Increased erythrocyte 3-DG and AGEs in diabetic hemodialysis patients: role of the polyol pathway.
BACKGROUND
3-Deoxyglucosone (3-DG) accumulating in uremic serum plays an important role in the formation of advanced glycation end products (AGEs). To determine if 3-DG is involved in the formation of intracellular AGEs, we measured the erythrocyte levels of 3-DG and AGEs such as imidazolone and N epsilon-carboxymethyllysine (CML) in hemodialysis (HD) patients with diabetes. Further, to determine if the polyol pathway is involved in the formation of erythrocyte 3-DG and AGEs, an aldose reductase inhibitor (ARI) was administered to these patients.


METHODS
The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were measured in ten diabetic HD patients before and after treatment with ARI (epalrestat) for eight weeks, and were compared with those in eleven healthy subjects. 3-DG was incubated in vitro with hemoglobin for two weeks to determine if imidazolone and CML are formed by reacting 3-DG with hemoglobin.


RESULTS
The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were significantly elevated in diabetic HD patients as compared with healthy subjects. The erythrocyte levels of 3-DG significantly decreased after HD, but sorbitol, imidazolone or CML did not. The administration of ARI significantly decreased the erythrocyte levels of sorbitol, 3-DG and imidazolone, and tended to decrease the CML level. Imidazolone was rapidly produced in vitro by incubating 3-DG with hemoglobin, and CML was also produced, but less markedly as compared with imidazolone.


CONCLUSIONS
The erythrocyte levels of 3-DG and AGEs are elevated in diabetic HD patients. The administration of ARI reduces the erythrocyte levels of 3-DG and AGEs, especially imidazolone, as well as sorbitol. Thus, 3-DG and AGEs, especially imidazolone, in the erythrocytes are produced mainly via the polyol pathway. ARI may prevent diabetic and uremic complications associated with AGEs.
Tsukushi
S
S
Nagoya University, Daiko Medical Center, Japan.
Katsuzaki
T
T
Aoyama
I
I
Takayama
F
F
Miyazaki
T
T
Shimokata
K
K
Niwa
T
T
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011108:Polymers / Q000378:metabolism*; D006435:Renal Dialysis; D013012:Sorbitol / Q000378:metabolism; D014511:Uremia / Q000378:metabolism
D017127:Glycation End Products, Advanced; D006454:Hemoglobins; D007093:Imidazoles; D011108:Polymers; C117197:imidazolone; C024617:polyol; C060458:3-deoxyglucose; D013012:Sorbitol; C048496:N(6)-carboxymethyllysine; D001120:Arginine; D003847:Deoxyglucose; D003404:Creatinine; D000449:Aldehyde Reductase; D008239:Lysine