THE PATHOPHYSIOLOGY OF DIABETIC COMPLICATIONS - HOW MUCH DOES THE GLUCOSE HYPOTHESIS EXPLAIN

Objective: To examine the putative pathogenetic mechanisms of the long -term, specific complications of diabetes mellitus. Data Sources: Lite rature review relevant to long-term diabetic complications and their p athogenesis. Study Selection: Studies of animal models of diabetes, ep idemiologic investigations of diabetes and its long-term complications , and interventional studies examining intensive treatment of diabetes and its effect on the development and progression of complications. D ata Synthesis: Diabetic retinopathy, nephropathy, and neuropathy occur in all clinical forms of diabetes mellitus, regardless of the cause o f the diabetes. Hyperglycemia appears to be the major variable shared among these different clinical forms; and epidemiologic data, studies in animal models of diabetes, and the results of recent interventional studies such as the Diabetes Control and Complications Trial, all sup port an important and perhaps dominant role of hyperglycemia in the pa thogenesis of complications. However, the diverse complications may no t share the same pathogenesis. Different pathogenetic mechanisms may o perate in different types of diabetic complications or at different st ages of specific complications, or both. Conclusions: The level of chr onic glycemia is the best established concomitant factor associated wi th diabetic complications. The mechanism by which hyperglycemia might cause complications remains unknown, and evidence for a uniform pathog enetic mechanism is far from established.