No abstract

Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(d-Ala)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(d-Ala)GIP/GLP-1-exe significantly (P < 0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P < 0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P < 0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P < 0.05) 8 h post-injection. Twice-daily injection of N-ac(d-Ala)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P < 0.05-P < 0.001) reduced body weight, HbA, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P < 0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P < 0.05-P < 0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(d-Ala)GIP/GLP-1-exe treated mice exhibited improved (P < 0.01) recognition memory which was accompanied by enhanced (P < 0.05-P < 0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(d-Ala)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.

These studies emphasize the potential of stable Oxm-based peptides, such as (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], as therapeutic agents for insulin-deficient type 1 diabetes.