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

点击翻译按钮获取中文摘要

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.