PATHOGENESIS OF DIABETES MELLITUS: MAIN HYPOTHESIS EXPLAINED

Four main hypotheses have been proposed to explain how hyperglycemia causes the neural and vascular pathology. These are;

a.      Increased aldose reductase (or polyol pathway) flux

b.      Enhanced formation of advanced glycation end products (AGE)

c.       Activation of protein kinase C

d.      Increased hexosamine pathway flux

e.      Generation of ROS and oxidative stress (other pathway)

 

ACTIVATION OF POLYOL PATHWAY

Here the enzyme aldose reductase involved in reduction of toxic aldehydes to their alcohols is diverted to reduce excess glucose (during intracellular hyperglycemia) to sorbitol which is further oxidized to fructose. This process consumes NADPH, which is not available for regeneration of reduced glutathione, thus rendering cells vulnerable to the effects of oxidative stress. Sorbitol accumulation in the lens may cause cataracts, or in nerves and renal glomeruli leading to retinopathy and nephropathy.

ACCUMULATION OF ADVANCED GLYCATION END PRODUCTS (AGES)

 

These are irreversibly formed by non-enzymatic glycosylation of matrix, cellular and plasma proteins. Glucose and amino acid combine to form unstable Schiff base adducts, which undergo chemical rearrangement over time to form Amadori products and eventually to stable AGEs which are irreversibly attached to proteins and these can trap other protein elements by covalent binding and promotion of cross linking These products can cause tissue damage by alterations in the structure and function of extracellular matrix, by activation of inflammatory cytokines, by alteration of cellular genetic material. This contributes to endothelial dysfunction, basement membrane thickening and increased vascular permeability.

INTRACELLULAR HYPERGLYCAEMIA DUE TO INCREASED DAG CONCENTRATION

 

This DAG activates NFkB pathway via activation of protein kinase C (PKC). This leads to vasoconstriction, hypercoagulability via increased endothelin-1, TGF-β and plasminogen activator inhibitor (PAI)-1 generation and reduced eNOS (endothelial nitric oxide synthase) generation.

SHUNTING OF EXCESS INTRACELLULAR GLUCOSE TO HEXOSAMINE PATHWAY

 

Glucose is shunted to hexosamine pathway via fructose 6-phosphate to glucosamine 6-phosphate, catalyzed by enzyme glutamine: fructose 6-phosphate amidotransferase. Glucosamine 6-phosphage converts to UDP N-acetyl glucosamine which by binding to serine and threonine residues on transcription factors, leads to increased pro-inflammatory cytokine activity (TGF- β, PAI-1 and others)

GENERATION OF ROS AND OXIDATIVE STRESS

 

Excess intracellular glucose or NEFA stimulate TCA by substrate accumulation. Citrate, formed from NEFA or glucose-derived acetyl-CoA and oxaloacetate, is converted to isocitrate by enzyme isocitrate dehydrogenase generating mitochondrial NADH. Excessive generation of NADH leads to ROS formation via increased ETC along inner mitochondrial membrane. Beta cells are more vulnerable this oxidative stress as they contain less antioxidants. PKC can also be activated by superoxide ions and AGE formation thus linking the oxidative stress, AGE and PKC pathway.