Ghrelin, Glucose Homeostasis, and Carotid Intima Media Thickness in Kidney Transplantation
Beatriz Bayés GenísMaría Luisa GranadaNúria AlonsoRicardo LauzuricaJose Angel Lopez JimenezEva BarluengaM. HomsMari Cruz PastorIsabel SalinasJuan Carlos QuinteroAnna Sanmartı́R. Romero
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Background. Abnormalities in glucose homeostasis (AGH) frequently occur in kidney transplantation and favor vascular lesions. The purpose of this study was to analyze whether C-reactive protein (CRP), adiponectin, and ghrelin are markers of AGH and indicators of carotid atherosclerosis in kidney transplant patients with fasting plasma glucose below 126 mg/dL. Methods. This was a cross-sectional study of 85 kidney transplant patients (59 men; mean age: 52.4±11.6 years; median posttransplant follow-up 31 (range 3–61) months). All patients underwent an oral glucose tolerance test. Abnormalities in glucose homeostasis were diagnosed following American Diabetes Association criteria. CRP, adiponectin, and ghrelin levels were determined. Doppler ultrasound of the carotid artery was performed to determine intima media thickness (IMT) and atheromatous plaque. Results. A total of 50.5% of patients had AGH (12.9% were diagnosed with new-onset diabetes mellitus after transplantation and 37.7% had impaired glucose tolerance or impaired fasting glucose), whereas 49.4% were normoglycemic. Patients with AGH were older (P=0.002), had greater carotid IMT (P=0.022), and lower ghrelin concentrations (P=0.017) than normoglycemic patients. Logistic regression analyses showed ghrelin to be an independent marker for AGH (P=0.012) and AGH to be related to greater IMT (P=0.041). No differences in adiponectin or CRP were found in relation to AGH or atherosclerosis; however, there was a positive correlation between adiponectin levels and prednisone dose (r=0.240; P=0.044). Conclusions. A total of 50.5% of the study patients had abnormalities in glucose homeostasis. Patients with AGH had a higher percentage of preclinical atherosclerosis (greater carotid IMT). Ghrelin is an independent marker for abnormalities in glucose homeostasis.Keywords:
Intima-media thickness
Background: Ghrelin is a stomach-derived octanoylated hormone that has been implicated in body weight regulation and glucose homeostasis. It mediates its pharmacological activities primarily through the ghrelin receptor (GhR). The discovery of small molecule GhR antagonists and other biological agents that can modulate ghrelin activity has attracted considerable interest over the past few years. Objectives: This review summarizes the role of ghrelin and its receptor in regulating body weight and glucose homeostasis and describes ghrelin system modulators that have appeared in the patent literature from 2002 to 2008. Results/conclusions: A variety of different agents that alter ghrelin activity have been disclosed, including peptidyl and non-peptidyl receptor antagonists as well as biological agents such as monoclonal antibodies, catalytic activating antibodies, vaccines and Spiegelmers. Many of these agents have been shown to decrease food intake and reduce body weight, although the effect of these modulators on glucose homeostasis has yet to be examined.
Homeostasis
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Ghrelin, an acylated 28-amino-acid peptide, is an endogenous ligand of the growth hormone secretagogue type 1a (GHS-R1a). Ghrelin is best known for its hypothalamic actions on growth hormone-releasing hormone neurons and neuropeptide Y/agouti-related peptide neurons; however, ghrelin affects multiple organ systems and the complexity of its functions is only now being realized. Although ghrelin is mainly produced in the stomach, it is also produced in low levels by the hypothalamus and by most peripheral tissues. GHS-R1a is expressed predominantly in the anterior pituitary gland, at lower levels in the brain including hypothalamic neurons that regulate feeding behavior and glucose sensing, and at even lower levels in the pancreas. A reciprocal relationship exists between ghrelin and insulin, suggesting that ghrelin regulates glucose homeostasis. Ablation of ghrelin in mice increases glucose-induced insulin secretion, and improves peripheral insulin sensitivity. This review focuses on the newly emerging role of ghrelin in glucose homeostasis and exploration of whether ghrelin is a potential therapeutic target for diabetes.
Homeostasis
Secretagogue
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Objective To study the expressions of Ghrelin and its receptor (GHSR) in the patients with Hirschsprungs disease (HD).Methods Eighteen patients who were diagnosed with HD and underwent transanal pull-through procedure were recruited in this study.The resected colon was collected to study the expressions of Ghrelin and GHSR by immunohistochemistry staining.Results Ghrelin and GHSR protein were consistently expressed in the glandular epithelium and villi of the ganglionic colon.In the aganglionic segment,the expressions of Ghrelin and GHSR were significantly reduced (Ghrelin:0.1460 ± 0.014,GHSR:0.1386 ± 0.016).However,the expressions of Ghrelin and GHSR were restored in the dilated segment of colon (Ghrelin..0.5103 ± 0.013,GHSR..0.5094 ±0.019).Moderate expressions of Ghrelin and GHSR were found in the transition zone.In the same tissue of colon,the expression of Ghrelin was not significantly different from that of GHSR (P＞0.05).Conclusions The expressions of Ghrelin and GHSR are reduced in the aganglionic colon of the patients with HD.
