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 His(7) and Tyr(1), 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.