ABSTRACT
This paper examines the question of whether diabetes in humans is associated with changes in aldose reductase and sorbitol dehydrogenase gene expression. The polyol pathway, which comprises the enzymes aldose reductase and sorbitol dehydrogenase, is recognised to play a central role in the pathogenesis of the diabetic complications. Whilst it is known that experimental diabetes in the rat is associated with increased aldose reductase gene expression, possibly as an osmoregulatory response to hyperglycaemia, little is known about aldose reductase and sorbitol dehydrogenase gene expression in diabetes in humans. White cell aldose reductase mRNA levels were increased in patients with insulin-dependent (by 135%, P < 0.05) and non-insulin-dependent (by 132%, P < 0.05) diabetes compared to levels in healthy volunteers. Levels of glycosylated haemoglobin were also increased (P < 0.001) in diabetes but there was no correlation between white cell aldose reductase mRNA and glycosylated haemoglobin levels. In contrast to aldose reductase, levels of white cell sorbitol dehydrogenase mRNA were not affected by diabetes. These results establish for the first time that diabetic patients show increases in white cell aldose reductase mRNA levels, possibly consistent with increased aldose reductase gene expression. This finding may have implications for the use of aldose reductase inhibitors in the treatment of the diabetic complications.
Subject(s)
Aldehyde Reductase/biosynthesis , Diabetes Mellitus/enzymology , Leukocytes/enzymology , Adult , Aged , Aged, 80 and over , Blotting, Northern , Diabetes Mellitus, Type 1/enzymology , Diabetes Mellitus, Type 2/enzymology , Female , Humans , L-Iditol 2-Dehydrogenase/biosynthesis , Male , Middle Aged , RNA, Messenger/analysisABSTRACT
The polyol pathway, which comprises the enzymes aldose reductase and sorbitol dehydrogenase, is recognised to play a major role in the pathogenesis of diabetic complications. Although there has been extensive research on aldose reductase, the role of sorbitol dehydrogenase has been overlooked. This study examined the response of sorbitol dehydrogenase gene expression to streptozotocin-diabetes (STZ-diabetes) in the rat and whether these changes were reversed by insulin. STZ-diabetes increased testicular sorbitol dehydrogenase gene expression in a manner that was not reversible by insulin but had no effect on gene expression in kidney and brain. A secondary question was the relationship between sorbitol dehydrogenase and aldose reductase gene expression in STZ-diabetes. STZ-diabetes increased renal aldose reductase gene expression in a manner that was not reversible by insulin but had no effect on gene expression in the brain, testes and muscle. Thus, STZ-diabetes causes changes in sorbitol dehydrogenase gene expression which do not parallel those in aldose reductase, implying that expression of the two genes is not regulated via a common mechanism. Furthermore, changes in sorbitol dehydrogenase and aldose reductase gene expression cannot be fully explained on the basis of the osmoregulatory hypothesis, suggesting that regulation is mediated via mechanisms that are multifactorial and tissue-specific.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , L-Iditol 2-Dehydrogenase/genetics , Aldehyde Reductase/genetics , Aldehyde Reductase/metabolism , Animals , Base Sequence , Brain/enzymology , Diabetes Mellitus, Experimental/drug therapy , Gene Expression , Glucose/analysis , Insulin/therapeutic use , Kidney/enzymology , L-Iditol 2-Dehydrogenase/metabolism , Male , Molecular Sequence Data , RNA, Messenger/analysis , Rats , Rats, Wistar , Sorbitol/analysis , Testis/enzymologyABSTRACT
Abnormal metabolism through the polyol pathway during episodes of hyperglycaemia is implicated in the development of the chronic complications of diabetes. Since aldose reductase is the first and ratelimiting enzyme of the polyol pathway, it is predicted that restriction fragment length polymorphisms at the aldose reductase gene locus may influence catalytic activity and determine individual susceptibility to the diabetic complications. This paper reports the existence of EcoRI and TaqI restriction fragment length polymorphisms at the human aldose reductase locus.