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

TL;DR

Empagliflozin, a diabetes drug, reduces liver fibrosis by boosting COMT activity linked to magnesium levels, offering a new health benefit.

Contribution

Shows SGLT2 inhibitors regulate sympathetic activity via COMT in diabetic mice, revealing a novel mechanism for liver fibrosis reduction.

Findings

Empagliflozin increased plasma magnesium and restored COMT activity in diabetic mice.

The drug reduced liver fibrosis and IL-6 levels in diabetic mice.

NMN preincubation attenuated NE-induced IL-6 production in human Kupffer cells.

Abstract

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 BKSdb/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.

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