In diabetes, glucose present in excess is a toxic substrate
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| Glucose undergoes auto-oxidation yielding reactive oxygen species and intracellular precursors of advanced glycation endproducts (AGE, see below). Also, hyperglycemia alters the cellular redox state by increasing the NADH/NAD+ ratio and decreasing NADPH/NADP+. This causes increases the flux of substrates through the polyol pathway. The reactive oxygen species create oxidative stress, which damages molecules and activates a number of signaling molecules such as protein kinase C or the transcription factor NFκB (NFκB is a key determinant of inflammatory response). Hyperglycemia itself also activates NFκB pathway.
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| Inflammatory reaction in diabetes may play a role in the vascular complications
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| Figure 20.16 Metabolism in diabetes mellitus. Hyperglycemia in diabetes mellitus is caused by the combined effect of the increased endogenous glucose production by the liver and the impaired peripheral glucose uptake. |
| The low grade inflammatory reaction affecting the vascular wall seems to be present not only in atherosclerosis (Chapter 17)
but also in obesity and type 2 diabetes, and leads to increased expression of mediators such as TNF and IL-6. It seems that the deterioration of carbohydrate intolerance leading from obesity to type 2 diabetes is faster if it happens on the background of low-grade inflammation.
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| Formation of the advanced glycation endproducts is a result of hyperglycemia
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| Hyperglycemia leads to the formation of glucose adducts with proteins, the AGE (Fig. 20.18). Some AGE function as protein crosslinks and, for instance, increase the ridigity of collagen molecules. They also bind to membrane receptors on the vascular endothelial cells, stimulate the generation of TNF-α, IL1-β and IL-6, and activate NFκB (Chapter 32). They may contribute to the development of atherosclerosis in diabetes.
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