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

Diabetologia. 2004 Feb;47(2):240-8. doi: 10.1007/s00125-003-1295-1. Epub 2004 Jan 13.

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 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.

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 AT1-receptor in islet transplants could have relevance to islet-graft function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin II Type 2 Receptor Blockers
  • Imidazoles
  • Insulin
  • Pyridines
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Angiotensinogen
  • Angiotensin II
  • PD 123319
  • Proinsulin
  • Peptidyl-Dipeptidase A
  • Glucose
  • Losartan