The light should pass through the cornea, aqueous humor, lens and vitreous humor before reaching the retina for triggering the process of vision. These structures should be transparent in order to allow the path of light.
The lens (m in the figure) is bathed in its anterior side by the aqueous humor (i) and in its posterior side by the vitreous humor (o). It has no blood capillaries (that would interfere with light path), so the aqueous humor is responsible of the nutrition of the lens and the disposal of metabolic products.
The energy necessary for the lens is provided mainly through anaerobic glicolysis; the Krebs cycle, located in peripheral cells, only provide about 5 % of the necessary energy. Pentose phosphate cycle is also another important metabolic pathway in lens since it provides NADPH necessary for the maintenance of the redox status of the lens proteins.
The majority of the proteins in the lens are alpha, beta and gamma crystallines. They should maintain a transparent environment, so they should be in a native, non aggregate state. Some disturbances, as changes in the redox states of these proteins or changes in osmolarity in the lens can produce lost of the native state and aggregation of these proteins.
Cataracts results from changes in solubility and aggregation of the crystallin proteins.
The most frequent kinds of cataracts are those that appear as result of aging (senile cataracts) or as a result of Diabetes Mellitus (diabetic cataracts). Other conditions can also result in cataracts: cataracts that appear in galactosemia are very similar in the way of production to the cataracts that appear in Diabetes.
Aldose reductase is an enzyme that usually reduce aldehyde group of aldoses to a primary alcohol, so the aldose becomes a polyalcohol. The enzyme uses NADPH as hydrogen donor.
Typical reactions catalyzed by aldose reductase are the formation of sorbitol (glucitol) and the formation of dulcitol (galactitol):
Glucose +NADPH —à Glucitol (Sorbitol) + NADP+
Galactose +NADPH —à Galactitol (Dulcitol) + NADP+
Aldehyde reductase function is mainly in the conversion of glucose to fructose.
The sequence of reactions is:
1. – Reaction of Aldehyde reductase:
Consist in the reduction of the aldehyde group of glucose to a primary alcohol group, with the conversion of the aldohexose glucose to a polyalcohol.
Glucose + NADPH.H+ —à Sorbitol + NADP+
2. – Reaction of Sorbitol dehydrogenase (SORD):
Consist in the oxidation of the secondary alcohol group of Carbon 2 of Sorbitol to
a ketone group. It results in the conversion of Sorbitol in Fructose, a ketohexose.
Sorbitol + NAD+ –à Fructose + NADH.H+
This sequence of reactions is particularly important in the formation of fructose in the seminal vesicles and the liver, and it has the advantage over the use of the sequence in glycolysis for obtaining fructose – Glucose 6 (P) to Fructose 6 (P) – that this polyalcohol pathway does not require the expending of ATP.
Lens contains aldehyde reductase and also a very low activity of sorbitol dehydrogenase, so some of the glucose that enter in the lens is converted in fructose. This quantity is usually very low since the enzyme aldehyde reductase has a very high Km for glucose.
In conditions of hyperglycemia, since the concentration of aldehyde reductase substrate (glucose) is high, this enzyme becomes very active, and a high quantity of sorbitol is formed. Unfortunately for diabetic patients, the activity of sorbitol dehydrogenase in lens is very low (enough for normal conditions, but not for this abnormal situation) and for complicating more the problem, sorbitol formed in the lens diffuse with difficulty out of it.
As a result, Sorbitol accumulates and increases the osmotic effects producing cell swelling and structural damage (this effect would explain also the neuropathy and vascular problems present in Diabetic patients).
In the lens, these changes in osmolarity will affect the native conformation of the crystalline proteins, in such a way that they aggregate and form structures that scatter the light: Cataracts are being formed.
In patients with galactosemia, a congenital disease in which the patient can not metabolize galactose and this sugar accumulates, the physiopathology of cataracts formation and nerve damage apparently is similar to the mechanism described for diabetes:
Through the reaction of Aldehyde reductase occurs the reduction of the aldehyde group of galactose to a primary alcohol group, with the conversion of the aldohexose galactose to its corresponding polyalcohol, galactitol:
Galactose + NADPH.H+ —à Galactitol + NADP+
Galactitol accumulates increasing the osmotic pressure with similar results to those found in sorbitol accumulation in Diabetes Mellitus.
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