Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases Insulin mRNA Expression and Prevents Diabetic Progression in db/db Mice

• Published in: The Journal of pharmacology and experimental therapeutics 2003-11, Vol.307 (2), p.490-496
• Main Authors: Thorkildsen, Christian, Neve, Søren, Larsen, Bjarne Due, Meier, Eddi, Petersen, Jørgen Søberg
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Carrier Proteins - therapeutic use; Diabetes Mellitus - prevention & control; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Glucagon - drug effects; Glucagon - metabolism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Hypoglycemic Agents - therapeutic use; Insulin - blood; Insulin - genetics; Mice; Mice, Inbred C57BL; Peptide Fragments - drug effects; Peptide Fragments - metabolism; Peptides - therapeutic use; Protein Precursors - drug effects; Protein Precursors - metabolism; Receptors, Glucagon - agonists; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.051987

We characterized the novel, rationally designed peptide glucagon-like peptide 1 (GLP-1) receptor agonist H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSK KKKKK-NH 2 (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 ED 50 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 (HbA 1C ) from 8.4 ± 0.4% (vehicle) to a minimum of 6.2 ± 0.3% (100 nmol/kg b.i.d.; p < 0.05 versus vehicle) in db/db mice. Fasting blood glucose (FBG), glucose tolerance after an OGTT, and HbA 1C 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.