Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes.
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.
Chu
Kwan Yi
KY
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories.
Lau
Tung
T
Carlsson
Per-Ola
PO
Leung
Po Sing
PS
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000188:drug therapy*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D011384:Proinsulin / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D011384:Proinsulin; D019808:Losartan