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

Abstract

Aims/hypothesis: We recently found evidence of an angiotensin-generating system in pancreatic islets. The present study investigated the effect of endogenously produced angiotensin II on microcirculation and function in transplanted islets. Materials and methods: Losartan, an angiotensin II type 1 receptor inhibitor, was administered either acute intravenously to mice with 4-week-old islet renal subcapsular transplants, or added to the drinking water for the final 14 days or throughout the 4-week post-transplantation period. The graft-bearing kidney was, in some cases, dissected out and perfused in vitro to evaluate the effect of angiotensin II and losartan on glucose-stimulated insulin release from the grafts. Results: Losartan treatment throughout the 4-week post-transplantation period had negative effects on islet revascularisation as well as on islet graft insulin release. However, administration of losartan, either intravenously or orally, after the formation of a new vascular network, improved islet graft blood perfusion. P O2 in the islet transplants was also effectively improved by the losartan treatment. Graft perfusion experiments showed a markedly better first phase of glucose-stimulated insulin release in transplanted islets when exposed to losartan. In contrast, acute administration of angiotensin II decreased islet graft blood flow, PO 2 and glucose-stimulated insulin release. Conclusions/interpretation: This study shows that inhibition of the islet reninangiotensin system may be a feasible strategy to increase the blood perfusion, PO 2 and function within islet grafts. Such treatment should not be initiated, however, before the islet vascular system has been formed.

Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets

“…The chosen model to evaluate graft function also enabled us to separately evaluate the effects of improved vascular engraftment on the insulin release kinetics from transplanted islets. It is noteworthy that the peak of the first phase of glucose-stimulated insulin secretion was substantially higher in the better revascularized islet grafts, which is similar to what we have previously observed when improving blood perfusion, but not revascularization, by angiotensin II receptor inhibition (47). However, in contrast to when only the blood perfusion was improved, we observed in the present study also an augmented second phase of glucose-stimulated insulin secretion.…”

Angiotensin II Type 1 Receptor Blockade Improves β-Cell Function and Glucose Tolerance in a Mouse Model of Type 2 Diabetes

“…Moreover, in humans, weight gain and obesity per se seem to activate the RAS (18). Note that the upregulation of AT1R expression in db/db islets from type 2 diabetes observed in the present study is similar to that observed following transplantation of normal islets (19). In that case, not only a disturbance in (pro)insulin biosynthesis regulation but also a defect in islet blood flow were attributed to impaired glucose-induced insulin release.…”

Improved vascular engraftment and function of autotransplanted pancreatic islets as a result of partial pancreatectomy in the mouse and rat

“…This may reflect a less than optimal vascular organisation in transplanted islets relative to native islets. A vascular dysfunction with altered blood flow regulation has also been reported in transplanted islets [48].…”

“…It should be noted that islet endothelial cells can directly stimulate beta cell insulin secretion through paracrine effects [40]. Additionally, an acute increase in graft oxygen tension, through stimulation of blood perfusion, of islet renal subcapsular grafts has been shown to improve the first phase of glucose-stimulated insulin release [48].…”