48. Pathobiochemistry of the late complications of diabetes mellitus

As explained in the previous topic are these four factors important in the development of microvascular disease in diabetes mellitus.

Pseudohypoxia

As already explained will hyperglycaemia increase the activity of the polyol pathway, which depletes NADPH and increases the NADH/NAD+ ratio. The latter causes a metabolic state of cells that is similar to hypoxia, called pseudohypoxia. The affected cells produce less ATP and more free radicals. Also, the amount of glyceraldehyde 3-phosphate increases, which glycates protein 200 times more easily than glucose does and therefore drastically increases the number of AGEs.

The depletion of NADPH decreases the level of glutathione, an important antioxidant. This makes the cells more prone to damage from free oxygen radicals.

Cells suffering from pseudohypoxia are more sensitive to injuries and vascular damage. They also have decreased electrical, mechanical and vascular functions.

Protein kinase C pathway

Protein kinase C (PKC) is activated by diacylglycerol (DAG). In diabetes mellitus is surplus glucose converted into DAG, which excessively activates PKC. This has many effects, but the summary is that there is increased inflammation and growth but also increased vascular occlusion.

Advanced glycation end-products

As already explained will chronic hyperglycaemia increase the number of advanced glycation end-products (AGEs), which are endogenous proteins and lipids that become non-enzymatically glycated. Especially collagen, crystallin (component of the lens and cornea), haemoglobin and LDL are important substrates for glycation.

The glycated proteins become dysfunctional, and AGEs themselves can bind to their specific receptor called RAGE (receptor for AGE). Activation of this receptor activates pathways like the PKC and MAPK pathways, activating NF-κB and altering gene expression, causing cellular damage and inflammation.

As collagen fibres in the basement membrane are glycated will the basement membrane thicken, which paradoxically increases its permeability. Glycation of the walls of arterioles decreases their contractility.

Glycated haemoglobin binds poorly to oxygen, decreasing tissue oxygenation.

Hexosamine pathway

Excess glucose isn’t just routed through the polyol pathway but through the hexosamine pathway as well. As the glycolysis is impaired (as it’s insulin-dependent) will fructose 6-phosphate accumulate. F-6-P is converted into glucosamine 6-phosphate by an enzyme called GFAT. Glucosamine 6-phosphate will go on to stimulate transdermal growth factor beta (TGF-β), which stimulates fibrosis and matrix expansion in the glomeruli.