Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets

• Published in: Diabetologia 2004-02, Vol.47 (2), p.240-248
• Main Authors: Lau, T, Carlsson, P-O, Leung, P S
• Format: Article
• Language: English
• Subjects: Angiotensin II - pharmacology; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensinogen - genetics; Animals; Blotting, Western; Dose-Response Relationship, Drug; Gene Expression - drug effects; Glucose - metabolism; Glucose - pharmacology; Imidazoles - pharmacology; Immunohistochemistry; In Vitro Techniques; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Islets of Langerhans Transplantation - methods; Losartan - pharmacology; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction - drug effects; Peptidyl-Dipeptidase A - genetics; Proinsulin - biosynthesis; Protein Biosynthesis; Pyridines - pharmacology; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Renin-Angiotensin System - genetics; Renin-Angiotensin System - physiology; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-003-1295-1

A local angiotensin-generating system has been found in the exocrine pancreas. This study aimed, primarily, to investigate the existence of a local angiotensin-generating system in the pancreatic islets and, secondly, to elucidate its role in regulating insulin secretion. Real-time RT-PCR and western blot were used to investigate if angiotensin-generating components are present in the mouse pancreatic islets, which are subject to regulation by islet transplantation. The localisation of AT1-receptors in islets was investigated by immunohistochemistry. Batch-type incubations of isolated islets were applied for studying the influence of angiotensin II on the glucose-stimulated insulin release, glucose oxidation and (pro)insulin, and total protein biosynthesis. Major components, namely angiotensinogen, ACE, AT1- and AT2-receptors, were expressed in endogenous islets. AT1-receptors were localised to pancreatic beta cells. Exposure of the isolated islets to angiotensin II induced a dose-dependent inhibition of glucose-stimulated insulin release and inhibited (pro)insulin biosynthesis. This inhibitory action was fully preventable by pretreatment of the islets with losartan, an AT1-receptor antagonist. We also investigated if the expression of these components was changed after islet transplantation. Notably, a markedly increased expression of mRNA for the AT1-receptor was observed in islets retrieved from 4-week-old syngeneic islet transplants, a finding that was confirmed at the protein level. These data indicate the existence of an islet angiotensin-generating system of potential importance in the physiological regulation of glucose-induced insulin secretion, thus diabetes mellitus. The increased expression of the AT1-receptor in islet transplants could have relevance to islet-graft function.