title: (Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.
abstract: OBJECTIVE
  Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro(3))GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro(3))GIP, (Pro(3))GIP mini-polyethylene glycol ((Pro(3))GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime.
  
  
  METHODS
  We studied the actions of (Pro(3))GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity.
  
  
  RESULTS
  (Pro(3))GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro(3))GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro(3))GIP[mPEG] administration, compared with (Pro(3))GIP. In contrast with (Pro(3))GIP, mice injected once every 3 days for 48 days with (Pro(3))GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro(3))GIP, (Pro(3))GIP[mPEG] or (Pro(3))GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro(3))GIP[mPEG] and (Pro(3))GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro(3))GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice.
  
  
  CONCLUSIONS
  These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro(3))GIP[mPEG] as a long-acting stable GIP receptor antagonist.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: P L
authors.initials: PL
authors.lastname: McClean
authors.forename: N
authors.initials: N
authors.lastname: Irwin
authors.forename: K
authors.initials: K
authors.lastname: Hunter
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004337:Drug Carriers / Q000737:chemistry*; D004435:Eating / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004041:Dietary Fats; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; D011092:Polyethylene Glycols; D005749:Gastric Inhibitory Polypeptide; C028210:monomethoxypolyethylene glycol