Evidence for an intrinsic angiotensin system in the canine pancreas

Mc, Chappell; Millsted, A; Diz, D. I.; Kb, Brosnihan; Cm, Ferrario

doi:10.1097/00004872-199108000-00008

Cited by 101 publications

(60 citation statements)

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“…There is convincing evidence of an intrinsic pancreatic RAS, through which Ang II is produced locally [7][8][9][10][11][30][31][32], but the physiological roles of this system remain unclear. The present results demonstrate unambiguously that human islets of Langerhans express both AGT and ACE, suggesting that the islets themselves may produce Ang II locally.…”

Section: Discussionmentioning

confidence: 99%

“…An intrinsic pancreatic angiotensin-generating system was demonstrated in the canine pancreas [8,9] by localisation of mRNA and protein for AGT and Ang II receptors, and subsequent studies have identified RAS components in rat, mouse and primate pancreas [7,10,11]. The highest densities of pancreatic Ang II receptors are reported to be localised to pancreatic ducts, vascular endothelium and acinar cells [10].…”

Section: Introductionmentioning

confidence: 99%

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Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

Ramracheya

Müller

et al. 2006

Diabetologia

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Aims/hypothesis: This study aimed to identify the expression of angiotensin II receptors in isolated human islets and beta cells and to examine the functional consequences of their activation. Materials and methods: Singlecell RT-PCR was used to identify whether human islet cells express mRNA for type 1 angiotensin II receptors (AT 1 ), and western blotting was used to determine AT 1 protein expression by human islets and MIN6 beta cells. We measured changes in intracellular calcium by microfluorimetry using Fura 2-loaded MIN6 cells and human islet cells. Dynamic insulin secretory responses were determined by RIA following perifusion of human islets and MIN6 cells. Results: Human islets expressed mRNAs for both the angiotensin precursor, angiotensinogen, and for angiotensin-converting enzyme. In addition, human and mouse beta cells expressed AT 1 . These were functionally coupled to increases in intracellular calcium, which occurred at least in part through phospholipase-C-sensitive mechanisms and calcium influx through voltage-operated calcium channels.Short-term exposure of human islets and MIN6 cells to angiotensin II caused a rapid, short-lived initiation of insulin secretion at 2 mmol/l glucose and potentiation of insulin secretion induced by glucose (at 8 and 16.7 mmol/l). Conclusions/interpretation: These data demonstrate that the AT 1 is expressed by beta cells and that angiotensin II effects a short-lived and direct stimulation of human and mouse beta cells to promote insulin secretion, most probably through elevations in intracellular calcium. Locally produced angiotensin II may be important in regulating a coordinated insulin secretory response from beta cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

Ramracheya

Müller

et al. 2006

Diabetologia

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“…All tissues were stained with the lectin Bandeirae simplicifolia (red) to visualise blood vessels within the pancreatic islets. Scale bar=50 μm effects [17][18][19][20][21][22][23][24]. The best known functions of angiotensin II, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…3 Vascular density in native mouse pancreatic islets and in islet grafts 4 weeks after transplantation beneath the renal capsule of syngeneic C57BL/6 mice. Some of the transplanted animals were subjected to treatment with the angiotensin II type 1 receptor inhibitor losartan (30 mg·kg −1 ·day −1 ) dissolved in the drinking water throughout the 4-week post-transplantation period (days 0-28) or for the final 14 days (days [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Values are given for the endocrine tissue (closed bars), the connective tissue stroma (hatched bars) and the whole islet graft (empty bars).…”

Section: Graft Insulin Release and Insulin Contentsmentioning

confidence: 99%

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

et al. 2005

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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.

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“…This implies that locally produced Ang II exerts local actions from such diverse targets as the heart [5], adrenals [6] and gonads [7] to the pancreas, recently reviewed [8]. Previous studies have shown the presence of such a local system in the pancreas of various species, including the dog [9], rat [10,11], mouse [12] and human [13]. Available data suggest some potential roles for the angiotensin-generating system in the exocrine and endocrine pancreas [14], such as regulation of ductal anion secretion in the exocrine pancreas [15].…”

Section: Measurements Of (Pro)insulin and Total Protein Biosynthesismentioning

confidence: 99%

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

2004

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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]

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Evidence for an intrinsic angiotensin system in the canine pancreas

Cited by 101 publications

References 0 publications

Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

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

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

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