Galectin-3 impairs calcium transients and β-cell function

TL;DR

Galectin-3, a protein from macrophages, impairs calcium signaling in pancreatic cells, leading to reduced insulin secretion in diabetes.

Contribution

This study identifies galectin-3 as a novel mediator of beta-cell dysfunction in diabetes through its interaction with CACNG1.

Findings

Galectin-3 levels are elevated in islets of diabetic mice and humans.

Galectin-3 inhibits calcium influx and glucose-stimulated insulin secretion by binding to CACNG1.

Inhibiting galectin-3 improves insulin secretion and glucose homeostasis in diabetic models.

Abstract

In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.

Galectin-3, mainly produced and secreted by macrophages, is elevated in diabetes. Here, the authors show that galectin-3 directly interacts with voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and blocks calcium transients and subsequent insulin secretion.

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