BACKGROUND Previously, we demonstrated that obese mice have marked elevations in systemic concentrations of angiotensin II (AngII). Drugs that inhibit the renin–angiotensin system (RAS), including angiotensin type 1 receptor (AT1R) antagonists, have been reported to delay the onset of type 2 diabetes (T2D), suggesting improvements in insulin sensitivity or regulation of pancreatic insulin secretion. Pancreatic islets possess components of the RAS, including AT1R, but it is unclear if AngII acts at islets to regulate insulin secretion during the development of T2D. METHODS We deleted AT1aR from pancreatic islets and examined effects on insulin secretion in mice fed a low-fat (LF) or high-fat (HF) diet. In separate studies, to exacerbate the system, we infused HF-fed mice of each genotype with AngII. RESULTS Pancreatic AT1aR deficiency impaired glucose tolerance and elevated plasma glucose concentrations in HF, but not LF-fed mice. In HF-fed mice, high glucose increased insulin secretion from islets of AT1aRfl/fl, but not AT1aRpdx mice. In AngII-infused mice, following glucose challenge, plasma glucose or insulin concentrations were not significantly different between genotypes. Moreover, high glucose stimulated insulin secretion from islets of AT1aRfl/fl and AT1aRpdx mice, presumably related to weight loss, and improved insulin sensitivity in both groups of AngII-infused HF-fed mice. CONCLUSIONS Our results suggest that during the adaptive response to insulin resistance from HF feeding, AngII promotes insulin secretion from islets through an AT1aR mechanism. These results suggest the timing of initiation of AT1R blockade may be important in the progression from prediabetes to T2D with β-cell failure.
|Number of pages||8|
|Journal||American Journal of Hypertension|
|State||Published - May 9 2019|
Bibliographical noteFunding Information:
This study was funded by the National Institutes of Health (NIH) Heart, Lung, and Blood Institute (grant R01HL73085 to L.C.), by the NIH General Medical Sciences (grant P20 GM103527 to L.C.), by the American Heart Association (grant 12PRE12050430 to R.S.), and by the Diabetes Research Center at Washington University (grant 5 P30 DK020579 to L.C.).
© American Journal of Hypertension, Ltd 2019. All rights reserved.
- Blood pressure
ASJC Scopus subject areas
- Internal Medicine