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

Abstract:

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

journal_name

Diabetologia

journal_title

Diabetologia

authors

Anis Y,Leshem O,Reuveni H,Wexler I,Ben Sasson R,Yahalom B,Laster M,Raz I,Ben Sasson S,Shafrir E,Ziv E

doi

10.1007/s00125-004-1444-1

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

1232-1244

issue

7

eissn

0012-186X

issn

1432-0428

pii

10.1007/s00125-004-1444-1

journal_volume

47

pub_type

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