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 melastatin transient receptor potential 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 disrupts insulin secretion and leads to progressive glucose intolerance. We indicate that the diminished insulinotropic response in β-cell-specific Trpm7 knockout mice is caused by decreased insulin production due to an impaired enzymatic activity of this protein. Accordingly, high-fat fed mice with a genetic loss of TRPM7 kinase activity (Trpm7 R/R ) display a marked glucose intolerance accompanied by hyperglycemia. These detrimental glucoregulatory effects are engendered by reduced compensatory β-cell responses due to mitigated protein kinase B (AKT)/ERK signaling. Collectively, our data identify TRPM7 kinase as a novel regulator of insulin synthesis, β-cell dynamics, and glucose homeostasis under obesogenic diet.

LncRNA SNHG8 regulates the migration and angiogenesis of pHUVECs induced by high glucose via the TRPM7/ERK1/2 signaling axis

“…TRPM7 is involved in the angiogenesis of ECs 39 . MiR-9-5p through the PI3K/AKT/autophagy pathway targeting TRPM7 to promote the proliferation, migration, and angiogenesis of ECs 40 .TRPM7 kinase is also a regulator of insulin synthesis, β-cell dynamics, and glucose homeostasis. TRPM7 reduces insulin secretion of β-cells by inhibiting AKT/ERK signaling pathway 41 .…”

Chronic Mg2+ Deficiency Does Not Impair Insulin Secretion in Mice

“…Recently, we generated tamoxifen-inducible β-cell-specific Trpm7 KO mice (β Trpm7 KO) and monitored the metabolic phenotype of this mouse model within 28 weeks. Notably, GIIS was severely diminished in isolated islets from β Trpm7 KO mice after 28 weeks of tamoxifen-induced recombination [ 21 ]. Here, we hypothesized that the progressive impairment in insulin secretion might be attributable to the chronic Mg 2+ deficiency in β-cell-specific Trpm7 KO mice; however, this difference may instead stem from the fact that TRPM7 is a bifunctional protein consisting of a serine/threonine protein kinase linked to the channel moiety [ 31 , 32 ].…”

“…Islets were loaded with 4 µM fluo-4 AM (Invitrogen, Waltham, MA, USA) for 2 h at room temperature in extracellular buffer containing 138 mM NaCl; 5.6 mM KCl; 2.6 mM CaCl 2 ; 1 mM MgCl 2 ; 5 mM HEPES; pH 7.4 [ 21 ]. Changes in [Ca 2+ ] i were recorded by laser scanning confocal microscopy using an LSM 510 Meta system (Zeiss, Jena, Germany) in conjunction with a water immersion objective (63X/NA1.2).…”

“…The calculation of calcium oscillation was previously described [ 21 ]. In brief, the algorithm is based on three stages that parse over an array of data (the “input data array” or IDA).…”

Inactivation of TRPM7 Kinase Targets AKT Signaling and Cyclooxygenase-2 Expression in Human CML Cells

“… 15 TRPM7 kinase-inactivated mice are viable but show defects in T-cell, pancreatic beta-cell, and platelet functions, ultimately protecting mice from acute graft-versus-host disease and arterial thrombosis. 3 , 9 , 16 , 17 Established TRPM7 kinase substrates include annexin A1, myosin II, phospholipase C gamma 2 (PLCγ2), Ras homology family member A (RHOA), and mothers against decapentaplegic homolog 2 (SMAD2). 2 , 3 , 18–22 The phosphoinositide-3-kinase/AKT serine/threonine kinase (PI3K/AKT) and extracellular signal-related kinase (ERK1/2) signaling hubs are functionally connected, 23–25 although direct phosphorylation via TRPM7 kinase was so far not reported.…”