Beta Cells Deletion of the Angiotensin‐II Type 1a Receptor Differentially Influences Insulin Levels in Male and Female Mice

Abstract

Renin‐angiotensin system (RAS) blockade with either Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin‐II type 1 receptor blockers improves type 2 diabetic (T2D) symptoms. We have shown that up‐regulation of islet AT1a receptors (AT1aR) may be associated with T2D in male mice. However, the role of islet AT1aR on the glucose regulating hormone “insulin”, is yet to be elucidated in a gender specific manner. Therefore, we hypothesized that β‐cell specific AT1aR loss of function positively regulates insulin in male and female C57BL/6 mice. To address this hypothesis, we used male and female 2 months old wildtype (WT) and transgenic β‐AT1a KO (β‐cell specific AT1aR knock out) mice. This new strain was generated by breeding AT1aR flox/flox mice with animals expressing Cre recombinase under the control of a mouse insulin 2 promoter. Basal non‐fasted plasma insulin levels were assessed using an ELISA kit. Plasma insulin levels were significantly increased in β‐AT1a KO male mice compared to gender‐matched WT mice (β‐AT1a KO: 1.24±0.17 vs. WT: 0.9±0.07 ng/mL, P<0.05). However, plasma insulin levels did not differ among β‐AT1a KO and WT females. In addition, β‐AT1a KO males displayed significantly higher plasma insulin levels compared to β‐AT1aKO females (β‐AT1a KO: 1.24±0.17 vs. WT: 0.73±0.09 ng/mL, P<0.05). Further, basal islet ACE2 activity levels were significantly (p<0.05) higher in females compared to males. In addition, we previously showed that, after 16 weeks of high fat diet (HFD) feeding, WT males had significantly increased body weight compared to animals on regular diet (RD) (HFD: 41±0.9 vs. RD: 30.3±0.6 g). Additional features included elevated plasma insulin levels (HFD: 7±0.1 vs. RD: 2.6±0.8 ng/mL) that were associated with hyperglycemia (HFD: 137.2±0.48 vs. RD: 90±3.2 mg/dL) and glucose intolerance (HFD: 44898±2297 vs. RD: 37928±1273 arbitrary units). These changes in glucose homeostasis were associated with an upregulation in islet AT1aR gene (−1.5 fold vs. RD) expression levels but not ACE2 gene expression and activity. Altogether, our results demonstrate that despite having higher basal islet ACE2 activity, islet AT1aR loss of function positively impacts plasma insulin levels in male but not female mice. Therefore, islet AT1aR plays an important role in the regulation of basal insulin levels. Although islet AT1aR levels are positively correlated to impaired glucose homeostasis as well as hyperinsulinemia in a diet induced obese mouse model, further studies are required to better our understanding about the role of islet AT1aR loss of function on blood glucose levels and glucose regulating hormone “insulin” in a diabetic milieu.Support or Funding InformationAmerican Heart Association: 12EIA8030004 and 14PRE18830012COBRE: P30GM106392