释放 ,并影响糖皮质激素受体的功能 ,而且与五羟色胺、内阿片肽等神经递质、调质相互联系 ;且下丘脑 垂体 肾上腺轴对松果腺褪黑素存在反馈作用。这种调节的广泛性使褪黑素用于内分泌、免疫、精神神经系统疾患的治疗成为可能。     

2型糖尿病患者下丘脑-垂体-肾上腺轴功能改变

糖尿病是一类由遗传、环境、免疫等因素引起的，具有明显异质性的慢性高血糖症及其并发症组成的综合征。近年来，糖尿病与神经内分泌免疫网络的关系已被引起重视，下丘脑-垂体-肾上腺（hypothalamic—pituitary-adrenal，HPA）轴作为一个重要的反馈调节系统，是神经内分泌免疫网络的枢纽，不仅对维持机体内环境平衡起重要作用，而且参与衰老、应激等病理过程。国内外研究发现部分2型糖尿病患者存在不同程度的HPA轴功能失调，HPA轴功能改变在2型糖尿病的发生、发展中可能起重要作用。     

2型糖尿病与下丘脑-垂体-肾上腺轴

2型糖尿病的发生往往由于胰岛素的绝对和(或)相对缺乏,此外还在一定程度上和下丘脑-垂体-肾上腺轴功能改变密切相关。2型糖尿病患者随着下丘脑-垂体-肾上腺轴的改变导致糖皮质激素水平增高,加重了糖代谢和脂代谢紊乱,使糖尿病患者的病情恶化,最终促使糖尿病并发症的发生。     

不同糖化血红蛋白水平的2型糖尿病患者下丘脑-垂体-肾上腺轴功能分析

研究不同HbA1C水平2型糖尿病患者的下丘脑-垂体-肾上腺(HPA)轴功能.发现HbA1C≤7%组HPA轴功能无亢进[ACTH(18.03±8.39)ng/L,血皮质醇(49.22±8.68)μg/L],7%11%组HPA轴功能持续性亢进使得其负反馈环路消失[ACTH(26.08±15.41)ng/L,血皮质醇(55.64±24.27)μg/L].提示糖代谢紊乱程度不同的2型糖尿病患者HPA轴功能及其影响因素不同.

Abstract：

Hypothalamic-pituitary-adrenal(HPA)axis-related factors in patients with type 2 diabetes were studied according to different levels of HbA1C.It showed that HPA axis was normal in HbA1C≤ 7% group[ACTH (18.03±8.39)ng/L,blood cortisol(49.22±8.68)μg/L],hyperactive in 7%11% group with weak feedback regulation[ACTH(26.08±15.41)ng/L,blood cortisol(55.64±24.27)μg/L].These results suggest that HPA axis-related factors in type 2 diabetic patients are different with different grades of glucose metabolic turbulence.     

老年大鼠下丘脑-垂体-肾上腺-胸腺轴基因表达谱的研究

目的　阐明衰老时下丘脑 -垂体 -肾上腺 -胸腺 (HPAT)轴基因表达规律 ,探索神经内分泌和免疫衰老的分子机制。方法　利用基因芯片技术研究老年大鼠与青年大鼠 HPAT轴差异表达的基因。结果　老年大鼠下丘脑多种神经递质或其受体如 GABA- AR、α1 ER、Glu R、多巴胺转运蛋白表达下调 ;垂体多种促性腺激素包括 FSH、LH、Gn RH下调 ;生长激素和生长激素释放因子受体下调 ;脾淋巴细胞促凋亡基因 caspase- 1、caspase- 3、CPP32β、Dnaseγ、PKC delta、Bnip31、p47上调 ,抗凋亡基因 cathepsin B、MTA1下调 ,抗增殖基因 Rb、BTG1表达上调 ,促增殖基因 Jagged1及 c- myc、c- fos、v- jun、Rgc32、Cyclin B1、Cyclin G- associated kinase下调。结论　衰老时 HPAT轴的衰退以下丘脑 -垂体 -性腺轴、下丘脑 -垂体 -生长激素轴、免疫系统受损最为明显 ,神经递质、生长激素、促性腺激素基因低表达及免疫细胞促凋亡基因高表达而抗凋亡基因低表达 ,促增殖基因低表达而抗增殖基因高表达是受损的分子机制。     

