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Modulation of insulinotropic hormone bioactivity with a focus on clucose-dependent insulinotropic polipeptide (GIP) and its receptor Hinke, Simon Amadeus

Abstract

Insulin secretory responses to oral glucose are compromised in type 2 diabetes. GIP receptor desensitization and internalization were studied as possible mechanisms for the blunted responsiveness to GIP in the human disease, employing in vitro cellular models. Using clonal insulin producing tumour cells (βTC-3) and rat GIP receptor transfected CHO-K1 cells, it was possible to characterize important aspects of receptor regulation. GIP receptor desensitization appeared to be slower than for other related receptors, and the rate appeared to parallel receptor internalization. Phosphorylation of receptor carboxyl terminal serine residues was implicated in both processes. Using co-transfection techniques and pharmacological agents, it was possible to partially delineate cellular proteins involved in GIP receptor desensitization and internalization. Dipeptidyl peptidase IV cleaves dipeptides from the N-termini of GIP, GLP-1 and glucagon, all of which are insulinotropic peptides involved in glucose homeostasis. Using cells transfected with the cognate receptors for these hormones, it was possible to demonstrate the importance of this enzyme in the modulation of hormone bioactivity. Structure-activity relationships for the peptides were designed to characterize the N-terminally truncated peptides, as well as design enzyme resistant molecules predicted to have superagonist activity in vivo. Such analogues with enhanced bioactivity may have a use in the treatment of diabetic states (GIP and GLP-1) or cardiovascular complications (glucagon). In vivo bioassay of these peptides confirmed their increased potency and highlighted their therapeutic potential. Additionally, fragment analysis was performed on GIP in an attempt to minimize the bioactive domain of the molecule, thus generating small molecular weight GIP receptor agonists.

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