Beneath the Surface of DMC: Exploring the Pathophysiology of Diabetic Microvascular Complications

Supported by an unrestricted educational grant from Eli Lilly and Company

Monday, June 13, 2005

5:30-7:45 AM

Chair:

Andrew JM Boulton, MD, DSc (hon), FRCP

Faculty:

Michael Brownlee, MD

Christopher D Saudek, MD

Reported by Kimberly McFarland, PhD

Diabetic microvascular complications (DMC) include diabetic neuropathy, retinopathy, and nephropathy. The link between hyperglycemia and DMC is undeniable, with an approximately 20% increase in DMC risk with each 1% increase in A1C. Hyperglycemia increases ROS formation and, thereby, activity in 4 metabolic pathways implicated in DMC development: the polyol pathway, advanced glycation endproduct (AGE) formation, protein kinase C (PKC) isoform activation, and the hexosamine pathway. Although tight glycemic control prevents all 3 DMC and slows progression of retinopathy and nephropathy, treatment guidelines are not met in > 50% of cases, and DMC are often already present at the time of diabetes diagnosis. Therefore, more treatment options are needed. Agents that interrupt the 4 pathogenetic pathways listed above are in development. A series of aldose reductase inhibitors (ARI) have been tested in clinical trials, but none are currently approved in the US. Aminoguanidine, an inhibitor of AGE formation, has also had some success in clinical trials for diabetic nephropathy. Clinical data from presentations of published abstracts indicate that the PKCβ inhibitor, ruboxistaurin, improved diabetic neuropathy symptoms and slowed progression of diabetic macular edema. Additionally, preclinical data in animal models also suggest that ruboxistaruin may be effective in nephropathy.