严重感染患者下丘脑-垂体-肾上腺轴功能的再评价

应用化学免疫发光法分组测定10例严重全身性感染（危重组）和12例感染性休克（休克组）患者在病程早期（确诊后1，3，5d）血清皮质醇和血浆ACTH水平，与12例对照组患者进行对照分析；并进行1μg ACTH刺激试验评价严重感染患者下丘脑-垂体-肾上腺（HPA）轴功能。结果显示，与对照组相比，危重组的ACTH明显升高（P〈0．05），休克组的ACTH明显降低（P〈0．05），ACTH与严重感染患者的病情危重程度密切相关（P〈0．05），在存活组和死亡组间存在显著差异（P〈0．05）。提示HPA轴在严重感染发生早期已经出现功能改变，ACTH水平与严重感染患者的病情危重程度及住院病死率密切相关。     

慢性多重应激大鼠ECG变化和下丘脑-垂体-肾上腺轴应激反应增高

目的研究慢性多重应激大鼠脱离应激源后心电图（Electrocardiogram,ECG）变化和下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenocortical,HPA）轴应激反应。方法健康雄性SD大鼠20只随机分为应激组和对照组。选用刺激脉冲随机变动的噪声、足底电击、强迫游泳、束缚和夜间光照的复合刺激为应激组大鼠应激源,应激刺激持续30d,建立大鼠慢性多重应激模型。于应激刺激前和完全脱离应激源后3d记录心电图,分析血清促肾上腺皮质激素（ACTH）和皮质酮（corticosterone,Cor）的变化。结果刺激4周后,脱离应激源3d,在1h心电图记录期中,大鼠心律失常类型和次数明显多于应激前和对照组:持续窦性心动过速或窦性不齐、房性期前收缩（应激前1.4±0.7vs应激后40.2±5,P<0.01）、室性期前收缩（应激前3.1±0.6vs应激后55.7±4,P<0.01）、阵发性室速（应激前0vs应激后23.8±6,P<0.01）。心率明显增快[（371.3±12）次/min→（508.7±10）次/min,P<0.01]、RR间期明显缩短[（171.6±5）ms→（111.5±0.5）ms,P<0.01]、ST段抬高或下移、T波高耸直立或低平,血清ACTH[（53.1±4）ng/L→（234.7±16）ng/L,P<0.01]和Cor[（16±4）μg/L→（279±50）μg/L,P<0.01]水平明显增高。结论慢性多重应激大鼠在脱离应激源后仍存在心律失常,并且HPA轴应激反应增高。     

Detection of tissue origin of a 43 kDa diabetogenic protein from alloxan-induced diabetic rats

BACKGROUND:

Earlier, we had found high levels of circulating immune complexes (CICs) in the serum of type 2 diabetes mellitus patients along with a novel 43 kDa protein.

METHODS:

Different tissues of alloxan-induced, diabetic, male albino rats (200–250 g in body weight) were collected for the present study. Tissue proteins were isolated and separated by 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE). A primary cell culture of polymorphonuclear neutrophils (PMNs) was used to evaluate the effects of the diabetogenic protein. Cell proliferative index, oxidant/antioxidant status, and ion-transporting ability were chosen as study parameters.

RESULTS:

SDS-PAGE of different tissues shows that the diabetic liver alone was the only tissue that contained the 43 kDa protein band compared to the normal liver. In vitro effects of the new liver protein on PMNs include significantly decreased cell proliferative activity, increased free radical levels, and decreased levels of antioxidant enzymes as well as ionic transporters. The new liver protein also exhibited protease activity when compared with standard trypsin.

CONCLUSIONS:

This study concluded that a novel 43 kDa protein obtained from the livers of alloxan-induced diabetic rats shows protease activity as well as antiproliferative activity. Also, this protein may act as a diabetogenic factor as it elicited a significantly gross elevation in the oxidant status level as well as in the levels of lysosomal enzymes and a decrease in the levels of antioxidative enzymes and ionic transporters of PMNs.     

Antidiabetic activity of the mangrove species Ceriops decandra in alloxan-induced diabetic rats

Background: Diabetes is a series of disorders characterized by increased fasting and postprandial glucose concentration and insulin deficiency and/or decreased insulin action. Although there are a number of commercially available drugs for the treatment of diabetes, their long‐term use may cause unwanted side effects. Consequently, many studies are underway to find natural remedies that can effectively reduce the intensity of diabetes. The aim of the present study was to evaluate the antidiabetic activity of the mangrove species Ceriops decandra. Methods: The effects of daily oral administration of an ethanolic extract from the leaves of C. decandra (30, 60, 120 mg/kg) for 30 days on blood glucose, hemoglobin (Hb), HbA1c, liver glycogen and some carbohydrate metabolic enzymes were evaluated in normal and alloxan‐induced diabetic rats. The effects of these extracts were compared with the effect of 30‐days treatment with 0.1 mg/kg, p.o., glibenclamide, a commercially available drug commonly used in the treatment of diabetes. Results: Oral administration of 120 mg/kg extract modulated all the parameters evaluated to levels seen in control rats. The effects of 120 mg/kg extract were comparable to those of glibenclamide. Conclusion: The extract of the mangrove plant C. decandra exhibited promising antidiabetic activity and could be considered for further evaluation in clinical studies and drug development.     

