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

• Published in: Diabetologia 2004-07, Vol.47 (7), p.1232-1244
• Main Authors: ANIS, Y, LESHEM, O, ZIV, E, REUVENI, H, WEXLER, I, BEN SASSON, R, YAHALOM, B, LASTER, M, RAZ, I, BEN SASSON, S, SHAFRIR, E
• Format: Article
• Language: English
• Subjects: Animals; Antidiabetics; beta-Adrenergic Receptor Kinases; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Line; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases - therapeutic use; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Gerbillinae; Glucose; Homeostasis; Hospitals; Hypoglycemic Agents - therapeutic use; Insulin resistance; Kinases; Medical research; Medical sciences; Melanoma, Experimental; Metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments - therapeutic use; Phosphorylation; Polypeptides; Proteins; Psammomys obesus; Rats; Rats, Zucker; Signal transduction
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-004-1444-1

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