TRPM7 kinase is required for insulin production and compensatory islet responses during obesity
Noushafarin Khajavi, … , Susanna Zierler, Thomas Gudermann
Noushafarin Khajavi, … , Susanna Zierler, Thomas Gudermann
Published December 27, 2022
Citation Information: JCI Insight. 2023;8(3):e163397. https://doi.org/10.1172/jci.insight.163397.
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Research Article Cell biology

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 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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Figure 4

TRPM7 kinase inactivation has no effect on TRPM7 current activity.

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TRPM7 kinase inactivation has no effect on TRPM7 current activity. Whole...
Whole-cell currents recorded from islet cells of WT (A, D, E, black trace, B) and Trpm7R/R mice (A, D, E, purple trace, C), using Mg2+-free pipette solution (buffered by 10 mM EDTA). (A) In- and outward current amplitudes at –80 mV (lower traces) and +80 mV (upper traces), extracted from whole-cell currents mediated by voltage ramps, applied at 0.5 Hz, spanning from –100 mV to 100 mV within 50 ms, in the absence of intracellular Mg2+ in WT and Trpm7R/R islet cells, plotted versus time. Divalent-free solution (DVF, buffered by EDTA) was applied from 600 to 660 seconds (bar). (B and C) Current-voltage relationships (IVs) of the minimal basic current (gray, light purple), the current at 600 seconds (black, purple, right before DVF) and in DVF solution (blue) in WT (B) and in Trpm7R/R islet cells (C). (D and E) IVs of the net current at 600 seconds (600 s net = current at 600 seconds minus basic current) and in DVF solution (DVF net = current in DVF minus basic current) in WT (black) and Trpm7R/R islet cells (purple). (F and G) Summary of the net current amplitudes at +80 mV from IVs at 600 seconds (600 s net; F) and in DVF solution (DVF net; G) in cells isolated from WT (black) and Trpm7R/R mice (purple). All currents were normalized to the cell capacitance (pA/pF). Data are plotted as means ± SEM (A, F, and G) or means (B–E). Data are from 13 cells for WT and 12 cells for Trpm7R/R. Data are given as means ± SEM (circles in bar graphs represent single values), and statistical differences were assessed by unpaired 2-tailed Student’s t test (F and G).