FBPase and Type 2 Diabetes. Fructose-1,6-bisphosphatase (FBPase), the penultimate enzyme in the pathway that makes glucose, is an allosteric enzyme inhibited by adenosine monophosphate (AMP) at the allosteric site. Our interest was to elucidate the mechanism of control of the active site by binding of AMP at a distant regulatory site (Ref. 1 and 2).

Then, Mark Erion of Metabasis Therapeutics and I began a collaborative project to reduce the abnormal increase of FBPase (Ref. 3) shown in Type 2 Diabetics by making analogues of the inhibitor AMP. During this 15 year collaboration, we have discovered oral AMP analogues which displace AMP, have low toxicity, do not interfere with critical other AMP functions, and especially that reduce glucose levels to moderate values. Studies of effective results in the rat model are summarized in Ref. 4. Human trials are in the final stages of phase 2, and possible interactions of a promising inhibitor (Ref. 4) with metformin (a medicine for Type 2 diabetes) are under evaluation.

Ref.1. Ke, et al. Proc. Natl. Acad. Sci., USA 87, 5243 (1990).
Ref.2. Ke, et al. Biochemistry, 30, 4412 (1991).
Ref.3. Rothman, et al., Science 254, 573 (1991).
Ref.4. Erion, et al., Proc. Natl. Acad. Sci., USA 102, 7970 (2005).