PATHOGENESIS OF DIABETIC MICROVASCULAR COMPLICATIONS

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Two factors form the major basis for this program project. First, it is becoming clear that we cannot at present rely solely on improved glycemic control to prevent microvascular complications of diabetes, both because of our inability to maintain good glycemic control to prevent microvascular complications of both diabetes, both because of our inability to maintain good glycemic control in many patients, and because evidence indicates that some patients develop retinopathy and other complications despite good glycemic control, Second, oxidative stress is a commonly reported sequelae of hyperglycemia, and we and others der developing evidence that the oxidative stress might play a role in the development of histopathology. This proposal assembles four projects and four cores to investigate, in a coordinated manner, the hypothesis that hyperglycemia leads to extra- and intracellular oxidative stress, which subsequently causes altered function and structure in the retina and kidney. This central hypothesis suggests two outcomes that have potential clinical significance: (1) we predict that specific chemical products of oxidative stress will exhibit higher levels in patients most prone to develop complications, and thus will predict, independently of measures of glycemic control, which patients will develop complications, and thus will predict independently of measures of glycemic control, which patients will develop complications, and (2) several steps along this metabolic scheme might be therapeutic targets where the develop complications, and (2) several steps along this metabolic scheme might be therapeutic targets where the development of complications, and (2) several steps among this metabolic schemes might be therapeutic targets where the development of complications could be inhibited. Project 1 investigates the inter-relationship between dicarbonyl stress, advanced glycation endproducts (AGEs) and oxidative stress and the relation of dicarbonyls to the development of microvascular complications. Project 2 investigates the postulate that the oxidative stress which develops in cell culture and in diabetic rats differs from that which develops in diabetic humans, and tests the hypothesis using a novel and powerful probe to assess oxidative stress in vivo using 19F-NMR spectroscopy in patients and animals. Project 3 postulates that tubular oxidative stress caused by exposure to AGEs and hyperglycemia leads to glomerular changes. Project 4 investigates the hypothesis that oxidative stress is a major cause of diabetic retinopathy, exerting this effect via stimulation of apoptosis of retinal cells. Projects 1,2 and 3 additionally seek to identify specific chemical products of oxidative stress which can act as surrogate markers to identify which patients are particularly susceptible to develop complications of diabetes.