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Hirschsprung' s discase; Ghrelin; Receptors, Ghrelin
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Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency.
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Carbohydrate Metabolism
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Carotid intima-media thickness(CIMT) is a well-established surrogate marker of subclinical atherosclerosis. Epidemiological studies show that subjects with impaired glucose regulation (IGR) are at higher risk for cardiovascular disease than subjects with normal glucose tolerance (NGT). However, results of CIMT in this population with IGR were not consistent. This might be related to methodological differences,and the other explanation for this discrepancy may be of races and ethnicities. Most researches support that CIMT has already increased in people with impaired glucose tolerance (IGT). It is important to identify the relationship between IGR and CIMT for early prevention and intervention of diabetic cardiovascular complications. The methods for measuring CIMT and the main researches on relationship between IGR and CIMT are reviewed in this article.
Key words:
Carotid intima-media thickness; Atherosclerosis; Impaired glucose regulation; Impaired fasting glucose; Impaired glucose tolerance
Intima-media thickness
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Subclinical infection
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Ghrelin 是为生长荷尔蒙促泌素受体(GHSR ) 用作自然配体的大脑勇气肽。它也在心血管的系统富有地存在。以便在动脉粥样硬化的发展评估 ghrelin 的可能的角色，房间区别抗原 40 的表示(CD40 ) 上的 ghrelin 的效果被学习。人的脐的静脉 endothelial 房间(HUVEC ) line-ECV 304 与 ghrelin 的不同集中被预先对待， des 酰 ghrelin 或[d-Lys ]-GHRP-6 (一个 ghrelin 受体对手) ，然后与肿瘤坏死 factor-alpha (TNF-alpha ) 和干扰素鲸鱼群妈(TFN-gamma ) 导致了。CD40 的 mRNA 层次被反向的抄写聚合酶链反应分析，并且在房间的 CD40 蛋白质的表情被流动 cytometry (FCM ) 并且西方的弄污测量。结果证明外长的 ghrelin 能显著地禁止 TNF-alpha/IFN-gamma 在以一种集中依赖者方式的 HUVEC 房间的导致的 CD40 表示。当与 ghrelin 的 1000 ng/ml 对待时，在房间的 CD40 的 mRNA 水平被约77%减少，但是当与 ghrelin 的 1000 ng/ml 和 1000 ng/ml 对待时[ d-Lys ]-GHRP-6,在房间的 CD40 的 mRNA 水平被减少由仅仅42%，建议那[ d-Lys ] -GHRP-6 能在这些房间抵抗 ghrelin 的禁止的效果。然而， CD40 表示没被 des 酰 ghrelin 在 1000 ng/ml 禁止。在 FCM 并且进一步的西方的弄污检测的蛋白质表示分析的结果证实了这些结果。我们的结果在心血管的系统建议了那， ghrelin 不仅有反煽动性的效果，而且有重要免疫可以通过 GHSR-1a 受体被调停的规章的效果。
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Ghrelin，新奇生长释放荷尔蒙的肽，原来从老鼠和人的胃被孤立。Ghrelin 为当外围地或集中地管理了时，生长激素(GH ) 的分泌物，食物摄取，和体重获得的增加所知。Ghrelin 也被知道刺激胃的活动性和胃的酸的分泌物。在以前的研究，酸分泌物上的 ghrelin 的行动被显示在 in-vivo 实验象组织安和促胃液素的一样猛烈。在研究，为 ghrelin 的行动的机制也被调查。迷走神经切断术完全在那根迷走神经神经在酸分泌物上为 ghrelin 的行动涉及机制的胃的酸的建议的分泌物上禁止了 ghrelin 的行动，这被显示出。当 famotidine 没由 Masuda 等在学习禁止导致 ghrelin 的酸分泌物，他们断定组织安不在酸分泌物上涉及 ghrelin 的行动。然而，我们证明了 famotidine 完全禁止了导致 ghrelin 的酸分泌物，组氨酸脱羧酶(HDC ) mRNA 被被迷走神经切断术禁止的 ghrelin 注射在胃粘膜增加我们组织安在酸上涉及 ghrelin 的行动的结果 indicate 分泌物。而且，胃的酸分泌物上的促胃液素和 ghrelin 的 synergistic 被显示出。尽管促胃液素在胃的酸的饭后的分泌物有重要角色， ghrelin 可能在 fasting 时期期间或在夜里与酸分泌物有关。然而，进一步的研究被需要阐明在酸的 ghrelin 的生理的角色分泌物。
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Ghrelin 首先从胃被分泌并且在吃行为和重量规定的协作被含有。Ghrelin 也在胃的粘膜防卫的机制起一个必要作用。因此，澄清哪个疾病首先在血浆 ghrelin 集中影响变化是重要的。Helicobacter pylori (H pylori ) 感染涉及胃炎的致病，胃并且十二指肠溃疡，胃的癌，和联系 mucosa 的淋巴组织淋巴瘤。H pylori 根除与体重变化有关。比较，在胃粘膜生产房间的 ghrelin 的感染的 H pylori 和有身体质量索引的正常的否定题目，血浆 ghrelin 集中，胃的 ghrelin mRNA，和数字在 H pylori 是显著地更低的比感染了题目在 H pylori 否定的控制。血浆 ghrelin 集中与胃的萎缩的前进减少。与 H pylori 感染导致的萎缩性胃炎联合的损害胃的 ghrelin 生产在血浆 ghrelin 集中说明减少。然而，到全部的 ghrelin 层次的血浆酰 ated ghrelin 的比率比在健康题目在有长期的萎缩性胃炎的病人是更高的。这可以源于血浆的补偿增加响应胃的萎缩的活跃 ghrelin 集中。在 H pylori 根除以后，胃的 preproghrelin mRNA 表示被增加将近在大多数情况中的 4 褶层。然而，在 H pylori 痊愈没与胃的 ghrelin 生产被联系前后，在血浆 ghrelin 集中变化。血浆 ghrelin 变化相反地与体重变化和起始的血浆 ghrelin 层次被相关。
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瞄准：在胆石疾病探索 ghrelin 的角色。方法：我们在 150 个题目，执行了代表性的研究 38 与胆石(盒子) 和 112 控制。我们也各在二十件胆囊样品做了即时 PCR-RT 研究。身体集体索引(BMI ) ，浆液胰岛素， ghrelin，和浆液类脂化合物被测量。逻辑回归分析(univariate 并且多变量) 被进行估计与浆液 ghrelin 集中联系的胆石疾病的概率。结果：盒子与在性分发的控制统计上不同(P = 0.01 ) ，年龄(53 对 44 年， P = 0.002 ) ， BMI (28 对 25；P = 0.004 ) ，并且葡萄糖(5.26 对 4.98 mmol/L；P = 0.05 ) 。没有新陈代谢的症候群，在第三 tercile 上面的 ghrelin 浆液层次的流行在题目是更低的(P < 0.05 ) 。在里面一多，变量当模特儿，当 ghrelin 价值比中部的价值高时，我们发现了保护的效果(或 = 0.27， 95%CI 0.09-0.82， P = 0.02 ) 。二十(20%) 胆囊标本表示了 ghrelin mRNA。结论：浆液 ghrelin 集中与 GD 的保护的效果被联系。
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瞄准：到在孩子和青少年的措施血浆 ghrelin 层次，分析联系因素，并且在肥胖，抗胰岛素性和繁殖生理学调查 ghrelin 的角色。方法：4.8-15.8 年的 283 个题目的一个总数被注册。禁食血样品被收集，血浆 ghrelin 层次被放射性免疫测定测量。禁食葡萄糖( FG )，禁食胰岛素( FI )，基线睾丸激素(T)，雌二醇( E2 )，催乳激素( PRL )， luteinizing ( LH )，刺激滤泡的荷尔蒙( FSH )，浆液总数胆固醇( TC )，甘油三酸酯( TG )，丙氨酸 aminotransferase (中高音)和尿酸( UA )被测量。身体集体索引(BMI ) ，由动态平衡模型(HOMA 红外) 的抗胰岛素性和由动态平衡的房间功能建模的贝它(HOMA 贝它) 是计算的。结果：中部的 ghrelin 水平是 290 ng/L (15.0-1325.0 ng/L ) 。二元变量关联分析证明 ghrelin 层次相反地与 BMI，中高音， TG， UA， LH， FI 和 HOMA 红外被相关(所有 P < 0.05 ) 。没有另外的重要关联在 ghrelin 之间被发现层次和年龄，性， TC， E2， FSH， PRL， FG 和 HOMA 贝它。逐步的多重回归分析显示出那唯一的 BMI， FI 是在这些孩子和青少年的血浆 ghrelin 层次的独立决定因素(P = 0.018 并且 P = 0.046，分别地) ，它解释了 25.4% 变化。结论：这些数据建议在肥胖的题目的更低的 ghrelin 层次可以是肥胖和血胰岛素增多的结果，它在肥胖的题目是很普通的。而且， ghrelin 可以间接地调整人的繁殖生理学。
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