糖尿病兔心房电生理及L型钙电流的变化

目的研究糖尿病时心房电生理参数、L型钙电流(ICa,L)变化,探讨糖尿病引起心房颤动(简称房颤)的机制。方法本研究分为离体电生理实验和全细胞膜片钳实验两部分,每部分均分为糖尿病组和对照组。糖尿病兔采用四氧嘧啶诱导。每组各8只兔,饲养8周,离体电生理部分在建立Langendorff灌流的离体兔心脏模型后,测量心房间传导时间(IACT)、高位右房、高位左房、低位左房有效不应期(AERP)、AERP的离散度(AERPD)、应用Burst刺激观察房颤诱发情况;膜片钳实验采用酶解法分离单个心房肌细胞,采用全细胞膜片钳技术记录ICa,L。结果与对照组比较,糖尿病组IACT延长(37.66±8.88 ms vs 27.70±2.12 ms),AERPD增大(28.37±7.52 ms vs 11.62±5.60 ms);房颤诱发率升高(6/8 vs 1/8);心房肌细胞ICa,L最大电流密度显著增加(8.94±3.81 pA/pF vs 5.16±1.10 pA/pF),P均<0.05。结论糖尿病时存在心房电重构。     

Melatonin inhibits lipid peroxidation and stimulates the antioxidant status of diabetic rats

Although melatonin has been established as a free radical scavenger and antioxidant, its effects in diabetes have not been thoroughly investigated. The purpose of this study, therefore, was to investigate the effects of melatonin administration on lipid peroxidation and antioxidant status in streptozotocin (STZ)-induced diabetes in rats. Concentrations of malondialdehyde (MDA) and reduced glutathione (GSH) in erythrocytes and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were compared in 3 groups of 10 rats each [control non-diabetic rats (group I), untreated diabetic rats (group II) and diabetic rats treated with melatonin (group III)]. In the study groups, diabetes developed 3 days after intraperitoneal (i.p.) administration of a single 60-mg/kg dose of STZ. Thereafter, while the rats in group II received no treatment, the rats in group III began to receive a 10-mg/kg i.p. dose of melatonin per day. After 6 wk, the rats in groups II and III had significantly lower body weights and significantly higher blood glucose levels than the rats of group I (P<0.001 and P<0.001, respectively). There were no significant differences in body weight or blood glucose levels between groups II and III. MDA levels in untreated diabetic rats were higher than those in control group rats and in diabetic rats treated with melatonin (P<0.01 and P<0.05, respectively). However, MDA levels in diabetic rats treated with melatonin were not different from those of the control group. The GSH, GSH-Px and SOD levels of untreated diabetic rats were significantly lower than those of the control group (P<0.02, P<0.002 and P<0.05, respectively). In group III, however, melatonin prevented decreases in the thiol antioxidant and the associated enzymes, and so these levels were not significantly different from those in the control group. These results confirm the presence of oxidative stress in STZ-induced experimental diabetes and indicate the beneficial free radical-scavenging and antioxidant properties of melatonin.     

Proteolytic activity in the brain of alloxan diabetic rats: Presence of a proteolytic activator in the cerebral extract

BACKGROUND AND AIM:

Diabetes mellitus is known to cause neurological disorders due to impaired glucose metabolism involving decreased utilization of glucose by the brain tissues. The mechanisms responsible for failure of glycemic regulation in type-2 diabetes leading to neurological impairment need to be thoroughly elucidated.

MATERIALS AND METHODS:

Type-2 diabetes was induced in albino rat models with alloxan monohydrate (40 mg/kg i.v.). Cerebral cortex and medulla oblongata were investigated 48 h after alloxan administration for the alterations in proteolytic activity.

RESULTS:

Diabetes caused an elevation (P < 0.001) of blood glucose and also proteolytic activity in the brain.

CONCLUSION:

Impaired glucose metabolism in the brain was the key factor which was responsible for the elevated (P < 0.001) proteolysis leading to brain dysfunction.     

