These include increased Protein C kinase activation, increased formation of advanced glycation end products (AGEs), accumulation of sorbitol via
polyol pathway, reactive oxygen species (ROS) mediated cellular damage and increased flux through hexosamine pathway.2 A recent addition to this list is down regulation of glyoxalase I (GLO I) in chronic hyperglycemia.3
In physiological condition, over 80% glucose enters the glycolysis pathway and almost no glucose enters the
polyol pathway, the key cascade of sugar cataract [3, 5].
One of the mechanisms that can cause diabetic cataracts is the activation of
polyol pathway enzymes and increasing their products, which cannot diffuse passively out of the lenses and cause osmotic stress leading to lens hydration and swelling.
Aldose reductase (alditol:[NAD(P).sup.+] 1-oxidoreductase, EC 1.1.1.21) is an enzyme which plays important role in the
polyol pathway. This enzyme catalyzes the reduction of glucose to sorbitol with oxidation of NADPH to [NADP.sup.+].
[4] Hyperglycemia may cause vessel damage through at least three apparently unrelated pathway: advanced glycation end product (AGE) formation, activation of protein kinase C (PKC) and sorbitol accumulation by way of
polyol pathway. [2]
The
polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose (Figure 2).
Some of the major pathways like
polyol pathway [5], advanced glycation end products [6], hexosamine flux [7], mitogen-activated protein kinases [8], altered activity of [Na.sup.+]/[K.sup.+]-ATPase [9], poly-ADP ribose polymerase (PARP) over activation [10], and cyclooxygenase-2 (COX-2) activation [11] have been reported to play a crucial role in development and progression of diabetic neuropathy (Figure 1).
The all important pericyte loss in DR is discussed in the next chapter, the
polyol pathway, the role of the pericyte in maintaining functional and structural integrity is well written.