Randomized cross-over designed study of the physiological impact of Αlpha-MSH on glycaemic response in patients with type 2 diabetes

Alpha-melanocyte stimulatory hormone (ɑ-MSH) is one of the melanocyte-stimulating hormones (MSH) that are produced by the hypothalamus and secreted from the pituitary gland into the circulation. It acts as an agonist to melanocortin 5 receptor (MC5R), a receptor found in human skeletal muscle that has been demonstrated to be responsible for glucose uptake and disposal by the muscle, thus lowering blood glucose levels. Published pre-clinical data has shownthat peripheral infusion of α-MSH in mice significantly improved glucose clearance during a glucose tolerance test (GTT). Increased glucose disposal in skeletal muscle as measured by hyperinsulinaemic-euglycaemic clamp and tracer studies suggest that skeletal muscle glucose uptake is responsible for improvements in glycaemic control.
Alpha-MSH and its analogues have been investigated extensively through human administration, with analogues such as afamelanotide for the treatment of photosensitivity, bremelanotide for the treatment of hypoactive sexual disorder, and setmelanotide for the treatment of obesity in patients with POMC mutations all gaining marketing authorization in recent years. Human studies to understand the physiological action of MC5R agonism by α-MSH are underway both in vitro and in vivo. Our collaborative group has generated data demonstrating that peripheral infusions of α-MSH significantly improve glucose tolerance in healthy humans. Additionally, we have shown that α-MSH promotes glucose uptake in human skeletal muscle cells in culture, further supporting our hypothesis that improvements in glucose tolerance are mediated by skeletal muscle glucose uptake in humans. This study seeks to answer the question of whether alpha-MSH improves glucose tolerance in patients with Type 2 Diabetes Mellitus (T2DM), a critical next step in assessing the therapeutic potential of this peptide. This will be addressed through measuring the impact of α-MSH infusion on glucose tolerance in patients with T2DM in a double-blinded, randomized, placebo-controlled crossover study.