We use multiple approaches such as culturing specific microvascular and arterial vascular cells from the retina, glomeruli and arteries in order to determine the actions of insulin on cytokine expressions and their actions such as those for vascular endothelial growth factor (VEGF), as well as the interfering effect of hyperglycemia and loss of insulin actions on the functions of these cells.
In addition, we approach the question of diabetic complications from clinical research studies. We have characterized a large group of type 1 diabetic patients of extreme duration, greater than 50 years of diabetes, The Joslin Medalist Study, and have found that 30% of these patients do not have significant retinopathy and nephropathy. From tissues derived from these patients using genomic, proteomic and metabolomic approaches, we are identifying protective factors which have prevented these patients from developing significant diabetic retinopathy, nephropathy and preservation of their beta cell function for over 50 to 80 years.
From these cell based and clinical studies, we have developed important mechanistic ideas such as activation of protein kinase C, the role of VEGF and selective insulin resistance as some of the basic mechanisms for the pathogenesis of diabetic microvascular and cardiovascular diseases which are now widely studied by multiple laboratories.
In addition, the identification of protective factors from the Medalist Study provided potential new therapies for treating diabetic complications such as retinopathy, nephropathy and wound healing.