Empagliflozin reduces liver fibrosis by restoring catechol-O-methyltransferase activity associated with magnesium levels

Catechol-O-methyltransferase (COMT), a magnesium (Mg)-dependent enzyme, metabolises catecholamines. Diabetic patients exhibit hypomagnesemia and sympathetic overactivity compared with non-diabetics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase serum Mg levels in diabetic patients. Sympathetic overactivity is associated with diabetic complications; however, the entire mechanism has not been elucidated. Type 2 diabetes model BKS^db/db male mice were fed either a control or an empagliflozin-supplemented diet. Mg²⁺ concentrations, catecholamines, and COMT activity and protein levels were measured. Human Kupffer cells (hKCs) were incubated with norepinephrine (NE) and normetanephrine (NMN), and interleukin (IL)-6 concentrations were quantified. In non-diabetic mice, Mg²⁺ deficiency was associated with decreased liver COMT activity. In diabetic mice, empagliflozin, an SGLT2 inhibitor, increased plasma Mg²⁺ levels and elevated the hepatic NMN/(NE + NMN) ratio. Liver COMT activity was suppressed in diabetic mice; however, empagliflozin restored COMT activity without altering COMT protein expression. Empagliflozin ameliorated fibrosis and IL-6 levels in the liver. In hKCs, NE stimulated IL-6 production, which was attenuated by NMN preincubation. We demonstrated that SGLT2 inhibitors regulate sympathetic activity by enhancing COMT activity in diabetic mice. These findings suggest a new potential health benefit of SGLT2 inhibitors.