Having previously identified variants of the receptor for the sleep hormone melatonin which are linked to an increased risk of type 2 diabetes, an Inserm team in collaboration with its international counterparts has recently published information on the mechanisms involved. And in the process, has identified targets for more specific drugs...
Biological clock disruption and sleep disorders promote the onset of type 2 diabetes (T2D). A well-known combination, which is worrying for shift workers, for example. It has been suggested that melatonin, the hormone produced during the night and implicated in the regulation of sleep cycles, could play a role in the onset of this form of diabetes. Yet, beyond environmental factors such as diet, T2D has an undeniable genetic component. Hence the idea of researching variations of the genes coding the cell receptors to melatonin in order to detect those variations which could potentially be related to an increased risk of developing the disease. A number of teams had already revealed such links, but it was not until 2012 that the teams of Ralf Jockers at Cochin Institute* and Philippe Froguel at the Pasteur Institute in Lille were to clearly establish a statistical and functional link between the risk of non-insulin dependent diabetes and certain rare variants of the gene coding for MT2 - one of the two melatonin receptors.
Understanding the mechanisms
But the mechanisms at play still had to be elucidated. The binding of melatonin to MT2 triggers in the cell a cascade of molecular events which "signal" this binding and induce a response. Or more precisely three cascades, because the receptors of this class can activate three signaling pathways. Do certain genetic variants of MT2 induce different responses? And what are the functional particularities potentially linked to an increased risk of T2D? To find out, the Cochin team characterized the functional response of no fewer than 40 genetic variants of the receptor, in the presence and absence of melatonin. A huge undertaking, which required joining forces with teams in Canada (Montréal), the US (Houston), France (Lille) and the UK (Cambridge and London). "We needed to mobilize expertise in genetics, cellular analysis, bioinformatics, ... that is to say go well beyond what my lab can do" explains Ralf Jockers.
One role of the MT2 receptor is to recruit G proteins – which participate in the transfer of intracellular information, and ß-arrestins – which regulate the activity of these proteins. Yet the analysis has shown that the genetic variants of MT2 most strongly linked to T2D risk present two types of functional losses. On the one hand, some weakly activate two classes of G proteins – namely Gαi1 and Gαz – during the binding of melatonin. On the other hand, and more surprisingly, some are distinguished by a low recruitment of β-arrestin2 in the absence of melatonin, therefore during the day. In other words, the spontaneous functioning of the receptor, in the absence of its ligand, could also play a role in T2D risk.
Towards more specific drugs
Ralf Jockers is subsequently devising a strategy for the development of new drugs. "The current drugs activate or deactivate all the functions of the receptor, without distinction. Yet we have shown that only some of these functions are related to a risk of T2D: so we need to find compounds that specifically activate or block these pathways, for example which step up the recruitment of the deficient G proteins" he explains. A distant vision? Not quite, he responds, arguing that the approach has already been successfully used for other receptors.
In addition, the activation of MT2 may have beneficial effects on Alzheimer’s disease. Ralf Jockers’ team is currently researching potential statistical liaisons between the variants of MT2 and this disease. And then, if the results are positive, it will apply the same functional characterization strategy as for type 2 diabetes.
*unit 1016 Inserm/CNRS/Université Paris Descartes, Functional Pharmacology and Physiopathology of Membrane Receptors team, Cochin Institute, Paris
Source : Karamitri et al. Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling. Science Signaling dated 28 August 2018, 11(545). pii: eaan6622. doi: 10.1126/scisignal.aan6622.