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 1

Tissue-specific TRPM7 deletion in β cells impairs glucose homeostasis and glucose-induced insulin secretion.

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Tissue-specific TRPM7 deletion in β cells impairs glucose homeostasis an...
(A) Body weight development for 36 weeks (n = 6 mice per genotype) monitored in male βTrpm7-KO and control littermate mice on chow diet. (B–D) For glucose tolerance test (GTT) mice were fasted overnight (n = 6 mice per genotype). Blood glucose levels (mg/dL) before and within 2 hours after i.p. injection of glucose (2 g/kg of body weight) in wild-type (WT) and βTrpm7-KO mice (left panels) and area under the curves (AUC in mg/dL × min; right panels) 4 (B), 16 (C), and 28 weeks (D) postrecombination. (E) Blood glucose (mg/dL) in freely fed (n = 6 per genotype) or fasted (n = 6 mice per genotype) and (F) plasma insulin levels (ng/mL) in freely fed (n = 6 mice per genotype) were measured in 36-week-old βTrpm7-KO and control littermate mice. (G) For insulin tolerance test (ITT) mice were fasted for 4 hours at the onset of the light cycle (n = 6 mice per genotype). Blood glucose levels (mg/dL) before and within 2 hours after i.p. injection of insulin (0.75 U/kg of body weight) in WT and βTrpm7-KO mice (left) and AUC (mg/dL × min; right). (H) Insulin secretion (ng/mL/h/8 islets) in isolated islets of male βTrpm7-KO and control littermate mice 4, 16, and 28 weeks postrecombination. Islets were incubated for 1 hour in the presence of low glucose and high glucose (n ≥ 3 mice per genotype, measured in duplicate). Data show means ± SEM, and statistical differences were assessed by 2-way ANOVA (B left–D left, and G left) or unpaired 2-tailed Student’s t test (B right–D right, E, F, G, right, H). Circles in bar graphs represent single values. P values are shown above the bars.