Circadian, Sleep and Caloric Intake Phenotyping in Type 2 Diabetes Patients With Rare Melatonin Receptor 2 Mutations and Controls: A Pilot Study.

Background: Melatonin modulates circadian rhythms in physiology and sleep initiation. Genetic variants of the locus, encoding the melatonin MT receptor, have been associated with increased type 2 diabetes (T2D) risk. Carriers of the common intronic rs10830963 T2D risk variant have modified sleep and circadian traits such as changes of the melatonin profile.

Melatonin MT and MT receptor ERK signaling is differentially dependent on G and G proteins.

G protein-coupled receptors (GPCRs) transmit extracellular signals into cells by activating G protein- and β-arrestin-dependent pathways. Extracellular signal-regulated kinases (ERKs) play a central role in integrating these different linear inputs coming from a variety of GPCRs to regulate cellular functions. Here, we investigated human melatonin MT and MT receptors signaling through the ERK1/2 cascade by employing different biochemical techniques together with pharmacological inhibitors and siRNA molecules.

O-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors.

A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16-24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and β-arrestin recruitment assays at MT and MT receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors.

Melatonin in type 2 diabetes mellitus and obesity.

Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide association studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT receptor (which is encoded by MTNR1B).