Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes

Diabetologia. 2004 Jul;47(7):1232-1244. doi: 10.1007/s00125-004-1444-1. Epub 2004 Jul 3.


Aims/hypothesis: G-protein-coupled receptor kinases (GRKs) play a key role in agonist-induced desensitisation of G-protein-coupled receptors (GPCRs) that are involved in metabolic regulation and glucose homeostasis. Our aim was to examine whether small peptides derived from the catalytic domain of GRK2 and -3 would ameliorate Type 2 diabetes in three separate animal models of diabetes.

Methods: Synthetic peptides derived from a kinase-substrate interaction site in GRK2/3 were initially screened for their effect on in vitro melanogenesis, a GRK-mediated process. The most effective peptides were administered intraperitoneally, utilising a variety of dosing regimens, to Psammomys obesus gerbils, Zucker diabetic fatty (ZDF) rats, or db/db mice. The metabolic effects of these peptides were assessed by measuring fasting and fed blood glucose levels and glucose tolerance.

Results: Two peptides, KRX-683(107) and KRX-683(124), significantly reduced fed-state blood glucose levels in the diabetic Psammomys obesus. In animals treated with KRX-683(124) at a dose of 12.5 mg/kg weekly for 7 weeks, ten of eleven treated animals responded with mean blood glucose significantly lower than controls (4.7+/-0.4 vs 16.8+/-0.8 mmol/l, p</=0.0001). Significant reductions in blood glucose compared with controls were also seen in ZDF rats administered KRX-683(124) and in db/db mice, which had significantly reduced fasting and 2-hour postprandial glucose levels after the treatment.

Conclusions/interpretation: Sequence-based peptides derived from GRK2/3 have an antidiabetic effect demonstrated in three different animal models of Type 2 diabetes. By modulating GRK2/3 activity, these peptides enhance GPCR-initiated signal transduction, resulting in improved glucose homeostasis. Sequence-based peptide modulation of GRK could prove useful in the treatment of Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / therapeutic use*
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy*
  • Female
  • Gerbillinae
  • Hypoglycemic Agents / therapeutic use*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Peptide Fragments / therapeutic use*
  • Rats
  • Rats, Zucker
  • beta-Adrenergic Receptor Kinases


  • Blood Glucose
  • Hypoglycemic Agents
  • Peptide Fragments
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases