Mildner Martin, Müller-Fielitz Helge, Stölting Ines, Jöhren Olaf, Steckelings Muscha, Raasch Walter
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2017 May;390(5):505-518. doi: 10.1007/s00210-017-1346-7. Epub 2017 Jan 31.
AT blockers (ARB) prevent diabetes by improving pancreatic β cell function. Less is known about whether α cells are affected although they express angiotensin II (AngII) receptors. We aimed to investigate glucagon release upon AngII stimulation. We determined glucagon release after AngII stimulation (0.01-100 μM) in α cells (InR1G9) and isolated murine islets. We determined plasma glucagon in rats that were chronically treated with AngII (9 μg/h) or the ARBs telmisartan (8 mg/kg/day) and candesartan (16 mg/kg/day) and correlated glucagon with additional hormones (e.g. leptin). Glucagon was only released from InR1G9 cells and islets at the highest AngII concentrations (>10 μM). This was not inhibited by losartan or PD123319. Ang(1-7) and AngIV were also almost ineffective. AngII did not alter glucagon secretion from islets. Plasma glucagon increased when obese Zucker rats were treated with AngII or candesartan and also when Sprague Dawley rats were treated with telmisartan in parallel to high-calorie feeding. Plasma glucagon and leptin negatively correlated in ARB-treated rats. The glucagon release from InR1G9 cells or islets after AngII, AngIV or Ang(1-7) is unspecific since it only occurs, if at all, after the highest concentrations and cannot be blocked by specific inhibitors. Thus, the AngII-dependent increase in plasma glucagon seems to be mediated by indirect mechanisms. The negative correlations between plasma leptin and glucagon confirm findings showing that leptin suppresses glucagon release, leading us to suppose that the increase in plasma glucagon is related to the decrease in leptin after ARB treatment.
血管紧张素Ⅱ受体阻滞剂（ARB）通过改善胰腺β细胞功能来预防糖尿病。虽然α细胞表达血管紧张素Ⅱ（AngII）受体，但关于α细胞是否受影响所知较少。我们旨在研究AngII刺激后胰高血糖素的释放情况。我们测定了AngII刺激（0.01 - 100 μM）后α细胞（InR1G9）和分离的小鼠胰岛中胰高血糖素的释放。我们测定了长期接受AngII（9 μg/h）或ARB替米沙坦（8 mg/kg/天）和坎地沙坦（16 mg/kg/天）治疗的大鼠的血浆胰高血糖素，并将胰高血糖素与其他激素（如瘦素）进行关联分析。只有在最高AngII浓度（>10 μM）时，InR1G9细胞和胰岛才会释放胰高血糖素。这不受氯沙坦或PD123319的抑制。血管紧张素（1 - 7）和血管紧张素Ⅳ也几乎没有作用。AngII不会改变胰岛中胰高血糖素的分泌。当肥胖的 Zucker 大鼠接受 AngII 或坎地沙坦治疗时，以及当 Sprague Dawley 大鼠在高热量喂养的同时接受替米沙坦治疗时，血浆胰高血糖素都会升高。在接受ARB治疗的大鼠中，血浆胰高血糖素和瘦素呈负相关。AngII、血管紧张素Ⅳ或血管紧张素（1 - 7）刺激后InR1G9细胞或胰岛释放胰高血糖素是非特异性的，因为只有在最高浓度时才会发生（如果发生的话），并且不能被特异性抑制剂阻断。因此，AngII依赖的血浆胰高血糖素升高似乎是由间接机制介导的。血浆瘦素和胰高血糖素之间的负相关证实了瘦素抑制胰高血糖素释放的研究结果，这使我们推测血浆胰高血糖素的升高与ARB治疗后瘦素的减少有关。
