title: Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Anis
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Leshem
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Reuveni
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.|Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Wexler
authors.affiliation: Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Ben Sasson
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Yahalom
authors.affiliation: Keryx Biopharmaceuticals, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Laster
authors.affiliation: Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Raz
authors.affiliation: Department of Experimental Medicine & Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Ben Sasson
authors.affiliation: Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Shafrir
authors.affiliation: Diabetes Research Center, Department of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel. ehud@hadassah.org.il.
authors.forename: E
authors.initials: E
authors.lastname: Ziv
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005849:Gerbillinae; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases