A novel, long-acting agonist of glucose-dependent insulinotropic polypeptide suitable for once-daily administration in type 2 diabetes.
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL(37)), in obese diabetic (ob/ob) mice. Once-daily injections of N-AcGIP(LysPAL(37)) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP(LysPAL(37)). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of N-AcGIP(LysPAL(37)) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL(37)), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.
Irwin
Nigel
N
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
Green
Brian D
BD
Mooney
Mark H
MH
Greer
Brett
B
Harriott
Patrick
P
Bailey
Clifford J
CJ
Gault
Victor A
VA
O'Harte
Finbarr P M
FP
Flatt
Peter R
PR
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000032:analysis / Q000097:blood; D007333:Insulin Resistance; D051379:Mice; D008820:Mice, Obese; D010179:Pancreas / Q000737:chemistry / Q000187:drug effects; D011964:Receptors, Gastrointestinal Hormone / Q000032:analysis / Q000502:physiology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor