Characterization of the role of orexin in controlling glucose and lipid metabolism - identification of potential novel therapeutic application in diabetes mellitus type 2

食欲素调节食物摄入。血清和脑脊液中食欲素浓度降低是嗜睡症的标志，嗜睡症与糖耐量受损有关。自身的初步数据表明，食欲素刺激胰岛素、降低胰高血糖素分泌和胰高血糖素原基因转录是一种新机制。在脂肪细胞中，食欲素可以刺激瘦素的产生，而瘦素可以增强胰岛素敏感性和能量消耗。目的是表征食欲素在调节葡萄糖稳态中的作用，并描述其潜在的机制。在体内，我们计划在正常血糖和2型糖尿病动物模型中研究食欲素在控制糖脂代谢中的作用。食欲素作用的分子机制将在细胞水平上进行评估，使用分离的啮齿动物和人胰岛、原代细胞制剂和胰腺A细胞、b细胞和脂肪细胞的永久模型。在人类中，将研究健康人、肥胖者以及2型糖尿病患者血浆促食欲素和血糖浓度之间的关系。此外，食欲素在调节人类胰岛分泌活性中的作用将被描述。本研究结果可能对解释食欲素在控制糖代谢中的作用及其在2型糖尿病的病理生理和可能的治疗中的作用具有临床意义。

Orexin modulates food intake. Decreased concentration of orexin in serum and cerebrospinal fluid is a hallmark of narcolepsy, Narcolepsia is associated with impaired glucose tolerance. Own preliminary data suggest that orexin stimulates insulin and decreases glucagon secretion, and proglucagon gene transcription through a novel mechanism. In adipocytes, orexin can stimulate the production of leptin, which is known to enhance insulin sensitivity and energy expenditure. Aim of the project is to characterize the role of orexin in regulating glucose homeostasis and to delineate the underlying mechanisms. In vivo, we plan to study the role of orexin in controlling glucose and lipid metabolism in normoglycemic and type 2 diabetic animal models. Molecular mechanisms of orexin action will be evaluated at the cellular level using isolated rodent and human pancreatic islets, primary cell preparations, and permanent models of pancreatic A- and B-cells, and adipocytes. In humans, the association between plasma orexin and blood glucose concentrations in healthy and obese individuals as well as in patients with type 2 diabetes mellitus will be studied. Furthermore, the role of orexin in regulating the secretory activity of human pancreatic islets will be delineated. The results of the study may have clinical implications to decipher the impact of orexin in controlling glucose metabolism and its contribution to the pathophysiology and possible therapy of type 2 diabetes mellitus.