Melatonin prevents oxidative stress,inflammatory activity,and DNA damage in cirrhotic rats

BACKGROUND Cirrhosis is an important health problem characterized by a significant change in liver parenchyma.In animals,this can be reproduced by an experimental model of bile duct ligation(BDL).Melatonin(MLT)is a physiological hormone synthesized from serotonin that has been studied for its beneficial properties,including its antioxidant potential.AIM To evaluate MLT’s effects on oxidative stress,the inflammatory process,and DNA damage in an experimental model of secondary biliary cirrhosis.METHODS Male Wistar rats were divided into 4 groups:Control(CO),CO+MLT,BDL,and BDL+MLT.MLT was administered(20 mg/kg)daily beginning on day 15 after biliary obstruction.On day 29 the animals were killed.Blood samples,liver tissue,and bone marrow were collected for further analysis.RESULTS BDL caused changes in biochemical and histological parameters and markers of inflammatory process.Thiobarbituric acid(0.46±0.01)reactive substance levels,superoxide dismutase activity(2.30±0.07)and nitric oxide levels(2.48±0.36)were significantly lower(P<0.001)n the groups that received MLT.DNA damage was also lower(P<0.001)in MLT-treated groups(171.6±32.9)than the BDL-only group(295.5±34.8).Tissue damage and the expression of nuclear factor kappa B,interleukin-1β,Nrf2,NQO1 and Hsp70 were significantly lower in animals treated with MLT(P<0.001).CONCLUSION When administered to rats with BDL-induced secondary biliary cirrhosis,MLT effectively restored the evaluated parameters.     

Melatonin protects against ischemic heart failure in rats

Ischemic injury, which occurs as a result of sympathetic hyperactivity, plays an important role in heart failure. Melatonin is thought to have antiatherogenic, antioxidant, and vasodilatory effects. In this study, we investigated whether melatonin protects against ischemic heart failure (HF). In Wistar albino rats, HF was induced by left anterior descending (LAD) coronary artery ligation and rats were treated with either vehicle or melatonin (10 mg/kg) for 4 weeks. At the end of this period, echocardiographic measurements were recorded and the rats were decapitated to obtain plasma and cardiac tissue samples. Lactate dehydrogenase, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lysosomal enzymes (β‐D‐glucuronidase, β‐galactosidase, β‐D‐N‐acetyl‐glucosaminidase, acid phosphatase, and cathepsin‐D) were studied in plasma samples, while malondialdehyde and glutathione levels and Na+, K+‐ATPase, caspase‐3 and myeloperoxidase activities were determined in the cardiac samples. Sarco/endoplasmic reticulum calcium ATPase (SERCA) and caveolin‐3 levels in cardiac tissues were evaluated using Western blot analyses. Furthermore, caveolin‐3 levels were also determined by histological analyses. In the vehicle‐treated HF group, cardiotoxicity resulted in decreased cardiac Na+, K+‐ATPase and SERCA activities, GSH contents and caveolin‐3 levels, while plasma LDH, CK, and lysosomal enzyme activities and cardiac MDA and Myeloperoxidase (MPO) activities were found to be increased. On the other hand, melatonin treatment reversed all the functional and biochemical changes. The present results demonstrate that Mel ameliorates ischemic heart failure in rats. These observations highlight that melatonin is a promising supplement for improving defense mechanisms in the heart against oxidative stress caused by heart failure.     

The pituitary-adrenal axis in the bird

Significant atrophy of the adrenal gland of the bird was obtained with either cortisol or corticosterone. Cortisone also induced atrophy of the adrenal gland but much higher doses were required than for the other two hormones. Similarly, cortisol and corticosterone inhibited bursa weight at much lower doses than did cortisone. Porcine ACTH suspended in a beeswax-oil mixture increased the relative weight of the adrenal gland by 40 to 193% following treatment with 1 to 10 USP units daily for 7 days. These results indicate the presence of some pituitary control over the adrenal gland of the bird but do not disprove partial independence of the adrenal from the anterior pituitary gland.     

Melatonin protects liver from intestine ischemia reperfusion injury in rats

AIM： To investigate the protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats. METHODS： One hundred and fifty male Wistar rats, weighing 190-210 g, aged 7 wk, were randomly divided into melatonin exposure group, alcohol solvent control group and normal saline control group. Rats in the melatonin exposure group received intraperitoneal （IP） melatonin （20 mg/kg） 30 min before intestinal ischemia-reperfusion （IR）, rats in the alcohol solvent control group received the same concentration and volume of alcohol, and rats in the normal saline control group received the same volume of normal saline. Serum samples were collected from each group 0.5, 1, 6, 12, and 24 h after intestinal IR. Levels of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were measured with an auto-biochemical analyzer. Serum TNF-α was tested by enzyme-linked immunosorbent assay （ELISA）. Malondialdehyde （MDA） in liver was detected by colorimetric assay. Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope. RESULTS： The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups （P 〈 0.05）. The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels （%） 6, 12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups （P 〈 0.05）. CONCLUSION： Exotic melatonin can inhibit the activity of ALT, AST and TNF-α, decrease the accumulation of MDA, and depress the expression of ICAM-1 in liver after intestinal IR injury, thus improving the liver function.