C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes.
Glucose-dependent insulinotropic polypeptide has been proposed as a potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24h. Both GIP[mPEG] and GIP concentration-dependently stimulated cAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p < 0.01 to p < 0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p < 0.05) and increased plasma insulin responses (p < 0.05). Furthermore, GIP[mPEG] markedly lowered plasma glucose when administered 4-24h prior to a glucose load (p < 0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p < 0.05). Moreover, glucose tolerance was significantly improved (p < 0.05) together with glucose-mediated plasma insulin responses (p < 0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. In summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and improve biological action thus representing a novel therapeutic option for type 2 diabetes.
Gault
Victor A
VA
School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, United Kingdom. va.gault@ulster.ac.uk
Kerr
Barry D
BD
Irwin
Nigel
N
Flatt
Peter R
PR
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D004355:Drug Stability; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000493:pharmacokinetics / Q000502:physiology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats
D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D011092:Polyethylene Glycols; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP