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    Melatonin and type 2 diabetes - the link becomes clearer

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    A study directed by Ralf Jockers

    Linking melatonin receptor variants to signal differences leads to potential new therapeutics of type 2 diabetes

    Previous work (Nat Genet 2012) has reported that rare variants of the MTNR1B gene increase the risk of developing type 2 diabetes (T2D) (1). This gene encodes the melatonin MT2 receptor, which belongs to the G protein-coupled receptor (GPCR) family targeted by many drugs and activating a variety of intracellular signaling pathways. In order to identify the signaling pathways altered by these genetic variations and specifically associated with T2D, a complete functional profiling of the 40 known gene variants was performed by an international consortium led by R. Jockers in collaboration with the teams of M. Bouvier (University of Montreal, Canada), P. Froguel (EGID, Pasteur Institute of Lille) and O. Lichtarge (Baylor College of Medicine, USA). Among all the signaling pathways studied, a defect in melatonin-induced Gi1 and Gαz protein activation, and spontaneous recruitment of β-arrestin 2 to MT2 are the three key events associated with the increased risk of developing T2D.
    This study shows for the first time that the risk of developing T2D is associated with a set of functional defects specific to a GPCR and opens new avenues for a personalized therapeutic intervention with drugs reinforcing these weakened functions. This study was published on August 28, 2018 in the journal Science Signaling (2).

    The disruption of the body clock and sleep disorders promotes the onset of T2D. Melatonin, the hormone that induces sleep, has been suspected of playing a key role in this process. For example, night workers, whose plasma levels of melatonin are reduced and circadian rhythms altered, are more susceptible to T2D. The works published here reinforce this link. They show that the two main GPCR signaling modules: G proteins and β-arrestins contribute to the risk of developing T2D. Identification of this alteration opens the door to personalized therapeutic interventions, but also provides information for candidate drug screening programs to improve the function of MT2. Finally, this functional approach can, on the one hand, provide new mechanistic links between melatonin and T2D but also provide new information on the physiological function of MT2, in particular on the role of its spontaneous activity during the day, in the absence of melatonin.

     

    Legend:

    Melatonin MT2 receptor mutants and signalling defects associated with T2D

    MT2 activates Gi1and Gz proteins, inhibits cAMP production, promotes ERK1/2 phosphorylation and recruits β-arrestin in a spontaneous and melatonin-induced manner. MT2 mutants are shown on the receptor sequence. Those mutants depicted in red color show defects in at least one of the aforementioned pathways. Defective activation of melatonin-induced Gi1and Gz proteins and spontaneous β-arrestin recruitment to MT2 are independently associated with T2D risk. Defective MT2 mutants are listed for each of these parameters.

     

    References:

    1. Bonnefond A, et al. Rare MTNR1B variants impairing melatonin MT2 receptor function contribute to type 2 diabetes. Nat Genetics, 44:297-301 (2012)
    2. Karamitri A, Plouffe B, Bonnefond A, Chen M, Gallion J, Guillaume JL, Hegron A, Boissel M, Canouil M, Langenberg C, Wareham NJ, Le Gouill C Lukasheva V, Lichtarge O, Froguel P, Bouvier M, Jockers R. Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling. Sci. Signal., 2018 Aug 28;11(545). pii: eaan6622.

     

    Contact:

    Ralf Jockers
    Team Functional pharmacology and pathophysiology of membrane receptor