Aldosterone Synthase Inhibition Improves Glucose Tolerance in Zucker Diabetic Fatty (ZDF) Rats
- 15 August 2016
- journal article
- Published by The Endocrine Society in Endocrinology
- Vol. 157 (10), 3844-3855
- https://doi.org/10.1210/en.2016-1358
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.Keywords
This publication has 53 references indexed in Scilit:
- Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic DisordersCurrent Hypertension Reports, 2015
- The renin–angiotensin–aldosterone system and glucose homeostasisTrends in Pharmacological Sciences, 2011
- Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine isletsDiabetologia, 2011
- Increased Aldosterone Levels in a Model of Type 2 Diabetes MellitusExperimental and Clinical Endocrinology & Diabetes, 2008
- Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, Peroxisome Proliferator-Activated Receptor-γ, and Proinflammatory AdipokinesCirculation, 2008
- A possible association between primary aldosteronism and a lower β-cell functionJournal of Hypertension, 2007
- Weight Loss and the Renin-Angiotensin-Aldosterone SystemHypertension, 2005
- The Pathophysiology of Aldosterone in the Cardiovascular SystemAnnals of the New York Academy of Sciences, 2002
- Plasma aldosterone, plasma lipoproteins, obesity and insulin resistance in humansProstaglandins, Leukotrienes & Essential Fatty Acids, 1999
- The Effect of Weight Reduction on Blood Pressure, Plasma Renin Activity, and Plasma Aldosterone Levels in Obese PatientsThe New England Journal of Medicine, 1981