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

Most overweight individuals do not develop diabetes due to compensatory islet responses to restore glucose homeostasis. Therefore, regulatory pathways that promote beta cell compensation are potential targets for treatment of diabetes. The transient receptor potential cation channel subfamily M member 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 beta cells disrupted insulin secretion and led to progressive glucose intolerance. We indicate that the diminished insulinotropic response in beta cell-specific Trpm7-knockout mice was caused by decreased insulin production because of impaired enzymatic activity of this protein. Accordingly, high-fat-fed mice with a genetic loss of TRPM7 kinase activity displayed a marked glucose intolerance accompanied by hyperglycemia. These detrimental glucoregulatory effects were engendered by reduced compensatory beta cell responses because of mitigated protein kinase B (AKT)/ERK signaling. Collectively, our data identify TRPM7 kinase as a potentially novel regulator of insulin synthesis, beta cell dynamics, and glucose homeostasis under obesogenic diet.

Automated summary

TRPM7 kinase is a potential regulator of insulin synthesis, beta cell dynamics, and glucose homeostasis. Its deletion disrupts insulin secretion and leads to glucose intolerance.