Modulation of in vivo 3-deoxyglucosone levels.
Fructoselysine 3-phosphate is synthesized in vivo by the recently discovered fructoseamine-3-kinase (F3K) from fructoselysine and ATP and decomposes to lysine, P(i) and 3-deoxyglucosone (3DG). This pathway appears to dominate 3DG production in vivo, making it possible to modulate 3DG levels by stimulating or inhibiting the reaction. Present inhibitors are non-reacting substrate analogues with relatively high K (i) values and can inhibit F3K sufficiently in vivo to reduce 3DG in diabetic rat plasma by approx. 50%. Stimulation of the F3K pathway by feeding glycated casein causes an increase of 10-20-fold in plasma levels of 3DG and 3-fold in kidney tubules. Consequences of this increase were studied in two systems: the Eker rat, a model of susceptible kidney tubules; and birth rates in two rat strains. In both cases substantial pathological effects were observed. In the Eker rats, an approx. 3-fold increase in kidney lesions was observed ( P <0.00001). In both Fischer 344 and Sprague-Dawley rats, birth rates were reduced by 56% ( P <0.0001) and 12% ( P <0.015) respectively. These results suggest that inhibition of F3K is a promising new therapeutic target for diabetic complications, as well as other 3DG-dependent pathologies.
Brown
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Departments of Radiology and Biomedical Engineering, Columbia University, New York, NY, U.S.A. trb11@columbia.edu
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Brown
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Schwartz
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Kappler
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D000818:Animals; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000097:blood*; D004032:Diet; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D003847:Deoxyglucose; D017853:Phosphotransferases (Alcohol Group Acceptor); C414347:fructosamine-3-kinase; C016350:3-deoxyglucosone