Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and

reductase has a low affinity (high K
m
) for glucose, and at the normal
glucose concentrations found in non-diabetics, metabolism of 
glucose by this pathway is a very small percentage of total glucose use.
But in a hyperglycaemic environment, increased intracellular glu-
cose results in its increased enzymatic conversion to the polyalcohol
sorbitol, with concomitant decreases in NADPH. In the polyol 
pathway, sorbitol is oxidized to fructose by the enzyme sorbitol 
dehydrogenase, with NAD
+
reduced to NADH. Flux through this
pathway during hyperglycaemia varies from 33% of total glucose use
in the rabbit lens to 11% in human erythrocytes. Thus, the contribu-
tion of this pathway to diabetic complications may be very much
species, site and tissue dependent (Fig. 1).
A number of mechanisms have been proposed to explain the
potential detrimental effects of hyperglycaemia-induced increases in
polyol pathway flux. These include sorbitol-induced osmotic stress,
decreased (Na
+
&K
+
)ATPase activity, an increase in cytosolic
NADH/NAD
+
and a decrease in cytosolic NADPH. Sorbitol does not
diffuse easily across cell membranes, and it was originally suggested
that this resulted in osmotic damage to microvascular cells. Sorbitol
concentrations measured in diabetic vessels and nerves are, however,
far too low to cause osmotic damage.
Another early suggestion was that increased flux through the
polyol pathway decreased (Na
+
&K
+
)ATPase activity. Although this
decrease was originally thought to be mediated by polyol pathway-
linked decreases in phosphatidylinositol synthesis, it has recently
been shown to result from activation of PKC (see below). Hypergly-
caemia-induced activation of PKC increases cytosolic phospholipase
A
2
activity, which increases the production of two inhibitors of
(Na
+
&K
+
)ATPase — arachidonate and PGE
2
(ref. 13).
More recently, it has been proposed that oxidation of sorbitol by
NAD
+
increases the cytosolic NADH:NAD
+
ratio , thereby inhibiting
activity of the enzyme glyceraldehyde-3-phosphate dehydrogenase
(GAPDH), and increasing concentrations of triose phosphate
14
.
Raised triose phosphate concentrations could increase formation of
both methylglyoxal, a precursor of AGEs, and diacylglycerol (DAG)
(through 
a-glycerol-3-phosphate), thus activating PKC (as discussed
later). Although hyperglycaemia does increase the NADH:NAD
+ 
ratio
in endothelial cells, this reflects a marked decrease in the absolute con-
centration of NAD
+
as a result of consumption by activated
poly(ADP-ribose) polymerase (PARP), rather than reduction of
NAD
+ 
to NADH
15
. Activation of PARP by hyperglycaemia is mediated
by increased production of reactive oxygen species (T. Matsumura 
et al., unpublished results). The source of hyperglycaemia-induced
reactive oxygen species is discussed later.
It has also been proposed that reduction of glucose to sorbitol by
NADPH consumes NADPH. As NADPH is required for regenerating
reduced glutathione (GSH), this could induce or exacerbate intracel-
lular oxidative stress (Fig. 1). Decreased levels of GSH have in fact
been found in the lenses of transgenic mice that overexpress aldose
reductase, and this is the most likely mechanism by which increased
flux through the polyol pathway has deleterious consequences
16
. This
conclusion is further supported by recent experiments with homozy-
gous knockout mice deficient in aldose reductase, which showed
that, in contrast to wild-type mice, diabetes neither decreased the
GSH content of sciatic nerve nor reduced motor nerve conduction
velocity (S. K. Chung, personal communication).
Studies of inhibition of the polyol pathway in vivo have yielded
inconsistent results. In a five-year study in dogs, aldose reductase 
inhibition prevented diabetic neuropathy, but failed to prevent
retinopathy or thickening of the capillary basement membrane in the
retina, kidney and muscle
17
. Several negative clinical trials have ques-
tioned the relevance of this mechanism in humans
18
. The positive effect
of aldose reductase inhibition on diabetic neuropathy has, however,
been confirmed in humans in a rigorous multi-dose, placebo-
controlled trial with the potent aldose reductase inhibitor zenarestat
19
.

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