Can Protein Kinase C β–Selective Inhibitor, Ruboxistaurin, Stop Vascular Complications in Diabetic Patients?
- Zhiheng He, MD, PHD and
- George L. King, MD
- From the Section on Vascular Cell Biology and Complications, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts
- Address correspondence and reprint requests to George L. King, Room M4504, Joslin Diabetes Center, 1 Joslin Place, Boston, MA, 02215. E-mail: george.king{at}joslin.harvard.edu
The life span and quality of life for diabetic patients are adversely affected mostly by systemic vascular injuries leading to nephropathy, retinopathy, neuropathy, and cardiovascular pathologies. Both the Diabetes Control and Complications Trial and the U.K. Prospective Diabetes Study have established that intensive glycemic control can delay the onset and progression of vascular complications (1,2). However, maintaining euglycemia in diabetic patients with present therapeutic agents has been challenging. In addition, recent reports using patients included in the Diabetes Control and Complications Trial suggested that previous history of hyperglycemia exposure will cause persistent vascular damage, even years after the resumption of intensive glucose management (3). Thus, it is of great clinical importance to develop therapeutic agents that can prevent vascular damage in diabetic patients, even in the presence of hyperglycemia. Over the last 20 years, there have been numerous studies on the molecular pathogenesis of diabetic vasculopathy. These theories can be separated into two categories, which are focused either on the formation of glucotoxins or on changes in cellular signalings induced by the glucotoxins. Theories on the formation of glucotoxins include 1) increased flux via the aldose-reductase pathway (4), 2) accelerated formation of advanced glycation end products (5), 3) elevated systemic and vascular-derived oxidative stress (4), and 4) enhanced flux via the hexosamine pathway (6). Furthermore, glucotoxin can also induce cellular signaling alterations, for example, the activation of protein kinase C (PKC), mitogen-activated protein kinase, and inflammatory signaling cascades such as the nuclear factor-κB pathway to cause vascular diseases (7). Studies using inhibitors to all of these diabetes-altered pathways have shown encouraging results either preventing or inhibiting the progression of vasculopathies in animal models of diabetes. However, clinical studies using inhibitors to many of these pathways have not yielded robust positive results (7).
Among the proposed theories, the …
