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Abstract
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 (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003).
Both the Diabetes Control and Complications Trial and the United Kingdom. Prospective Diabetes Study have established that intensive glycemic control can delay the onset and progression of vascular complications. However, maintaining euglycemia in diabetic patients with present therapeutic agents has been challenging (The Diabetes Control and Complications Trial Research Group, 1993), (UK Prospective Diabetes Study Group, 1998).
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 (Epidemiology of Diabetes Interventions and Complications Study, 2003).
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 (American Diabetes Association, 2005).
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 2) accelerated formation of advanced glycation end products 3) elevated systemic and vascular-derived oxidative stress, and 4) enhanced flux via the hexosamine pathway. Furthermore, glucotoxin can also induce cellular signaling alterations, for example, the activation of protein kinase C (PKC) and inflammatory signalling cascades such as the nuclear factor-B pathway to cause vascular diseases (Umberto and Guseppe, 2003).