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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

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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 6

TRPM7 kinase disruption impairs insulin production.

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TRPM7 kinase disruption impairs insulin production.
(A) Total insulin co...
(A) Total insulin content of pooled WT versus Trpm7R/R islets. At least 40 groups of 10 size-matched WT and Trpm7R/R islets were compared. (B) Percentage of insulin content secreted from intact WT or Trpm7R/R islets after incubation with either low glucose (2.8 mM) or high glucose (20 mM) (n = 6 mice per genotype, measured in duplicate). (C and D) Western blot detection of the insulin in lysates of purified islets from WT and Trpm7R/R mice (n ≥ 5, 4 mice per genotype). Insulin was normalized to ERK2 as loading control. (E) Expression levels of Ins2, Pdx1, and MafA analyzed by qRT-PCR from RNAs isolated from pancreatic islet from WT and Trpm7R/R mice. (F and G) Western blot detection of the PDX1 in lysates of purified islets from WT and Trpm7R/R mice (n = 4, 4 mice per genotype). PDX1 was normalized to histone H3 as loading control. (H) Confocal images of WT and Trpm7R/R islets stained for DAPI (blue), insulin (green), PDX1 (red). The scale bar represents 100 μm. (I) Percentage of PDX1-positive cells from the population (100%) of insulin-positive cells per pancreatic islet in WT and Trpm7R/R mice (n = 8, 4 mice per genotype). Data are given as means ± SEM (circles in bar graphs represent single values), and statistical differences were assessed by Mann-Whitney test (A) or unpaired 2-tailed Student’s t test (B, D, E, G, and I). P values are shown above the bars.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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