SMi Source Lesson Diabetes: Pathology Complications - Hyperglycemia and Glucotoxicity

  • SMi Source lesson Diabetes: Pathology Complications - Hyperglycemia and Glucotoxicity has the following microlearning topics

  • 1. Underlying Mechanisms of Chronic Complications

  • Lesson Diabetes: Pathology Complications - Hyperglycemia and Glucotoxicity teaches these concepts

  • Diabetes, Underlying Mechanisms of Chronic Complications, Hyperglycemia and Glucotoxicity

  • Lesson Diabetes: Pathology Complications - Hyperglycemia and Glucotoxicity addresses these key points

  • 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.