Biochemistry and molecular cell biology of diabetic complications


Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

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Figure 1: Aldose reductase and the polyol pathway.
Figure 2: Mechanisms by which intracellular production of advanced glycation end-product (AGE) precursors damages vascular cells.
Figure 3: Consequences of hyperglycaemia-induced activation of protein kinase C (PKC).
Figure 4: The hexosamine pathway.
Figure 5: Production of superoxide by the mitochondrial electron-transport chain.
Figure 6: Potential mechanism by which hyperglycaemia-induced mitochondrial superoxide overproduction activates four pathways of hyperglycaemic damage.


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This work was supported by grants from NIH, Juvenile Diabetes Research Foundation and American Diabetes Association. Owing to space limitations, a comprehensive list of reference citations could not be included. I apologize to those colleagues whose work is not specifically referenced, and gratefully acknowledge their contributions to the field.

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Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

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