Diabetes, Underlying Mechanisms of Chronic Complications, Hyperglycemia and Glucotoxicity

Normoglycemia:

• Glucose is oxidized by glycolytic pathway and tricarboxylic acid cycle to form NADH and FADH₂.
• These electron donors feed into the mitochondrial electron transport system to generate ATP by oxidative phosphorylation.

Hyperglycemia:

• Some of the glucose is diverted through these and other pathways forming molecules which can damage cells such as endothelial cells lining blood vessels.

• Aldose reductase has a relatively low affinity for glucose, but in hyperglycemia, some glucose is converted to sorbitol, which is oxidized to fructose.
• Increased flux of glucose through the polyol pathway increases intracellular NADH, decreases NADPH, and depletes the natural antioxidant, glutathione (GSH), exacerbating potential oxidative stress.

• Excess fructose-6-phosphate can be diverted from glycolysis to the hexosamine pathway where it is converted to glucosamine-6-phosphate.
• UDP serves as a carrier of N-acetylglucosamine for the glycosylation of proteins.
• One protein that is glycosylated is transcription factor Sp1, which then becomes more active.
• Sp1 activates transcription of genes including those for prothrombotic factors, PAI-1 and TGFβ.

• Dihydroxyacetone phosphate can be reduced and acylated to form diacylglycerol, a lipid cellular second messenger.
• Diacylglycerol activates beta and delta isoforms of protein kinase C. 
• Protein kinase C activation has multiple consequences in the endothelium.
• Many of the deleterious effects involve alteration in the levels of vasoactive molecules such as nitric oxide and vascular endothelial growth factor.
• Protein kinase C actvation also leads to increases in fibrogenic proteins such as TGFβ, collagens, and fibronectin.

• Reactive dicarbonyls are formed from glucose and intermediates of glycolysis.
• Glycation of intracellular proteins can disrupt normal cellular processes.
• Modification of extracellular matrix proteins causes abnormal interactions with other matrix proteins and with integrins on neighboring cells, disrupting normal intercellular communications. 
• Glycation of plasma proteins allows them to interact with AGE receptors on endothelial cells, mesangial cells, and macrophages.
• Binding to AGE receptors activates NF-κB and alters gene expression.
• All of these can activate cascades of factors that cause cellular and tissue damage.

• Increased glucose oxidation and electrons flowing into the electron-transport chain creates an abnormally high mitochondrial membrane potential that inhibits electron transport at complex III.
• This allows coenzyme Q to donate electrons to oxygen to form the free radical superoxide.

• Free radicals induce DNA strand breaks and in turn activate the enzyme poly(ADP-ribose) polymerase or PARP.
• Glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase is ADP-ribosylated and inactivated.
• All intermediates upstream of glyceraldehydes-3-phosphate accumulate and are diverted to these pathways that mediate hyperglycemic damage.