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

Abstract

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 SGLT2iinduced ketoacidosis.

The Effects of Erchen Decoction on Gut Microbiota and Lipid Metabolism Disorders in Zucker Diabetic Fatty Rats

“…In particular, visceral adipocyte hypertrophy results in decreased insulin sensitivity, a weakened insulin anti-lipolytic effect, and enhanced lipolytic activity in adipocytes (Roden and Shulman, 2019). Studies have found that the anti-lipolytic effect of insulin can be adjusted through the AKT/PKA/HSL signaling pathway (Yin et al, 2019), and inhibiting excessive lipolysis of adipose tissue (Park et al, 2020) is an important way to treat metabolic diseases. Consistent with previous results, we found that adipocytes expanded, IRS1 phosphorylation increased, AKT activity decreased, and insulin signal transduction was impaired, while PKA-mediated HSL activity was upregulated and the ability to release FFA into the circulation was enhanced in the WAT of ZDF rats.…”

Melatonin mitigates aflatoxin B1‐induced liver injury via modulation of gut microbiota/intestinal FXR/liver TLR4 signaling axis in mice

“…Melatonin (MT) is a tryptophan‐derived substituted indoleamine that is synthesized by the pineal gland and peripheral organs 6,7 . Previous studies have found that MT has been widely used to treat various diseases due to its antioxidant, anti‐inflammation, antidiabetes, and antiobesity properties 8–10 . Indeed, MT has been demonstrated to alleviate many liver diseases, such as heavy metal‐induced liver injury, liver inflammation, and liver fibrosis 11–13 .…”

Sodium glucose cotransporter 2 inhibitor dapagliflozin depressed adiposity and ameliorated hepatic steatosis in high-fat diet induced obese mice

“…These effects seem to be independent of the improvement of the glycolipid metabolism or tissue inflammation but are related to the alleviation of local oxidative stress in adipose tissue [ 33 ]. Several studies reported the risk of SGLT2 inhibitors on liver steatosis by promoting fat lysis and its hepatic transporting [ 25 , 34 ]. However, increasing evidences supported that SGLT2 inhibitors could improve hepatic steatosis in rodents or humans [ 32 , 33 , 35 , 36 ].…”