1. Table 1. Pharmacokinetic Parameters of ZP2929 (from ref 1 & 2)
The New Dual Glucagon-GLP-1 Agonist ZP2929 Actually Improves Glycemic Control in High Fat Fed C57BL/6J Mice Jens R. Daugaard, Eddi Meier, Ditte Riber, Camilla Æ. Bæk & Kjeld S. Larsen Zealand Pharma A/S, Smedeland 36, DK-2600 Glostrup, Copenhagen, Denmark
Background
ZP2929 is a novel and potent dual glucagon-GLP-1(GluGLP-1) agonist invented at Zealand Pharma A/S. The peptide acts both on the glucagon receptor and on the GLP-1 receptor (1 & 2). ZP2929 decreases body weight gain in short (4 weeks) and long (30 weeks) term high fat fed C57Bl/6J mice (1 & 2). In addition, in long term (30 weeks) high fat fed C57Bl/6J mice, ZP2929 improves glucose tolerance as assessed by an oral glucose tolerance test (1 & 2). The acute effect of ZP2929 on oral glucose tolerance is not known. Therefore, the acute effect of ZP2929 on oral glucose tolerance in the short term high fat fed mouse was evaluated.
Material and Methods
Fig. 2. Acute effect of ZP2929 (s.c.) on fasting glucose (4h) at the indicated time points after dosing in HFD C57BL/6J mice. Data are mean ± SEM, * P < vs. vehicle at same time point.
C57BL/6J male mice, 6 weeks old, were fed a high fat diet (HFD) for 4 weeks. The animals were randomized into groups with similar average fasting (4 hours) blood glucose. 2, 4, 6, 8, 10, 12 and 24 hours after peptide (10 nmol/kg) or vehicle dosing a blood sample was taken. Immediately thereafter, an oral dose of glucose, dissolved in phosphate buffer was given, and the animals were returned to their cages (t = 0). Blood glucose levels were measured at t=15 min, t=30 min, t=60 min and t=90 min.
ZP2929 improved glucose tolerance (fig.1) by 37%, 54%, 48%, 57 %, 48%, 50% and 24% measured at 2, 4, 6, 8, 10, 12 and 24 h after dosing, respectively. The decreasing effect of ZP2929 on fasting blood glucose first became significant after 4 h (fig. 2) and remained significant up to 24 hours after dosing. The decrease in fasting blood glucose was 39%, 56%, 58%, 38%, 54% and 28% measured at 4, 6, 8, 10, 12 and 24 h after dosing, respectively. This fits well the ZP2929 pharmacokinetics, which showed maximal peptide concentration (Cmax) at 6 hours (Tab. 1)
Results
Table 1. Pharmacokinetic Parameters of ZP2929 (from ref 1 & 2)
Species
Dose (nmol/kg)
T½ I.V. (hours)
T½ S.C (hours)
Tmax (hours)
Fsc
(%)
Mouse 40
3.6
6.2
6.0 30
Monkey 20
5.6 ± 0.3
6.2 ± 0.7
6.0 ± 2.8
36 ± 11
Conclusion
ZP2929 (10 nmol/kg) acutely improved glucose tolerance for up to 24 hours after dosing in high fat fed C57BL/6J mice.
References
Daugaard JR, Meier E, Bæk CÆ, Larsen K. The new dual GluGLP-1 agonist ZP2929 improves glycemic control and reduces body weight in murine models of obesity and type 2 diabetes. Poster at ADA, Orlando June 2010.
Daugaard JR, Meier E, Bæk CÆ, Larsen K, Kampen G. The new dual GluGLP-1 agonist ZP2929 improves glycemic control and reduces body weight in murine models of obesity and type 2 diabetes. Poster at EASD, Stockholm September 2010
Fig. 1. Acute effect of ZP2929 (s.c.) on glucose tolerance (measured as AUC during an oral glucose tolerance test) at indicated time points after dosing in HFD C57BL/6J mice. Data are mean ± SEM, * P < vs. vehicle at same time point.