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: Anja Hofmann, Coy Brunssen, Mirko Peitzsch, Melanie Martin, Jennifer Mittag, Anett Jannasch, Felix Engelmann, Nicholas F Brown, Steven M Weldon, Jochen Huber, Rüdiger Streicher, Andreas Deussen, Graeme Eisenhofer, Stefan R Bornstein, Henning Morawietz
• Journal: Endocrinology (Endocrinology) Vol. 157 Issue 10 Pg. 3844-3855 (Oct 2016) ISSN: 1945-7170 [Electronic] United States
• PMID: 27526033 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Glycated Hemoglobin A
• Insulin
• Mineralocorticoid Receptor Antagonists
• Triglycerides
• Spironolactone
• Aldosterone
• Eplerenone
• Sodium
• Cytochrome P-450 CYP11B2
• Fadrozole
• Potassium

Topics

• Adrenal Glands (drug effects)
• Aldosterone (blood)
• Animals
• Blood Glucose (drug effects)
• Body Weight (drug effects)
• Cytochrome P-450 CYP11B2 (antagonists & inhibitors)
• Diabetes Mellitus, Type 2 (prevention & control)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Eating (drug effects)
• Eplerenone
• Fadrozole (pharmacology, therapeutic use)
• Glucose Tolerance Test
• Glycated Hemoglobin (metabolism)
• Insulin (metabolism)
• Insulin Resistance
• Insulin Secretion
• Liver (drug effects, metabolism)
• Male
• Mineralocorticoid Receptor Antagonists (pharmacology, therapeutic use)
• Organ Size (drug effects)
• Potassium (blood)
• Random Allocation
• Rats, Zucker
• Sodium (blood)
• Spironolactone (analogs & derivatives, pharmacology, therapeutic use)
• Triglycerides (metabolism)