title: Glucagon increase after chronic AT1blockade is more likely related to an indirect leptin-dependent than to a pancreatic α-cell-dependent mechanism.
abstract: AT1blockers (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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mildner
authors.affiliation: 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.|Center of Brain, Behavior and Metabolism (CBBM), Lübeck, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Müller-Fielitz
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Stölting
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.|Center of Brain, Behavior and Metabolism (CBBM), Lübeck, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Jöhren
authors.affiliation: Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Muscha
authors.initials: M
authors.lastname: Steckelings
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. walter.raasch@pharma.uni-luebeck.de.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany. walter.raasch@pharma.uni-luebeck.de.|Center of Brain, Behavior and Metabolism (CBBM), Lübeck, Germany. walter.raasch@pharma.uni-luebeck.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D020738:Leptin; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D005934:Glucagon; C081643:candesartan; D000077333:Telmisartan
keywords: AT1 receptor; Angiotensin II; Glucagon; Leptin; Obesity; α Cells