TRPM7 kinase is required for insulin production and compensatory islet responses during obesity.
Sprache des Titels:
Most overweight individuals do not develop diabetes due to compensatory islet responses to restore glucose homeostasis. Therefore, regulatory pathways that promote ?-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 ?-cells disrupts insulin secretion and leads to progressive glucose intolerance. We indicate that the diminished insulinotropic response in ?-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 ?-cell responses due to mitigated AKT/ERK signaling. Collectively, our data identify TRPM7 kinase as a novel regulator of insulin synthesis, ?-cell dynamics, and glucose homeostasis under obesogenic diet.