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: Literature review relevant to long-term diabetic complications and their pathogenesis. STUDY SELECTION: Studies of animal models of diabetes, epidemiologic 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. DATA SYNTHESIS: Diabetic retinopathy, nephropathy, and neuropathy occur in all clinical forms of diabetes mellitus, regardless of the cause of 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 support an important and perhaps dominant role of hyperglycemia in the pathogenesis of complications. However, the diverse complications may not share the same pathogenesis. Different pathogenetic mechanisms may operate in different types of diabetic complications or at different stages of specific complications, or both.
CONCLUSIONS: The level of chronic glycemia is the best established concomitant factor associated with diabetic complications. The mechanism by which hyperglycemia might cause complications remains unknown, and evidence for a uniform pathogenetic mechanism is far from established.