Studies On Glucagon Like Peptide-1and Its Stable Analogues

Diabetes is a global health threat, type2diabetes occupy more than90%of the total number of patients, the disease process is accompanied by insulin resistance and β-cells dysfunction. Glucagon like peptide-1(GLP-1) is an incretin hormone that could increase insulin secretion glucose-dependently, the increase of insulin secretion only in high glucose concentration and does not have this effect at normal blood glucose levels, thereby eliminating the hypoglycemia. In addition, GLP-1could inhibit death of P-cells and promote cells regeneration, which provides a new option for the treatment of type2diabetes.β-cells are extremely sensitive to endoplasmic reticulum stress (ER stress), ER stress would mediate β-cells apoptosis, which plays an important role in the process of diabetes. Thapsigargin (TG) could induce ER stress in INS-1cells, thus triggers unfolded protein response (UPR).To investigate the effects of Liraglutide, an GLP-1analogue, on major signaling molecules of UPR. In these results, Liraglutide could reduce the levels of signaling molecules and inhibit β-cells death, these results suggesting that Liraglutide has a protective effect on beta cells.With a clear effect on T2DM, human GLP-1has a great therapeutic potency, however, half-time of GLP-1is only2-5minutes in vivo. Because of extreme short half-time, GLP-1in clinical treatment has been greatly limited. Studies focus on prolonging endogenous or exogenous biological activity of GLP-1, mainly divided into two categories:long-acting GLP-1analogues (long-acting GLP-1receptor agonist) and DPP IV (dipeptidyl peptidase IV, an endogenous enzyme with degradation effect of GLP-1) inhibitors. The formers prolong the half-time and achieve slow release effect through protecting the specific degradation sites, and the latters extend the half-time of GLP-1by inhibiting the DPP IV directly. In addition, we designed a series of GLP-1analogues, through modification of the structure, not only retain the biological activity of the native GLP-1, but also to prolong the half-time and slow down the metabolic rate in vivo. In this thesis, we have selected the most stable GLP-1analogue from a series of peptides. Both in vivo and in vitro results suggested that GLP-1analogue peptides have the ability to control of acute hyperglycemia.