Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes
2006 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 2, 367-374 p.Article in journal (Refereed) Published
We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.
Place, publisher, year, edition, pages
2006. Vol. 55, no 2, 367-374 p.
Angiotensin II Type 1 Receptor Blockers/*pharmacology/*therapeutic use, Animals, Blood Glucose/drug effects, Diabetes Mellitus; Type 2/*drug therapy/genetics, Disease Models; Animal, Gene Expression Regulation, Glucose Intolerance/*drug therapy, Insulin/metabolism, Insulin-Secreting Cells/cytology/*drug effects/metabolism/physiology, Losartan/*pharmacology/therapeutic use, Mice, Mice; Obese, Proinsulin/biosynthesis, Receptor; Angiotensin; Type 1/genetics/*metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-24724DOI: 10.2337/diabetes.55.02.06.db05-1022PubMedID: 16443769OAI: oai:DiVA.org:uu-24724DiVA: diva2:52498