The decarboxylated and deiodinated thyroid hormone derivative, 3-iodothyronamine (3-T1AM) is suggested to be involved in energy metabolism and thermoregulation. G protein-coupled receptors (GPCRs) are known as the main targets for 3-T1AM; however, transient receptor potential channels (TRPs) were also recently identified as new targets of 3-T1AM. This article reviews the current knowledge of a putative novel role of 3-T1AM in the modulation of TRPs. Specifically, the TRP melastatin 8 (TRPM8) was identified as a target of 3-T1AM in different cell types including neoplastic cells, whereby 3-T1AM significantly increased cytosolic Ca2+ through TRPM8 activation. Similarly, the β-adrenergic receptor is involved in 3-T1AM-induced Ca2+ influx. Therefore, it has been suggested that 3-T1AM-induced Ca2+ mobilization might be due to β-adrenergic receptor/TRPM8 channel interaction, which add to the complexity of GPCR regulation by TRPs. It has been revealed that TRPM8 activation leads to a decline in TRPV1 activity, which may be of therapeutic benefit in clinical circumstances such as treatment of TRPV1-mediated inflammatory hyperalgesia, colitis, and dry eye syndrome. This review also summarizes the inverse association between changes in TRPM8 and TRPV1 activity after 3-T1AM stimulation. This finding prompted further detailed investigations of the interplay between 3-T1AM and the GPCR/TRPM8 axis, and indicated the probability of additional GPCR/TRP constellations that are modulated by this thyroid hormone derivative.

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.

Aims/hypothesis: Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets. Methods: Islets were isolated from wild-type (WT), Gipr-knockout (Gipr ^−/−), Gcgr-knockout (Gcgr ^−/−), Glp-1r (also known as Glp1r)/Gipr double-knockout and Trpm5-knockout (Trpm5 ^−/−) mice, followed by assessment of beta cell function and insulin secretion in response to mono- and multi-agonist administration. Metabolic phenotypes of WT and Trpm5 ^−/− mice under chow and high-fat diets were investigated following triagonist application. Results: The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9–39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5 ^−/− mice demonstrated the absence of triagonist-induced therapeutic effects on glycaemic management. Conclusions/interpretation: Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq–TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist. Graphical

Transient receptor potential channel subfamily M member 7 (TRPM7) regulates cellular and systemic Mg ²⁺ homeostasis through its channel domain and induces protein phosphorylation via its kinase domain. We recently found that mice with selective deletion of Trpm7 in β‐cells develop glucose intolerance and declines in insulin secretion, primarily due to the impaired enzymatic activity of this protein. Accumulating evidence suggests that Mg ²⁺ supplementation effectively mitigates the detrimental effects of TRPM7 disruption in various cell types. However, the impact of Mg ²⁺ supplementation on metabolic impairments caused by TRPM7 inactivation remains unclear. In the present study, we found that Mg ²⁺ supplementation significantly ameliorates glucose intolerance observed in high‐fat‐fed TRPM7 kinase‐deficient mice ( Trpm7 ^R/R ). However, our ex vivo analysis of islets isolated from Trpm7 ^R/R mice revealed that Mg ²⁺ supplementation does not enhance glucose‐induced insulin secretion. Instead, the improvement appears to be partially driven by enhanced insulin sensitivity and increased β‐cell proliferation. The pharmacological analysis in MIN6 cells showed that inhibiting TRPM7 with either NS8593 or VER155008 disrupts β‐cell proliferation. These effects mimicked the phenotype seen in Trpm7 ^R/R mice. We attribute this impairment to diminished ERK1/2 signaling, which suppressed PDX1 expression, while Mg ²⁺ supplementation in vitro partially restored ERK1/2 phosphorylation levels. Collectively, Mg ²⁺ supplementation enhances glucose metabolism in Trpm7 ^R/R mice and mitigates the ERK1/2 signaling disruptions and proliferation arrest induced by TRPM7 inactivation in vitro. These findings provide compelling evidence that Mg ²⁺ supplementation can reverse the adverse metabolic and cellular phenotypes associated with the loss of TRPM7 function.

Magnesium is an essential mediator of a vast number of critical enzymatic cellular reactions in the human body. Some clinical epidemiological studies suggest that hypomagnesemia accounts for declines in insulin secretion in patients with type 2 diabetes (T2D); however, the results of various experimental studies do not support this notion. To address this discrepancy, we assessed the short- and long-term effects of hypomagnesemia on β-cell function and insulin secretion in primary mouse islets of Langerhans and in a mouse model of hypomagnesemia known as Trpm6^{Δ17 /fl};Villin1-Cre mice. We found that lowering the extracellular Mg²⁺ concentration from 1.2 mM to either 0.6 or 0.1 mM remarkably increased glucose-induced insulin secretion (GIIS) in primary islets isolated from C57BL/6 mice. Similarly, both the plasma insulin levels and GIIS rose in isolated islets of Trpm6^{Δ17 /fl};Villin1-Cre mice. We attribute these rises to augmented increases in intracellular Ca²⁺ oscillations in pancreatic β-cells. However, the glycemic metabolic profile was not impaired in Trpm6^{Δ17 /fl};Villin1-Cre mice, suggesting that chronic hypomagnesemia does not lead to insulin resistance. Collectively, the results of this study suggest that neither acute nor chronic Mg²⁺ deficiency suppresses glucose-induced rises in insulin secretion. Even though hypomagnesemia can be symptomatic of T2D, such deficiency may not account for declines in insulin release in this disease.

Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway. Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (Trpm7^R/R). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor. Ex vivo analysis revealed impaired mTOR signaling in Trpm7^R/R islets. Trpm7^R/R islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including Gcg and Mafb. Morphological analysis identified reduced proliferation and enhanced apoptosis of Trpm7^R/R α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells. Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.