GIP(Lys16PAL) and GIP(Lys37PAL): novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential

J Med Chem. 2006 Feb 9;49(3):1047-54. doi: 10.1021/jm0509997.


Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(Lys(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blood Glucose / analysis
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / biosynthesis
  • Dipeptidyl Peptidase 4 / chemistry
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gastric Inhibitory Polypeptide / chemical synthesis
  • Gastric Inhibitory Polypeptide / chemistry*
  • Gastric Inhibitory Polypeptide / pharmacology
  • Glucose Tolerance Test
  • Hydrolysis
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacology
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Mice
  • Mice, Obese
  • Molecular Sequence Data
  • Protein Binding
  • Serum Albumin / chemistry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Structure-Activity Relationship
  • Time Factors


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Serum Albumin
  • glucose-dependent insulinotropic polypeptide, epsilon-palmitoyl-Lys(16)-
  • glucose-dependent insulinotropic polypeptide, epsilon-palmitoyl-Lys(37)-
  • Gastric Inhibitory Polypeptide
  • Cyclic AMP
  • Dipeptidyl Peptidase 4