Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1.
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.
Green
B D
BD
School of Biomedical Sciences, University of Ulster, Coleraine, N. Ireland, UK. b.green@ulster.ac.uk
Liu
H K
HK
McCluskey
J T
JT
Duffy
N A
NA
O'Harte
F P M
FP
McClenaghan
N H
NH
Flatt
P R
PR
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats
D007328:Insulin; D009842:Oligopeptides; D011480:Protease Inhibitors; D052216:Glucagon-Like Peptide 1; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4