Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice.
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 < 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 beta-cell function. ZP10A is considered one of the most promising new drug candidates for preventive and therapeutic intervention in type 2 diabetes.
Thorkildsen
Christian
C
Zealand Pharma A/S, Smedeland 26B, DK-2600 Glostrup, Denmark. cth@zp.dk
Neve
Søren
S
Larsen
Bjarne Due
BD
Meier
Eddi
E
Petersen
Jørgen Søberg
JS
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018027:Receptors, Glucagon / Q000819:agonists*; D000067758:Glucagon-Like Peptide-2 Receptor
D001786:Blood Glucose; D002352:Carrier Proteins; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D018027:Receptors, Glucagon; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor