Chronic Mg Deficiency Does Not Impair Insulin Secretion in Mice.

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 mice.

TRPM7 kinase is required for insulin production and compensatory islet responses during obesity.

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.

Evaluation of a rare glucose-dependent insulinotropic polypeptide receptor variant in a patient with diabetes.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that augments insulin secretion in pancreatic β-cells via its glucose-dependent insulinotropic polypeptide receptor (GIPR). Recent genome-wide association studies identified a single nucleotide variant (SNV) in the GIPR encoding gene (GIPR), rs1800437, that is associated with obesity and insulin resistance. In the present study, we tested whether GIPR variants contribute to obesity and disturb glucose homeostasis or diabetes in specific patient populations.

3-Iodothyronamine Activates a Set of Membrane Proteins in Murine Hypothalamic Cell Lines.

3-Iodothyronamine (3-TAM) is an endogenous thyroid hormone metabolite. The profound pharmacological effects of 3-TAM on energy metabolism and thermal homeostasis have raised interest to elucidate its signaling properties in tissues that pertain to metabolic regulation and thermogenesis. Previous studies identified G protein-coupled receptors (GPCRs) and transient receptor potential channels (TRPs) as targets of 3-TAM in different cell types.

An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation.

Recently, a unimolecular tri-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tri-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists.

Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level.

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release.

Treatment of Diabetes and Obesity by Rationally Designed Peptide Agonists Functioning at Multiple Metabolic Receptors.

Obesity and its comorbidities such as type 2 diabetes constitute major worldwide health threats, and the identification of an effective medical intervention has emerged as a global priority. The limited effectiveness of historical, anti-obesity treatments is commonly attributed to the complexity of the disease and the redundancy of metabolic regulatory mechanisms that sustain body weight. At the forefront of obesity research is the development of combinational drug therapies that simultaneously target multiple regulatory pathways, which promote dysfunctional metabolism.

3-Iodothyronamine, a Novel Endogenous Modulator of Transient Receptor Potential Melastatin 8?

The decarboxylated and deiodinated thyroid hormone (TH) derivative, 3-iodothyronamine (3-TAM), is suggested to be involved in energy metabolism and thermoregulation. G protein-coupled receptors (GPCRs) are known as the main targets for 3-TAM; however, transient receptor potential channels (TRPs) were also recently identified as new targets of 3-TAM. This article reviews the current knowledge of a putative novel role of 3-TAM in the modulation of TRPs.

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality.

Role of TRPV channels in regulating various pancreatic β-cell functions: Lessons from in vitro studies.

Pancreatic β-cell functions are regulated by a variety of endogenous and exogenous factors. Calcium is one of the most potent triggers of β-cell growth, insulin production and exocytosis. Recently, others and we showed that TRPV channels are expressed in insulin producing cell lines and/or primary β-cells.

3-Iodothyronamine Decreases Expression of Genes Involved in Iodide Metabolism in Mouse Thyroids and Inhibits Iodide Uptake in PCCL3 Thyrocytes.

Background: 3-Iodothyronamine (3-TAM) is an endogenous decarboxylated thyroid hormone (TH) metabolite. Pharmacological doses of 3-TAM decrease heart rate, body temperature, and metabolic rate in rodents-effects that are contrary to classic TH excess. Furthermore, a single dose of 3-TAM was shown to suppress the hypothalamic-pituitary-thyroid (HPT) axis in rats.

TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells.

Highly Ca(2+) permeable receptor potential channel vanilloid type 6 (TRPV6) modulates a variety of biological functions including calcium-dependent cell growth and apoptosis. So far, the role of TRPV6 in controlling growth of pancreatic neuroendocrine tumour (NET) cells is unknown. In the present study, we characterize the expression of TRPV6 in pancreatic BON-1 and QGP-1 NET cells.

Upregulation of Transient Receptor Potential Vanilloid Type-1 Channel Activity and Ca2+ Influx Dysfunction in Human Pterygial Cells.

Purpose: The heat-sensitive transient receptor potential vanilloid type-1 (TRPV1) channel (i.e., capsaicin [CAP] receptor) is upregulated in numerous cancers.

3-Iodothyronamine increases transient receptor potential melastatin channel 8 (TRPM8) activity in immortalized human corneal epithelial cells.

3-Iodothyronamine (3T1AM) is an endogenous thyroid hormone metabolite that interacts with the human trace amine-associated receptor 1 (hTAAR1), a G-protein-coupled receptor, to induce numerous physiological responses including dose-dependent body temperature lowering in rodents. 3T1AM also directly activates cold-sensitive transient receptor potential melastatin 8 (TRPM8) channels in human conjunctival epithelial cells (HCjEC) at constant temperature as well as reducing rises in IL-6 release induced by transient receptor potential vanilloid 1 (TRPV1) activation by capsaicin (CAP). Here, we describe that 3T1AM-induced TRPM8 activation suppresses through crosstalk TRPV1 activation in immortalized human corneal epithelial cells (HCEC).

The Multitarget Ligand 3-Iodothyronamine Modulates β-Adrenergic Receptor 2 Signaling.

Background: 3-Iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones, induces numerous physiological responses including reversible body temperature decline. One target of 3-T1AM is the trace amine-associated receptor 1 (TAAR1), which is a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). Interestingly, the effects of 3-T1AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3-T1AM such as adrenergic receptors.

Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells.

3-Iodothyronamine (T1AM), an endogenous thyroid hormone (TH) metabolite, induces numerous responses including a spontaneously reversible body temperature decline. As such an effect is associated in the eye with increases in basal tear flow and thermosensitive transient receptor potential melastatin 8 (TRPM8) channel activation, we determined in human conjunctival epithelial cells (IOBA-NHC) if T1AM also acts as a cooling agent to directly affect TRPM8 activation at a constant temperature. RT-PCR and quantitative real-time PCR (qPCR) along with immunocytochemistry probed for TRPM8 gene and protein expression whereas functional activity was evaluated by comparing the effects of T1AM with those of TRPM8 mediators on intracellular Ca(2+) ([Ca(2+)]i) and whole-cell currents.

L-carnitine reduces in human conjunctival epithelial cells hypertonic-induced shrinkage through interacting with TRPV1 channels.

Background/aims: Ocular surface health depends on conjunctival epithelial (HCjE) layer integrity since it protects against pathogenic infiltration and contributes to tissue hydration maintenance. As the same increases in tear film hyperosmolarity described in dry eye disease can increase corneal epithelial transient receptor potential vanilloid type-1 (TRPV1) channel activity, we evaluated its involvement in mediating an osmoprotective effect by L-carnitine against such stress.

Methods: Using siRNA gene silencing, Ca(2+) imaging, planar patch-clamping and relative cell volume measurements, we determined if the protective effects of this osmolyte stem from its interaction with TRPV1.

Role of Somatic Testicular Cells during Mouse Spermatogenesis in Three-Dimensional Collagen Gel Culture System.

Objective: Spermatogonial stem cells (SSCs) are the only cell type that can restore fertility to an infertile recipient following transplantation. Much effort has been made to develop a protocol for differentiating isolated SSCs in vitro. Recently, three-dimensional (3D) culture system has been introduced as an appropriate microenvironment for clonal expansion and differentiation of SSCs.

Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.

Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia.