PT - JOURNAL ARTICLE AU - Christian Thorkildsen AU - Søren Neve AU - Bjarne Due Larsen AU - Eddi Meier AU - Jørgen Søberg Petersen TI - Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in <em>db/db</em> Mice AID - 10.1124/jpet.103.051987 DP - 2003 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 490--496 VI - 307 IP - 2 4099 - http://jpet.aspetjournals.org/content/307/2/490.short 4100 - http://jpet.aspetjournals.org/content/307/2/490.full SO - J Pharmacol Exp Ther2003 Nov 01; 307 AB - We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH2 (ZP10A). Receptor binding studies demonstrated that the affinity of ZP10A for the human GLP-1 receptor was 4-fold greater than the affinity of GLP-1 (7-36) amide. ZP10A demonstrated dose-dependent improvement of glucose tolerance with an ED50 value of 0.02 nmol/kg i.p. in an oral glucose tolerance test (OGTT) in diabetic db/db mice. After 42 days of treatment, ZP10A dose-dependently (0, 1, 10, or 100 nmol/kg b.i.d.; n = 10/group), decreased glycosylated hemoglobin (HbA1C) from 8.4 ± 0.4% (vehicle) to a minimum of 6.2 ± 0.3% (100 nmol/kg b.i.d.; p &lt; 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA1C levels were significantly improved in mice treated with ZP10A for 90 days compared with vehicle-treated controls. Interestingly, these effects were preserved 40 days after drug cessation in db/db mice treated with ZP10A only during the first 50 days of the study. Real-time polymerase chain reaction measurements demonstrated that the antidiabetic effect of early therapy with ZP10A was associated with an increased pancreatic insulin mRNA expression relative to vehicle-treated mice. In conclusion, long-term treatment of diabetic db/db mice with ZP10A resulted in a dose-dependent improvement of FBG, glucose tolerance, and blood glucose control. Our data suggest that ZP10A preserves β-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes. The American Society for Pharmacology and Experimental Therapeutics