Handbook of Diabetes, 4th Ed., Excerpt #13: Control and Complications

An increased flux of glucose can result in activation of the hexosamine pathway. Fructose-6-phosphate is diverted from glycolysis to form UDP-N-acetylglucosamine, which is used in the synthesis of glycoproteins. The rate-limiting step in the conversion of glucose to glucosamine is regulated by glutamine:fructose-6-phosphate amidotransferase (GFAT). It is thought that glycation of transcription factors by N-acetylglucosamine increases the activity of many genes. Amongst these are TGF-beta (a key profibrogenic cytokine), acetyl CoA carboxylase (the rate-limiting enzyme for fatty acid synthesis and which might increase insulin resistance) and plasminogen activator inhibitor-1 (PAI-1) which promotes thrombosis (Figure 14.13).

All the mechanisms listed above have a common effect of increasing reactive oxygen species and thus increasing oxidative stress (Figure 14.14). Some workers feel that this is the final common path which underpins the development of all diabetes complications.

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