Polyol pathway activation and glutathione redox status in non-insulin-dependent diabetic patients.
The current study aimed to evaluate whether nicotinamide adenine dinucleotide phosphate (NADPH) alteration in erythrocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM) is responsible for the impaired glutathione (GSH) redox status, and to assess if short-term inhibition of the polyol pathway normalizes NADPH levels and GSH redox status via an amelioration of the NADPH/total NADP (tNADP) ratio. For this purpose, erythrocyte NADPH and GSH levels were measured in 18 NIDDM patients at baseline and then after 1 week of random double-blind assignment to treatment with either tolrestat (an aldose reductase inhibitor, 200 mg daily) (n = 12) or placebo (n = 6). A group of 16 healthy volunteers served as the control. In the basal condition, mean GSH (P < .0001) and NADPH (P < .0001) levels and NADPH/tNADP (P < .0001) and GSH/ glutathione disulfide (GSSG) (P < .005) ratios were lower in NIDDM patients than in control subjects. Tolrestat treatment increased GSH levels (P < .05 v placebo and baseline) and the NADPH/tNADP ratio (P < .05 v placebo and baseline). Interestingly, tolrestat-induced changes in GSH and NADPH levels and in GSH/GSSG and NADPH/tNADP ratios were significant only in patients who showed a decreased NADPH/tNADP ratio at baseline (n = 8). In these latter patients, we also found a direct correlation between percentage increments in GSH levels and NADPH/tNADP ratios after tolrestat treatment (r = .71, P < .05). In conclusion, our findings support the hypothesis that polyol pathway activation decreases NADPH and GSH levels. Accordingly, short-term inhibition of this enzymatic route increased both the GSH level and the NADPH/tNADP ratio. These changes were observable only in the subgroup of patients with an abnormal NADPH/tNADP ratio at baseline. Polyol pathway inhibition could be useful for decreasing oxidative stress in NIDDM.
Bravi
M C
MC
First Institute of Internal Medicine, University La Sapienza, Rome, Italy.
Pietrangeli
P
P
Laurenti
O
O
Basili
S
S
Cassone-Faldetta
M
M
Ferri
C
C
De Mattia
G
G
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000097:blood; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood*; D019803:Glutathione Disulfide; D006801:Humans; D008297:Male; D008875:Middle Aged; D009249:NADP / Q000097:blood*; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D012016:Reference Values
D004791:Enzyme Inhibitors; D009281:Naphthalenes; C040550:tolrestat; D009249:NADP; D000449:Aldehyde Reductase; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D019803:Glutathione Disulfide