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GRK 1482 Jahrbuch 2011-2014

Abstract Angiotensin II is the main effector of the renin-angiotensin system, a hormone system responsible for blood pressure regulation. Its pre- sence was also demonstrated in gut epithelial cells. We found AT1 receptor expression on NCI-H716 cells, a model for enteroendocrine GLP-1 secreting L cells. Cell culture experiments showed an augmen- ting effect of Ang II on isoprenalin stimulated GLP-1 secretion from intestinal crypt cells. In further experiments this effect and the signa- ling pathways involved will be investigated. Ultimately a human study is planned to determine the effect of angiotensin receptor blockade on GLP-1 levels in pre-diabetic, mildly hypertensive patients. Introduction The renin-angiotensin-system (RAS) is a hormone system responsible for fluid homeostasis and blood pressure regulation. The components of the classical RAS are found in liver, kidney and lungs [1]. Angiotensinogen is cleaved to angiotensin I by re- nin and subsequently processed to the active an- giotensin II (Ang II) by the Angiotensin Converting Enzyme (ACE). Ang II, the main effector of the RAS binds to angiotensin receptors 1 (AT1) and 2 (AT2), while most of its effects are exerted through AT1. Various antihypertensive medications, which target the RAS are available: ACE inhibitors, which prevent the formation of Ang II and angiotensin receptor blockers targeting the subtype 1 receptor. Beside the classical RAS, tissue and organ specific RAS have been discovered. Among others the adipose tissue has been shown to be an angiotensinogen secreting organ and Ang II levels are elevated in ob- esity [2]. In various studies treatment of hyperten- sion with Ang II receptor blockers or ACE inhibitors showed a reduction of new onset diabetes [2]. On the other hand GLP-1 is an endocrine hormone secreted by intestinal L cells upon nutrient stimula- tion. L cells are distributed in ileum and colon and represent only a very small percentage of intestinal cells. After oral nutrient ingestion GLP-1 release into the circulation is induced by sugars, fatty acids or by stimulation of enteric nervous system. GLP-1 acts on various organs: it stimulates insulin release from ╬▓ cells in the pancreas, decreases appeti- te in the brain, slows down gastric emptying and inhibits glucagon release from liver cells [3]. Due to its insulinotropic actions GLP-1 has become a popular target for research on diabetes treatment. Moreover GLP-1 levels were shown to be lowered in obese people and diabetic patients after nutrient ingestion [4]. Since angiotensinogen levels are in- creased in obesity and components of the RAS are also present in the gastrointestinal tract, the effect of Ang II on GLP-1 secreting enteroendocrine cells and the mechanisms behind this effect are to be investigated. PhD FELLOWS Page 58 | GRK Progress Report 2011-2014 Sebastian Dreyer (M.Sc.) Nutritional Medicine PhD 14/2 Effects of the renin-angiotensin-system on GLP-1 release from entero endocrine cells