Role of exendin-4 in the Gila monster: Further lessons regarding human oral glucagon-like peptide-1 therapy?

The discovery of glucagon‐like peptide‐1 (GLP‐1) and demonstration of its insulin‐releasing and glucose‐lowering properties represent important milestones leading to the present drug exploitation of the GLP‐1 receptor (GLP‐1R) as a therapeutic target for both type 1 and particularly type 2 diabetes.1 This journey was initially thwarted by the short half‐life of native GLP‐1 (7‐36) in the circulation, which necessitated continuous infusion of the peptide. It was not until the serendipitous finding that exendin‐4 from the saliva of the Gila monster was both an agonist of the human GLP‐1R and resistant to degradation by dipeptidyl peptidase‐4 (DPP‐4) that the therapeutic potential of GLP‐1R activation could be clinically exploited.2 Thus, although exendin‐4 shows only 53% sequence identity with human GLP‐1, it was a full agonist at mammalian GLP‐1R, with amino acid sequence at the N‐terminal of His1‐Gly2‐Glu3 rather than His7‐Ala8‐Glu9. This conferred enzyme resistance to cleavage by DPP‐4 that otherwise cuts between Ala8‐Glu9, generating GLP‐1 (9‐36), which is inactive or even a mild GLP‐1R antagonist.1 The demonstration of its glucose‐lowering properties in humans was quickly followed by full exploitation of the GLP‐1R as a target in type 2 diabetes using synthetic exendin‐4 under the trade name of Byetta.3 Initially this was administered twice daily, but has since been replaced by modified forms facilitating only once‐weekly administration. Other enzyme‐resistant forms of human GLP‐1 followed onto the market, using acylation and/or amino substitution at position 9 in the N‐terminus to confer DPP‐4 resistance.4