title: Aldosterone Synthase Inhibition Improves Glucose Tolerance in Zucker Diabetic Fatty (ZDF) Rats.
abstract: Plasma aldosterone is elevated in type 2 diabetes and obesity in experimental and clinical studies and can act to inhibit both glucose-stimulated insulin secretion by the β-cell and insulin signaling. Currently mineralocorticoid receptor antagonism is the best characterized treatment to ameliorate aldosterone-mediated effects. A second alternative is inhibition of aldosterone synthase, an approach with protective effects on end-organ damage in heart or kidney in animal models. The effect of aldosterone synthase inhibition on metabolic parameters in type 2 diabetes is not known. Therefore, male Zucker diabetic fatty (ZDF) rats were treated for 11 weeks with the aldosterone synthase inhibitor FAD286, beginning at 7 weeks of age. Results were compared with the mineralocorticoid receptor antagonist eplerenone. Plasma aldosterone was abolished by FAD286 and elevated more than 9-fold by eplerenone. The area under the curve calculated from an oral glucose tolerance test (OGTT) was lower and overall insulin response during OGTT was increased by FAD286. In contrast, eplerenone elevated blood glucose levels and blunted insulin secretion during the OGTT. Fasting glucose was lowered and fasting insulin was increased by FAD286 in the prediabetic state. Glycated hemoglobin was lowered by FAD286, whereas eplerenone showed no effect. We conclude that aldosterone synthase inhibition, in contrast to mineralocorticoid receptor antagonism, has the potential for beneficial effects on metabolic parameters in type 2 diabetes.
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Anja
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Coy
authors.initials: C
authors.lastname: Brunssen
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Mirko
authors.initials: M
authors.lastname: Peitzsch
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Martin
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mittag
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Anett
authors.initials: A
authors.lastname: Jannasch
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Felix
authors.initials: F
authors.lastname: Engelmann
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Brown
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weldon
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Jochen
authors.initials: J
authors.lastname: Huber
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Streicher
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Division of Vascular Endothelium and Microcirculation (A.H., C.B., J.M., F.E., H.M.) and Division of Clinical Neurochemistry (M.P., G.E.), Institute of Clinical Chemistry and Laboratory Medicine, Department of Medicine III (G.E., S.R.B.), University Hospital Carl Gustav Carus Dresden, and Institute of Physiology (M.M., A.D.) and Department of Cardiac Surgery (A.J.), Herzzentrum Dresden, Medical Faculty, Technische Universität Dresden, 01307 Dresden, Germany; Department of Cardio Metabolic Diseases (N.F.B., S.M.W.), Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877; Department of Cardio Metabolic Diseases (J.H., R.S.), Boehringer Ingelheim Pharma GmbH and Co KG, 88400 Biberach, Germany; and Department of Endocrinology and Diabetes (S.R.B.), Division of Diabetes and Nutritional Sciences, Rayne Institute, Faculty of Life Sciences and Medicine, Kings College London, London, SE5 9PJ, United Kingdom.
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D000077545:Eplerenone; D017316:Fadrozole / Q000494:pharmacology / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000097:blood; D011897:Random Allocation; D011924:Rats, Zucker; D012964:Sodium / Q000097:blood; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000450:Aldosterone; D001786:Blood Glucose; D019405:Cytochrome P-450 CYP11B2; D000077545:Eplerenone; D017316:Fadrozole; D006442:Glycated Hemoglobin; D007328:Insulin; D000451:Mineralocorticoid Receptor Antagonists; D011188:Potassium; D012964:Sodium; D013148:Spironolactone; D014280:Triglycerides