Author Affiliations: Lilly Research Laboratories, Indianapolis, Ind (Dr Sheetz); Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Mass (Dr King).
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
Sheetz MJ, King GL. Molecular Understanding of Hyperglycemia's Adverse Effects for Diabetic Complications. JAMA. 2002;288(20):2579–2588. doi:10.1001/jama.288.20.2579
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