Diabetic hyperglycemia results in an increase in free-radical production by a mechanism involving glucose oxidation followed by protein glycation and oxidative degeneration . Glycation (nonenzymatic glycosylation) involves the condensation of glucose with the ε-amino group of lysine, the -amino group of an Nterminal amino acid or the amines of nucleic acids .
The first reaction is the formation of an unstable Schiff base, which reaches a steady state within hours and is reversible. Rearrangement of the Schiff base into an Amadori product reaches a steady state in approximately 28 days and is also reversible. When molecules have slow turnover rates, these Amadori products undergo multiple dehydration reactions and rearrangements to irreversibly form AGEs. AGEs are believed to be involved in the genesis of many of the irreversible complications of diabetes, including expanded extracellular matrix, cellular hypertrophy, hyperplasia, and vascular complications .
Markers used for estimating the degree of protein glycation in diabetes include fructosamine and glycated hemoglobin levels. Nonenzymatic glycation may also alter the structure and function of antioxidant.
Normoglycemia is a desired effect of any drug used either singly or in combination in the treatment of diabetes, but apart from insulin, only a limited number of drugs including melatonin, probucol, vitamins C and E plus beta-carotene, and alfa-lipoic acid reduce high blood glucose levels in diabetes. The majority of antioxidants do not reverse diabetes-induced hyperglycemia, and these agents must be given as adjuvants to insulin therapy.
Elevated glycosylated hemoglobin and fructosamine concentrations in diabetic Wistar rats are restored to normal levels after treatment with beta- carotene (50 mg/kg) for a period of 40 days. STZ induced diabetic Sprague-Dawley rats demonstrate hyperglycemia, high levels of glycated hemoglobin A1c and AGEs, as well as impaired acetylcholine-induced relaxations of the vascular segments. However, treatment with acarbose immediately after STZ, supplemented with low dose insulin (1 unit/day), restores both blood glucose and glycated hemoglobin A1c to normal levels, but not the AGE content. Addition of 100U/mLSODnormalizes the impaired vascular relaxation, suggesting an important role of superoxide radicals in diabetes-induced endothelial dysfunction. Increased nonenzymatic glycation and AGEs are also postulated to contribute to cataract formation. Administration of aldose reductase inhibitors (0.06% tolrestat or polnalrestat, 0.0125% AL-1576 for 8 weeks) in the diet of STZ-induced diabetic rats results in reduced sorbitol levels, inhibition of cataract formation, lowered concentrations of glycosylated lens proteins, and slightly reduced lenticular AGE levels compared to untreated diabetic rats after 45 and 87 days of diabetes.
Treatment of diabetes in male CF1 mice with acetylsalicylic acid (0.16% w/w in diet starting 30 min after STZ injection) blocks the accumulation of lipoperoxide
aldehydes, reduces hyperglycemia, and prevents the inactivation of heme enzymes, -aminolevulinic dehydrase, and porphobilinogen deaminase. This inhibition of protein glycosylation through acetylation of free amino groups and lowering of blood glucose by acetylsalicylic acid may prevent some of the complications of diabetes.
STZ-diabetes induces a 10-fold increase in – glutamyl transferase activity in rat liver, resulting in decreased biliary excretion of glutathione and other chemicals. Although regulation of -glutamyl transferase activity has been shown to be independent of message or expression, alterations in kinetic and other physical characteristics of the enzyme in diabetic rats implicate glycation as a mechanism of regulation. A decrease in glutathione excretion into bile in diabetics may have important consequences such as impairing the capacity of the intestine to detoxify dietary lipid peroxides or carcinogens. Onthe other hand, increased reclamation of glutathione may benefit the liver by increasing its ability to detoxify reactive prooxidants within the liver.
STZ- or alloxan-induced diabetes in rats represent well-established animal models of type 1 insulindependent, diabetes mellitus. Increased production of high levels of oxygen free radicals has been linked to glucose oxidation and nonenzymatic glycation of proteins which contribute to the development of diabetic complications. Protective effects of exogenously administered antioxidants have been extensively studied in animal models within recent years, thus providing some insight into the relationship between free radicals, diabetes, and its complications. In vitro and clinical studies may provide additional useful ways to probe the interconnections of oxidant stress and diabetes, and there is a need to continue to explore the mechanisms by which increased oxidative stress accelerates the development of complications in diabetes.