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Experience |
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University of Toronto
Supervisor: Dr. P. Brubaker (Department of Physiology)
Project: Design of an oral GLP-1 delivery system for the treatment of type 2 diabetes.
The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), has been proposed for the treatment of patients with type 2 diabetes. Since GLP-1 is rapidly inactivated by dipeptidyl-peptidase IV (DP IV), we had previously developed a DP IV degradation-resistant analog of GLP-1, D-ala2-GLP-1, that exhibits enhanced bioactivity when administered sc to mice. However, the glycemic-lowering effects of this peptide are lost within 4 hour of injection, thus necessitating frequent and invasive administration if it is to be used as a treatment for type 2 diabetes. To circumvent these problems, we have designed a therapeutic microsphere [prepared by encapsulating D-ala2-GLP-1 in a modified poly(lactide-co-glycolide)-COOH (PLGA-COOH) polymer] that significantly reduces the glycemic area under the curve (AUC) in response to repeated oral glucose tolerance tests (OGTT) at 4 and 8 hours after administration in non-diabetic mice. We have also shown that when these D-ala2-GLP-l-containing microspheres are given orally to diabetic db/db mice (a model of type 2 diabetes) at t=0 hours, followed by repeated OGTT at 0, 4 and 8 hours. Basal blood glucose levels and AUC were similar between the two groups of mice at 0 hours (control mice: 14±2 mM and 2775±123 mM*120 minutes, respectively; and treated mice: 14±2 mM and 2713±174 mM*120 minutes, respectively; n=6). However, the basal blood glucose values were reduced at 4 hours (from 13±1.4 to 10±1.4 mM) and significantly reduced at 8 hours (from 12±1.1 to 8±0.9 mM, P<0.05, n=6) in microsphere-treated as compared to untreated mice. In addition, the absolute glycemic AUC was reduced significantly as compared to controls at both the 4 and 8 hour time points (from 2589±105 to 1921±138 mM*120 minutes, at 4 hours, P<0.001, and from 2460±152 to 1835±88 mM*120 minutes at 8 hours, P<0.001; n=6). The delta glycemic AUC (AUC independent of the initial basal blood glucose value) was also significantly reduced in comparison to controls at the 4 hour time point (from 1000±140 to 714±49 mM*120 minutes, P<0.05, n=6). These findings demonstrate that in diabetic mice, oral administration of D-ala2-GLP-1 encapsulated into modified PLGA-COOH microspheres is effective in delivering therapeutic levels of GLP-1 over an 8 hour period, thereby reducing both basal blood glucose levels and the glycemic response to repeated OGTT.
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