Function of a long‐term, GLP‐1‐treated, insulin‐secreting cell line is improved by preventing DPP IV‐mediated degradation of GLP‐1

Abstract

Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N-acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9-36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N-acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic beta cells and that prolonged exposure to GLP-1(9-36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N-acetyl-GLP-1.

Effects of long-term dipeptidyl peptidase-IV inhibition on body composition and glucose tolerance in high fat diet-fed mice

“…Indeed, it has been reported that continuous GLP-1 stimulation results in desensitization of GLP-1R, which can subsequently reduce insulin secretion in response to GLP-1 in insulin-secreting cell lines (Widmann et al 1996;Green et al 2005). However, the expression of GLP-1R and GIPR in islets did not change in DPP-IV inhibitor-treated mice in the present study.…”

Combination of the Dipeptidyl Peptidase IV Inhibitor LAF237 [(S)-1-[(3-Hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the Angiotensin II Type 1 Receptor Antagonist Valsartan [N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-l-valine] Enhances Pancreatic Islet Morphology and Function in a Mouse Model of Type 2 Diabetes

“…Because dipeptidyl peptidase-IV (DPP-IV) is responsible for the degradation of GLP-1 (Kieffer et al, 1995), orally available inhibitors of DPP-IV have been developed for therapeutic use in T2DM. A number of in vitro and in vivo studies support the view that DPP-IV inhibition improves ␤-cell function by enhancing insulin secretion and augmenting ␤-cell proliferation (Burkey et al, 2005;Green et al, 2005). Human data also indicate DPP-IV inhibition contributes to better glycemic control ).…”

Bioactivity of a modified human Glucagon-like peptide-1

“…Hence, GLP-1 is an excellent candidate for use as a prophylactic treatment for maintaining glucose homeostasis in diabetic patients and has been extensively investigated. The very short plasma half-life (less than 2 minutes in the circulatory system), however, limits its pharmacotherapy study and clinical application [ 9 – 11 ]. Dipeptidyl peptidase IV (DPP-IV)-mediated cleavage at Ala 8 of mature N-terminal GLP-1 results in the production of inactivated N-terminal truncated peptides, GLP-1(9–36) or GLP-1 (9–37).…”