A comparison of the cellular and biological properties of DPP-IV-resistant N-glucitol analogues of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide

Aim: The two major incretin hormones – glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) – are being actively researched by the pharmaceutical industry because of their glucose‐lowering and potential anti‐diabetic properties. Unfortunately, the inactivation of GLP‐1 and GIP in the circulation brought about by dipeptidyl‐peptidase‐IV (DPP‐IV) degradation makes their biological actions short‐lived. This study directly compares the cellular and biological properties of GLP‐1, GIP and their N‐terminally modified counterparts, with glucitol extension at positions His7 and Tyr1, respectively, to confer DPP‐IV resistance. Methods: Using both the glucose‐responsive pancreatic beta‐cell line, BRIN BD11, and the obese diabetic (ob/ob) mouse, we assessed adenosine 3′,5′‐cyclic monophosphate (cAMP) production and insulinotropic action in vitro as well as in vivo glucose‐lowering and insulin‐releasing actions. Results: The results reveal that glycation of the N‐terminus of GLP‐1 or GIP stabilized both peptides against DPP‐IV degradation. However, N‐glucitol‐GLP‐1 displayed reduced cAMP production, insulinotropic activity and glucose‐lowering potency, compared to native GLP‐1. By contrast, N‐glucitol‐GIP exhibited substantially improved biological activities, compared to native GIP, and possessed similar or enhanced in vivo potency to GLP‐1. N‐terminal extension by means of glucitol addition is more beneficial to bioactivity of GIP than it is to GLP‐1. Conclusions: N‐terminal glycation generates a super GIP agonist, which possesses acute in vivo glucose‐lowering and insulinotropic actions superior to native GLP‐1. Therefore, N‐glucitol‐GIP is a particularly attractive potential candidate molecule for drug therapy of type 2 diabetes.