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Function of a long‐term, GLP‐1‐treated, insulin‐secreting cell line is improved by preventing DPP IV‐mediated degradation of GLP‐1
Author(s) -
Green B. D.,
Liu H. K.,
McCluskey J. T.,
Duffy N. A.,
O'Harte F. P. M.,
McClenaghan N. H.,
Flatt P R.
Publication year - 2005
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2004.00430.x
Subject(s) - insulin , glucagon like peptide 1 , endocrinology , medicine , beta cell , chemistry , type 2 diabetes , glucagon , biology , diabetes mellitus , islet
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 β 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.