We propose to study a Self-Regulating Insulin Delivery System - Artificial Pancreas - based on the concept of competitive and complementary binding between a glycosylated insulin and glucose to a lectin substrate. The glycosylated insulin is bound to specific sites on lectin, Con A, which are also complementary to glucose. This glycosylated insulin is then displaced from the Con A by an excess amount of glucose, thus providing glycosylated insulin release in response to and proportional to the amount of glucose present. Our preliminary studies demonstrated that; 1) synthesized glycosylated insulin (mannopyranoside or glucopyranoside coupled) retain bioactivity. 2) the response of glycosylated insulin release through a polymer membrane is proportional to the glucose concentration, in in vitro study. 3) peritoneal implant containing glycosylated insulin - Con A complex, functions to control blood glucose level in depancreatized dogs. Selected glycosylated insulins having higher binding affinity to Con A than that of glucose will be synthesized and characterized to obtain optimum binding constant to Con A and bioactivity. Three types (hydrophilic, hydrophobic, amphiphilic) of polymer membranes will be synthesized to provide optimum permeability (glucose influx and glycosylated insulin efflux). Also, the biocompatibility and mechanical integrity of polymer membranes will be determined. Mathematic kinetic model will be evaluated according to the in vitro data and will be utilized to optimize design parameters for in vivo study. Short and long term animal studies using a depancreatized diabetic animal model will provide a criteria for clinical use of this proposed artificial pancreas.
| Liu, F; Song, S C; Mix, D et al. (1997) Glucose-induced release of glycosylpoly(ethylene glycol) insulin bound to a soluble conjugate of concanavalin A. Bioconjug Chem 8:664-72 |
| Baudys, M; Uchio, T; Mix, D et al. (1995) Physical stabilization of insulin by glycosylation. J Pharm Sci 84:28-33 |
| Makino, K; Mack, E J; Okano, T et al. (1991) Self-regulated delivery of insulin from microcapsules. Biomater Artif Cells Immobilization Biotechnol 19:219-28 |
