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Molecular Understanding of Hyperglycemia's Adverse Effects for Diabetic Complications

Matthew J. Sheetz, MD, PhD; George L. King, MD
JAMA. 2002;288(20):2579-2588. doi:10.1001/jama.288.20.2579.
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Diabetic complications are the major cause of morbidity and mortality in persons with diabetes. Chronic hyperglycemia is a major initiator of diabetic microvascular complications (eg, retinopathy, neuropathy, nephropathy). Glucose processing uses a variety of diverse metabolic pathways; hence, chronic hyperglycemia can induce multiple cellular changes leading to complications. Several predominant well-researched theories have been proposed to explain how hyperglycemia can produce the neural and vascular derangements that are hallmarks of diabetes. These theories can be separated into those that emphasize the toxic effects of hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or glycation products) on tissues directly and those that ascribe pathophysiological importance to a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases) induced by the products of glucose metabolism. This article summarizes these theories and the potential therapeutic interventions that may prevent diabetic complications in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.

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Figure 1. Overall Categorization of Signaling Pathways Involved in Diabetic Complications
Graphic Jump Location
AR indicates aldose reductase; RAGE, receptor for advanced glycation endproducts; PKC, protein kinase C.
Figure 2. Aldose Reductase Pathway Theory
Graphic Jump Location
NADPH indicates reduced nicotinamide-adenine dinucleotide phosphate; NADP+, oxidized nicotinamide-adenine dinucleotide phosphate; NAD+, oxidized nicotinamide adenine dinucleotide; and NADH, reduced nicotinamide adenine dinucleotide.
Figure 3. Advanced Glycation Endproduct (AGE) Pathway Theory
Graphic Jump Location
Figure 4. Reactive Oxygen Intermediate Pathway Theory
Graphic Jump Location
AGE indicates advanced glycation endproduct; oxLDL, oxidized low-density lipoprotein; GSH, glutathione; GSSG, glutathione disulfide; and NADPH, nicotinamide-adenine dinucleotide phosphate.
Figure 5. Protein Kinase C Theory
Graphic Jump Location
OXPHOS indicates oxidative phosphorylation; ROI, reactive oxygen intermediate; AGE, advanced glycation endproduct; and NADPH, nicotinamide-adenine dinucleotide phosphate.



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