Glucagon increase after chronic AT1 blockade is more likely related to an indirect leptin-dependent than to a pancreatic α-cell-dependent mechanism.
AT1 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.
['Mildner|Martin|M|', 'Müller-Fielitz|Helge|H|', 'Stölting|Ines|I|', 'Jöhren|Olaf|O|', 'Steckelings|Muscha|M|', 'Raasch|Walter|W|']
D000804:Angiotensin II D047228:Angiotensin II Type 1 Receptor Blockers D000818:Animals D001562:Benzimidazoles D001565:Benzoates D001713:Biphenyl Compounds D002460:Cell Line D004305:Dose-Response Relationship, Drug D005934:Glucagon D007004:Hypoglycemic Agents D007515:Islets of Langerhans D020738:Leptin D008297:Male D008810:Mice, Inbred C57BL D017207:Rats, Sprague-Dawley D011924:Rats, Zucker D044140:Receptor, Angiotensin, Type 1 D000077333:Telmisartan D013777:Tetrazoles D013997:Time Factors D015854:Up-Regulation
Glucagon α Cells Angiotensin II Leptin Obesity AT1 receptor