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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Lau
T
T
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Carlsson
P-O
PO
Leung
P S
PS
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000379:methods; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011384:Proinsulin / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D007328:Insulin; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D000804:Angiotensin II; C073402:PD 123319; D011384:Proinsulin; D007703:Peptidyl-Dipeptidase A; D005947:Glucose; D019808:Losartan