Biological activity of EXf, a peptide analogue of exendin-4.
Exendin-4 is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. EXf is an available carboxy-terminal truncated fragment of exendin-4 with two amino acid substitutions. The purpose of these studies was to evaluate the biological activity of EXf. After a single subcutaneous injection, EXf significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge both in non-diabetic (ICR), monosodium l-glutamate induced insulin resistance (MSG-IR) and diabetic KK-ay mice. Meanwhile, EXf resulted in an increase of first-phase insulin secretion in normal mice and KK-ay mice following the glucose challenge. EXf was also shown to inhibit small intestinal transit in rodent models. EXf activated the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1) GFP-construct in a dose-dependent manner in the cultured mouse insulinoma cell line, termed NIT-1, and this agonist activity was blocked by the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). In summary, EXf, an analogue of exendin-4, has agonist activity to GLP-1 receptor in vitro and glucoregulatory activities in vivo, thus it can be considered as a new candidate for the treatment of type 2 diabetes.
Song
Guang-ming
GM
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
Huan
Yi
Y
Sun
Su-juan
SJ
Chen
Yue-teng
YT
Liu
Quan
Q
Shen
Zhu-fang
ZF
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics; D000077270:Exenatide; D005215:Fasting; D005260:Female; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D019518:Postprandial Period; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014688:Venoms / Q000737:chemistry*
D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP