Anzeige
Erschienen in:
01.07.2004 | Article
Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes
Erschienen in: Diabetologia | Ausgabe 7/2004
Einloggen, um Zugang zu erhaltenAbstract
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-683107 and KRX-683124, significantly reduced fed-state blood glucose levels in the diabetic Psammomys obesus. In animals treated with KRX-683124 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-683124 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.