Authors: Muzamil Hussain1, Brett Johnson1,2, Neil Tanday1, Chris McGee1, Grace Curry1, Patrick Swan1, Ruth Price1, Carel W. le Roux3, Michael Cowley4 & Alexander Dimitri Miras1,2

Affiliations: 1 Ulster University NI, UK, 2 Imperial College London, UK 3 University College Dublin, IRL, 4 Monash University Melbourne, AUS

Background/ Introduction: Despite advancements in insulin delivery systems, 64% of people with T1DM do not reach HbA1c targets of ≤58 mmol/l (7.5%). There is a clear need for adjunctive therapies for T1DM patients. Our group has demonstrated that peripheral administration of α-melanocyte stimulating hormone (α-MSH) improves glucose tolerance via potentiation of skeletal muscle glucose uptake in rodents, monkeys and healthy humans. It is unknown whether this α-MSH glucoregulatory axis is conserved in people with diabetes.

Material & Methods: Paired oral glucose tolerance tests (OGTT, n=22) and hyperinsulinaemic-euglycaemic clamps (n=24) were performed in humans with type-1 diabetes (male/female, aged 18-50 years, BMI ≥18 and < 30 kg/m2) during intravenous infusions of saline or α-MSH (1,500 ng/kg/hr). Studies were conducted at the NIHR Imperial Clinical Research Facility (London) and the Human Intervention Studies Unit at Ulster University and approved by the London-Fulham Research Ethics committee (20/LO/0355). Plasma glucose was screened by NHS pathology labs, whilst plasma GLP-1, GIP, glucagon and serum insulin were quantified by ELISA.

Results: During OGTT in humans with T1DM, peripheral administration of α-MSH was well tolerated, and significantly reduced plasma glucose incremental area under the curve by 24% at 60 minutes (p=0.003), 12.9% at 120 minutes and 8.2% at 180 minutes. Circulating insulin, glucagon and incretin hormones GLP-1 and GIP were similar at saline and α-MSH infusion. During hyperinsulinaemic-euglycaemic clamps, α-MSH had no significant impact on glucose infusion rate, metabolic clearance rate of glucose or plasma GLP-1, GIP and glucagon levels during steady state.

Conclusion: The glucose lowering actions of α-MSH is conserved between healthy individuals and people with T1DM. This improvement in glucose control occurs in the absence of insulin and is not attributable to changes in incretin hormones. As a result, this novel mechanism of promoting muscle glucose uptake represents a promising target for glycaemic control in people with diabetes. Future work will unravel the mechanism of action and develop pharmacotherapies that specifically target this α-MSH glucoregulatory axis to treat diabetes.