Molecular understanding of hyperglycemia's adverse effects for diabetic complications

JAMA. 2002 Nov 27;288(20):2579-88. doi: 10.1001/jama.288.20.2579.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Aldehyde Reductase / metabolism
  • Diabetic Angiopathies / etiology*
  • Diabetic Angiopathies / prevention & control
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / prevention & control
  • Diabetic Neuropathies / etiology*
  • Diabetic Neuropathies / prevention & control
  • Glycation End Products, Advanced / metabolism
  • Glycolysis
  • Glycosylation
  • Humans
  • Hyperglycemia / physiopathology*
  • Hyperglycemia / prevention & control
  • Oxidative Phosphorylation
  • Protein Kinase C / metabolism
  • Reactive Oxygen Species
  • Signal Transduction


  • Glycation End Products, Advanced
  • Reactive Oxygen Species
  • Aldehyde Reductase
  • Protein Kinase C