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during post-hyperglycaemic periods of normal glycaemia. Hyper-
glycaemia-induced increases in superoxide would not only increase
polyol pathway flux, AGE formation, PKC activity and hexosamine
pathway flux, but might also induce mutations in mitochondrial
DNA. Defective subunits of the electron-transport complexes
encoded by mutated mitochondrial DNA could eventually cause
increased superoxide production at physiological concentrations of
glucose, with resulting continued activation of the four pathways
despite the absence of hyperglycaemia.
The second general area concerns the genetic determinants of 
susceptibility to both microvascular and macrovascular complica-
tions. Their role in microvascular complications is supported by
familial clustering of diabetic nephropathy and retinopathy. In two
studies of families in which two or more siblings had type 1 diabetes,
if one diabetic sibling had advanced diabetic nephropathy, the other
diabetic sibling had a nephropathy risk of 83% or 72%, whereas the
risk was only 17% or 22% if the index case did not have diabetic
nephropathy
93
. The DCCT reported familial clustering of retinopa-
thy with an odds ratio of 5.4 for the risk of severe retinopathy in 
diabetic relatives of retinopathy-positive subjects from the 
conventional treatment group compared with subjects with no
retinopathy
94
. For macrovascular complications, coronary artery
calcification (an indicator of subclinical atherosclerosis) also shows
familial clustering, with an estimated heritability of at least 40% (ref.
95). Thus, gene-mapping studies designed to identify genes that 
predispose to complications, as well as the interaction of these genes
with metabolic factors, are warranted.
Finally, the paradigm discussed in this review suggests that 
interrupting the overproduction of superoxide by the mitochondrial
electron-transport chain would normalize polyol pathway flux, AGE
formation, PKC activation, hexosamine pathway flux and NF-
kB
activation. But it might be difficult to accomplish this using 
conventional antioxidants, as these scavenge reactive oxygen species
in a stoichiometric manner. Thus, although long-term administra-
tion of a multi-antioxidant diet inhibited the development of early
diabetic retinopathy in rats
96
, and vitamin C improved endothelium-
dependent vasodilation in diabetic patients
97
, low-dose vitamin E
failed to alter the risk of cardiovascular and renal disease in patients
with diabetes
98
. New, low-molecular-mass compounds that act as
SOD or catalase mimetics have the theoretical advantage of 
scavenging reactive oxygen species continuously by acting as catalysts
with efficiencies approaching those of the native enzymes
99
. Such
compounds normalize diabetes-induced inhibition of aortic prosta-
cyclin synthetase in animals (M. B. et al., unpublished results), and
significantly improve diabetes-induced decreases in endoneurial
blood flow and motor nerve conduction velocity
100
. These and other
agents discovered using high-throughput chemical and biological
methods might have unique clinical efficacy in preventing the 
development and progression of diabetic complications.
■
■
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1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications.

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