TRPM7 kinase is required for insulin production and compensatory islet responses during obesity.

Abstract

Most overweight individuals do not develop diabetes due to compensatory islet responses to restore glucose homeostasis. Therefore, regulatory pathways that promote β-cell compensation are potential targets for treatment of diabetes. The melastatin transient receptor potential 7 protein (TRPM7), harboring a cation channel and a serine/threonine kinase, has been implicated in controlling cell growth and proliferation. Here, we report that selective deletion of Trpm7 in β-cells disrupts insulin secretion and leads to progressive glucose intolerance. We indicate that the diminished insulinotropic response in β-cell-specific Trpm7 knockout mice is caused by decreased insulin production due to an impaired enzymatic activity of this protein. Accordingly, high-fat fed mice with a genetic loss of TRPM7 kinase activity (Trpm7R/R) display a marked glucose intolerance accompanied by hyperglycemia. These detrimental glucoregulatory effects are engendered by reduced compensatory β-cell responses due to mitigated AKT/ERK signaling. Collectively, our data identify TRPM7 kinase as a novel regulator of insulin synthesis, β-cell dynamics, and glucose homeostasis under obesogenic diet.