Melatonin ameliorates SGLT2 inhibitor-induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice.

Autor: Park JH; Department of Physiology, Keimyung University School of Medicine, Daegu, Korea., Seo I; Department of Physiology, Keimyung University School of Medicine, Daegu, Korea., Shim HM; Department of Physiology, Keimyung University School of Medicine, Daegu, Korea., Cho H; Division of Endocrinology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
Jazyk: angličtina
Zdroj: Journal of pineal research [J Pineal Res] 2020 Mar; Vol. 68 (2), pp. e12623. Date of Electronic Publication: 2019 Dec 06.
DOI: 10.1111/jpi.12623
Abstrakt: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective hypoglycemic agents that can induce glycosuria. However, there are increasing concerns that they might induce diabetic ketoacidosis. This study investigated the effect of melatonin on SGTL2i-induced ketoacidosis in insulin-deficient type 2 diabetic (T2D) mice. The SGLT2i dapagliflozin reduced blood glucose level and plasma insulin concentrations in T2D mice, but induced increases in the concentrations of plasma β-hydroxybutyrate, acetoacetate, and free fatty acid and a decrease in the concentration of plasma bicarbonate, resulting in ketoacidosis. Melatonin inhibited dapagliflozin-induced ketoacidosis without inducing any change in blood glucose level or plasma insulin concentration. In white adipose tissue, melatonin inhibited lipolysis and downregulated phosphorylation of PKA, HSL, and perilipin-1. In liver tissue, melatonin suppressed cellular cyclic AMP levels and downregulated phosphorylation of PKA, AMPK, and acetyl-CoA carboxylase (ACC). In addition, melatonin increased hepatic ACC activity, but decreased hepatic CPT1a activity and acetyl-CoA content. These effects of melatonin on lipolysis and hepatic ketogenesis were blocked by pretreatment with melatonin receptor antagonist or PKA activator. Collectively, these results suggest that melatonin can ameliorate SGLT2i-induced ketoacidosis by inhibiting lipolysis and hepatic ketogenesis though cyclic AMP/PKA signaling pathways in T2D mice. Thus, melatonin treatment may offer protection against SGLT2i-induced ketoacidosis.
(© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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