Alpha-melanocyte stimulatory hormone: a novel player in post-prandial glucose disposal in skeletal muscle in humans

Background and Aims: Studies in rodents demonstrate that increases in circulating pituitary‐derived alpha‐melanocyte stimulatory hormone (α‐MSH) contribute to post‐prandial glycaemic control. Moreover, intravenous administration of exogenous α‐MSH lowers glucose excursions during oral glucose tolerance testing (OGTT) in mice. We set out to interrogate whether this action translated to human physiology both in vivo and in vitro Methods: Using a randomized double‐blinded cross‐over design, fifteen healthy volunteers received infusions of physiological saline, 15, 150 and 1500 ng/kg/hr α‐MSH initiated 30 minutes prior to the administration of a standard OGTT. Plasma glucose and insulin was measured during the OGTT. To assess the effect of α‐MSH on glucose disposal into skeletal muscle disposal, 15 subjects underwent sequential hyperinsulinaemic‐euglycaemic clamp, concomitant to either saline or 150ng/kg/hr α‐MSH infusion. In a separate cohort of healthy volunteers (n = 6), vastus lateralis muscle biopsies were obtained and used to establish cultures of primary human myotubes. Tritiated 2‐deoxy‐D‐glucose was used to monitor glucose uptake in response to α‐MSH. Results: Infusion of α‐MSH (1500ng/kg/hr) reduced the incremental area under the curve (iAUC) for plasma glucose (p = 0.02), and plasma insulin (p = 0.006) by approximately 20%. At high steady state insulin concentrations in clamp studies, α‐MSH increased glucose requirements for the maintenance of euglycaemia. Primary human myotube cultures expressed melanocortin receptor subtypes (MC1R>MC3R≈MC4R) and both 10nM and 100nM α‐MSH increased glucose uptake by two‐fold versus vehicle (p = 0.001). Conclusions: These findings substantiate a role for peripheral α‐MSH as a hitherto undescribed component of the endocrine control of glycaemia in human physiology