Glycogen metabolism and its regulation are abnormal in liver and muscle in both Type 1 and Type 2 diabetes mellitus. Liver glycogen metabolism is particularly important to maintaining blood glucose homeostasis through regulating the uptake and release of glucose and provides an attractive target for the action of antidiabetic drugs which until recently has not been fully exploited. The principal objective of this proposal is to design, synthesize and purify a series of novel alkylmaltosides and to test these compounds in vitro and in vivo for their ability to serve as artificial primers for glycogen synthesis that can increase glucose disposal into liver glycogen and thereby lower blood glucose levels. The ability of the O-alkylmaltosides to serve as acceptors for glucose transfer by the glycogen biosynthetic enzymes glycogenin and glycogen synthase will be determined in soluble and particulate fractions of mouse liver in vitro. Those compounds with the most activity as substrates for these enzymes will be converted to S-alkylmaltosides which will also be tested in vitro as glucose acceptor substrates for the glycogen biosynthetic enzymes. The most active 0- and/or S-alkylmaltosides in the in vitro enzymatic screening procedure will be tested orally in vivo in the obese-hyperglycemic (ob/ob) mouse model of type 2 diabetes for their ability to lower blood glucose levels and improve glucose tolerance in these animals. There are four specific aims in this phase I proposal: 1. Design and Synthesis of a Series of Novel Alkylmaltosides 2. Purification and Characterization of the Alkylmaltosides 3. Testing of the Alkylmaltosides as Substrates for the Glycogen Biosynthetic Enzymes 4. Determine the Effects of the Most Active O- and/or S-Alkylmaltosides on Blood Glucose and Glucose tolerance in the ob/ob Mouse Model.
