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

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

Author information

Keryx Biopharmaceuticals, Jerusalem, Israel.
Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.
Department of Experimental Medicine & Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.



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.


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.


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.


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.

[Indexed for MEDLINE]

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