A comparison of the cellular and biological properties of DPP-IV-resistant N-glucitol analogues of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.
OBJECTIVE
The two major incretin hormones--glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)--are being actively researched by the pharmaceutical industry because of their glucose-lowering and potential anti-diabetic properties. Unfortunately, the inactivation of GLP-1 and GIP in the circulation brought about by dipeptidyl-peptidase-IV (DPP-IV) degradation makes their biological actions short-lived. This study directly compares the cellular and biological properties of GLP-1, GIP and their N-terminally modified counterparts, with glucitol extension at positions His7 and Tyr1 respectively, to confer DPP-IV resistance.


METHODS
Using both the glucose-responsive pancreatic beta-cell line, BRIN BD11, and the obese diabetic (ob/ob) mouse, we assessed adenosine 3',5'-cyclic monophosphate (cAMP) production and insulinotropic action in vitro as well as in vivo glucose-lowering and insulin-releasing actions.


RESULTS
The results reveal that glycation of the N-terminus of GLP-1 or GIP stabilized both peptides against DPP-IV degradation. However, N-glucitol-GLP-1 displayed reduced cAMP production, insulinotropic activity and glucose-lowering potency, compared to native GLP-1. By contrast, N-glucitol-GIP exhibited substantially improved biological activities, compared to native GIP, and possessed similar or enhanced in vivo potency to GLP-1. N-terminal extension by means of glucitol addition is more beneficial to bioactivity of GIP than it is to GLP-1.


CONCLUSIONS
N-terminal glycation generates a super GIP agonist, which possesses acute in vivo glucose-lowering and insulinotropic actions superior to native GLP-1. Therefore, N-glucitol-GIP is a particularly attractive potential candidate molecule for drug therapy of type 2 diabetes.
Green
B D
BD
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. b.green@ulster.ac.uk
Gault
V A
VA
O'Harte
F P M
FP
Flatt
P R
PR
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology* / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology* / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D013012:Sorbitol / Q000494:pharmacology* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013012:Sorbitol; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4