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 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 β cells disrupted insulin secretion and led to progressive glucose intolerance. We indicate that the diminished insulinotropic response in β 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 β 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, β cell dynamics, and glucose homeostasis under obesogenic diet.
Authors
Noushafarin Khajavi, Andreas Beck, Klea Riçku, Philipp Beyerle, Katharina Jacob, Sabrina F. Syamsul, Anouar Belkacemi, Peter S. Reinach, Pascale C.F. Schreier, Houssein Salah, Tanja Popp, Aaron Novikoff, Andreas Breit, Vladimir Chubanov, Timo D. Müller, Susanna Zierler, Thomas Gudermann
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