Combined use of derivatives of GLP-1 analogs and PPAR ligands

The present invention provides methods and compositions for treatment and/or prevention of type 1 and type 2 diabetes, dyslipdemia, impaired glucose tolerance, insulin resistance, obeity, and beta-cell apoptosis, as well as methods for increasing the size and number of beta-cells in a subject and/or stimulating beta-cell proliferation, which comprise administering both a stable GLP-1 analogue and a non-thiazolidinedione PPAR ligand.

Experimental Synergistic effect of combining (−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid and Arg 34 , Lys 26 (N &egr; -(&ggr;-Glu(N &agr; -hexadecanoyl)))-GLP-1(7-37) on glucose and HbA 1 (glycosylated hemoglobin) in the male ZDF rat. 
 Study Design Ninety male ZDF rats aged 15-16 weeks were used in the study. Before treatment start, measurements of glucose and HbA 1c were performed. All animals were overtly diabetic at the beginning of the study. Animals were allocated into the following 4 treatment groups: Group 1: Vehicle-1&plus;Vehicle-2 (n&equals;10) Group 2: (−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid, 1 mg/kg&plus;Vehicle-2 (n&equals;10) Group 3: Vehicle-1&plus;Arg 34 , Lys 28 (N &egr; -(&ggr;-Glu(N &agr; -hexadecanoyl)))-GLP-1(7-37), 50 &mgr;g/kg (n&equals;10) Group 4: (−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid, 1 mg/kg&plus;Arg 34 , Lys 26 (N &egr; -(&ggr;-Glu(N &agr; -hexadecanoyl)))-GLP-1(7-37), 50 &mgr;g/kg (n&equals;10) (−)-2-Ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid and Vehicle-1 were administered by oral gavage once daily at approx. 07:30. Arg 34 , Lys 26 (N &egr; -(&ggr;-Glu(N &agr; -hexadecanoyl)))-GLP-1(7-37) and Vehicle-2 were administered subcutaneously twice daily at approx. 07:30 and 14:30. After four weeks treatment, HbA 1 was measured and 24-hour glucose profiles were assessed. 
 Results The findings of group 1, 2, 3 and 4 are listed in the table below (mean±SEM). Delta HbA 1c refers to the numerical difference between the measurement after treatment and the measurement before treatment. Glucose 24 hAuc refers to the total area under the glucose con- centration curve during the 24-hour period. A two-way analysis of variance was performed for each parameter and the significance of the interaction term evaluated. 2 P value of interaction term in two- Group 1 Group 2 Group 3 Group 4 way ANOVA Delta HbA 1C 1.24 ± 0.17 −0.81 ± 0.36 0.28 ± 0.19 −3.78 ± 0.18 p < 0.0002 (% points) Glucose 24hAUC 538 ± 6 456 ± 38 508 ± 4 256 ± 27 p <0.001 (mM × h) The highly significant interaction terms demonstrate that four weeks combination treatment with (−)-2-ethoxy-3-(4-(2-phenoxazin-10-yl-ethoxy)-phenyl)-propionic acid (1 mg/kg, once daily) and Arg 34 , Lys 26 (N &egr; -(&ggr;-Glu(N 60 -hexadecanoyl)))-GLP-1(7-37) (50 &mgr;g/kg, twice daily) has synergistic (greater than additive) effects on HbA 1 and 24-hour glucose profiles in overtly diabetic ZDF rats. All patents, patent applications, and literature references referred to herein are hereby incorporated by reference in their entirety. Many variations of the present invention will suggest themselves to those skilled in the art in light of the above detailed description. Such variations are within the full intended scope of the appended claims.