Diabetologia co-auth.: B.Thorens

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GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion

Nikhil R Gandasi 1 2, Rui Gao 3, Lakshmi Kothegala 1, Abigail Pearce 4, Cristiano Santos 1, Samuel Acreman 1 3, Davide Basco 5, Anna Benrick 1, Margarita V Chibalina 3, Anne Clark 3, Claudia Guida 3, Matthew Harris 4, Paul R V Johnson 6 7, Jakob G Knudsen 8, Jinfang Ma 3, Caroline Miranda 1 3, Makoto Shigeto 3, Andrei I Tarasov 3 9, Ho Yan Yeung 4, Bernard Thorens 5, Ingrid W Asterholm 1, Quan Zhang 3, Reshma Ramracheya 3, Graham Ladds 4, Patrik Rorsman 10 11 12 13

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Abstract

Aims/hypothesis: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes.