User:Andrew Nutter/Sorbitol Pathway

Forming the biochemical basis of Diabetes Mellitus

Sorbitol Pathway and how it forms the biochemical basis of Diabetes Mellitus

There are 3 Metabolic fates of Glucose:

1. GLYCOLYSIS
2. PENTOSE PHOSPHATE PATHWAY
3. SORBITOL PATHWAY

The Sorbitol Pathway is a minor bypass pathway that bypasses the regulatory steps of Glycolysis (e.g., Hexokinase Regulation). In brief, Sorbitol Pathway/Polyol Pathway includes conversion of Glucose to Fructose via the polyol compound "Sorbitol" through a set of enzymes and co-factors.

THE PATHWAY IN DETAIL

The First Step

The first step of the Sorbitol Pathway is conversion of Glucose to Sorbitol.
Enzyme: Aldose Reductase
Co-factor: NADPH
Hence Glucose is reduced to Sorbitol by Aldose Reductase, and one molecule of NADPH is oxidised to NADP⁺ in the process.

The Second Step

The second step of the pathway is conversion of Sorbitol to Fructose.
Enzyme: Sorbitol Dehydrogenase
Co-factor: NAD⁺
Hence Sorbitol is oxidised to Fructose by Sorbitol Dehydrogenase, and one molecule of NAD⁺ is reduced to NADH in the process.

SORBITOL PATHWAY IN THE HUMAN BODY
In the following tissues, Sorbitol Pathway is of vital importance. Here, concentration of Sorbitol Dehydrogenase is more than Aldose Reductase. So all the Sorbitol that is being formed gets converted to Fructose. These tissues are:
Brain: Fructose, along with Glucose, helps in fulfilling the brain's constant energy demands.
Male Accessory Sex Organs: Fructose is an important part of Seminal fluid.
Placenta: Fructose plays an osmoregulatory role.
Pancreas: Fructose plays a metabolic role via Insulin regulation.

But, in some tissues in the body, concentration of Sorbitol Dehydrogenase is less than that of Aldose Reductase. So the net reaction favours Sorbitol - not Fructose - Synthesis. Specific cells of this group are:
- Eye Lens Cells
- Kidney Cells
- Schwann Cells
These 3 tissues are Insulin-insensitive. So they do not respond to Insulin regulation. Under normal conditions, amount of Glucose entering these tissues is quite less so the Sorbitol that is being formed does not have any adverse effects. But, in case of uncontrolled Diabetes Mellitus(Hyperglycemia), amount of Glucose entering these tissues becomes very large, so a lot of Sorbitol is being formed. Its accumulation causes various Diabetic complications, mainly:
RETINOPATHY
NEUROPATHY
NEPHROPATHY.

How Sorbitol Accumulates

Sorbitol, being hydrophilic, cannot escape from the cell. It accumulates inside the cell and attracts water because it is highly osmotically active. This causes swelling of the cell, leading to:
Lens Cataract
Peripheral Neuropathy of Schwann cells
Nephritis in Kidney

Oxidative Stress

Uncontrolled Sorbitol pathway causes depletion of NADPH, beacuse it is a co-factor for the first step of the pathway. Depletion of NADPH has adverse effects on various metabolic pathways in the body.
Glutathione Reductase is an enzyme that itself gets oxidized to reduce free radicals of Oxygen in the body, which are highly dangerous (they cause RBC membrane rupture). So depletion of NADPH will reduce the activity of Glutathione Reductase, leading to OXIDATIVE STRESS.

Vascularization

NADPH is also a co-factor for Nitric Oxide Synthase. This enzyme helps in the formation of Nitric Oxide or EDRF (Endothelial-Derived Relaxation Factor). As the name suggests, NO helps in relaxation of blood vessels. In its absence, blood vessels remain constricted, leading to Vascularization and Ischemia. In Retinopathy, this Vascularixation causes Retinal Ischemia, which ultimately leads to blindness.

So, it is quite evident that Sorbitol pathway and Diabetic complications go hand in hand.