title: A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.
abstract: OBJECTIVE
  Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794.
  
  
  METHODS
  AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2) ]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14) ] exenatide. Human GIP or [d-Ala(2) ]GIP(1-42) were used for comparison.
  
  
  RESULTS
  AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174.
  
  
  CONCLUSIONS
  These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.
authors.affiliation: Amylin Pharmaceuticals, LLC, San Diego, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Tatarkiewicz
authors.forename: D M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: C M
authors.initials: CM
authors.lastname: Jodka
authors.forename: B R
authors.initials: BR
authors.lastname: Gedulin
authors.forename: P A
authors.initials: PA
authors.lastname: Smith
authors.forename: J A
authors.initials: JA
authors.lastname: Hoyt
authors.forename: A
authors.initials: A
authors.lastname: Lwin
authors.forename: L
authors.initials: L
authors.lastname: Collins
authors.forename: L
authors.initials: L
authors.lastname: Mamedova
authors.forename: O E
authors.initials: OE
authors.lastname: Levy
authors.forename: L
authors.initials: L
authors.lastname: D'Souza
authors.forename: S
authors.initials: S
authors.lastname: Janssen
authors.forename: V
authors.initials: V
authors.lastname: Srivastava
authors.forename: S S
authors.initials: SS
authors.lastname: Ghosh
authors.forename: D G
authors.initials: DG
authors.lastname: Parkes
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: C000592575:AC163794; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054795:Incretins; D005749:Gastric Inhibitory Polypeptide
keywords: DPP-IV resistant; GIP; Trp-cage; diabetes; rodents