Targeting Vascular Endothelial Cell Insulin Resistance in Type 2 Diabetes Mellitus
Is Protein Kinase Cβ the Bullseye for Reducing Vascular Risk in Diabetes?
More than 25 million Americans, or 8.3% of the population, have diabetes mellitus, of which ≈95% of diagnosed cases are type 2 diabetes mellitus.1 Between 1990 and 2010, the number of new cases of diabetes mellitus has almost tripled in the United States, and the Centers for Disease Control projects that 1 in 3 Americans will have diabetes mellitus by 2050 if this trend continues. The presence of type 2 diabetes mellitus increases the risk of microvascular complications, such as retinopathy and nephropathy, and macrovascular disease, most notably atherosclerotic coronary artery disease. Indeed, coronary artery disease–related death remains the primary cause of mortality in patients with type 2 diabetes mellitus, even on standard glucose control.1 However, more intensive glucose control is not associated with reduced coronary artery disease risk and may even increase mortality,2 therefore there remains a critical need to determine novel adjunct therapy to standard glycemic control that will reduce vascular risk in patients with type 2 diabetes mellitus.
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In 1996, a seminal study by Ishii et al3 demonstrated that selective inhibition of the β isoform of protein kinase C (PKCβ), a serine/threonine protein kinase that becomes activated in nutrient excess states such as hyperglycemia, resulted in significant improvement in retinal and glomerular microvascular function in diabetic rats in the absence of any alterations in glycemia or blood pressure. This study elucidated PKCβ as a potential novel target in diabetes-related vascular complications and identified increased tissue concentrations of diacylglcyerol, likely as a result of excess de novo synthesis in hyperglycemia, as the primary activator of PKCβ in rats. Consistent with this, diacylglcyerol concentration and PKCβ activity are increased in aortas of obese insulin-resistant rats and are associated with reduced insulin-stimulated activation of protein kinase B (Akt).4 Akt is a …