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

Abstract

Aims/hypothesis. 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 AT 1 -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, AT 1 -and AT 2 -receptors, were expressed in endogenous islets. AT 1 -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 AT 1 -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 AT 1 -receptor was observed in islets retrieved from 4-week-old syngeneic islet transplants, a finding that was confirmed at the protein level. Conclusion/interpretation. 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 AT 1 -receptor in islet transplants could have relevance to islet-graft function. [Diabetologia (2004) 47:240-248]

Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and first phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts

“…improvement has also recently been described in islets of the type 2 diabetic Zucker rat [27]. The improved first phase of glucose-stimulated insulin release in our experiments may be caused by direct effects of losartan on pancreatic beta cells, but this seems less likely in view of the fact that losartan, in our previous experiments in this strain [11], had no acute effects on glucose-stimulated insulin release, glucose oxidation or (pro)insulin biosynthesis in isolated islets. The latter finding was also confirmed for retrieved islet grafts in the present study.…”

“…In the present study, we found that the oxygenation and the first and second phases of glucosestimulated insulin release were decreased by angiotensin II in transplanted islets. Some of the effects of exogenously administered angiotensin II, especially on the second phase, may not just be related to vascular effects but may be direct negative effects on (pro)insulin biosynthesis, as recently reported [11].…”

“…On the contrary, mainly beneficial effects, such as reduced cardiovascular morbidity and mortality and reduced diabetes incidence, have been described [26]. Mouse pancreatic islets were recently shown to have a local RAS, which means that angiotensin II may be formed locally in high concentrations within the islets [11]. Moreover, the AT 1 receptor for angiotensin II was markedly upregulated in islet transplants [11].…”

“…Mouse pancreatic islets were recently shown to have a local RAS, which means that angiotensin II may be formed locally in high concentrations within the islets [11]. Moreover, the AT 1 receptor for angiotensin II was markedly upregulated in islet transplants [11].…”

“…However, our previous studies have indicated that islet grafts may be even more sensitive than native islets to the vasoconstrictive effects of angiotensin II [9,10]. Moreover, the presence of a local reninangiotensin system (RAS) in pancreatic islets [11] means that angiotensin II may be formed within islets in high local concentrations. The present study aimed to investigate the effect of endogenously produced angiotensin II on islet microcirculation and function in transplanted islets.…”