Head: George L King, MD

Elucidating the Mechanism of Diabetic Vascular Complications

The complications of diabetes affect many organs, which make them very difficult to study by organ-specific approaches. Since Joslin has had strong research efforts in ocular research for many years, there is a separate Eye Research section. The Vascular Cell Biology section has focused on the basic pathogenesis of diabetes-induced microvascular and cardiovascular pathologies. Using multiple methods, these labs have characterized how glucose alters signaling and function in cultured vascular cells. In addition, they have studied the actions of hormones and cytokines such as insulin, VEGF, endothelin, CTGF and angiotensin on vascular cells, and how these molecules may cause vascular pathologies in vivo. The findings derived from cultured vascular cells are evaluated in rodent models of diabetic retinopathy, nephropathy, cardiomyopathy and atherosclerosis, some of which were developed here at Joslin. Lastly, efforts are made to determine whether the results on cultured cells and from animal models can be extrapolated to diabetes patients. Such confirmation is essential because many of the findings regarding vascular dysfunctions derived from cultured cells and rodent models have not been replicated in diabetes patients. The section has established cultured vascular cells from retina, renal glomeruli, myocardium and large arteries from rodents and humans. Using these cells, it has employed cutting-edge methods of cell biology, imaging, genomics and proteomics, molecular biology, animal physiology, kinase biology and drug design to understand the pathobiology of, and to design therapeutics for, diabetic vascular complications.


King lab:

This lab focuses on two areas. First, it has proposed that hyperglycemia induces vascular dysfunctions through the activation of protein kinase C (PKC) and MAP kinases (p38). Hyperglycemia can increase the synthesis of diacylglycerol (DAG) and thereby induce the activation of PKC, especially the β isoforms. PKC activation has, in turn, been reported to change the activation and expression of many enzymes and transcription factors, eventually leading to vascular dysfunction and pathologies. Using small-chemical inhibitors designed to selectively bind PKC-β isoforms, and molecular approaches, Dr. King’s lab has been determining which of the many vascular pathologies found in diabetic retinopathy, nephropathy and cardiovascular diseases are due to PKC activation. Clinically, one of the selective inhibitors of the PKC-b isoform has been shown to preserve vision in diabetic macular edema, thus proving a role for PKC activation in the development of diabetic retinopathy. Second, the role of insulin in inducing or preventing the vascular diseases associated with diabetes or the metabolic syndrome is being characterized. Dr. King’s lab suggested that insulin has many anti-atherosclerotic actions such as increasing the actions of eNOS and the expression of VEGF via activation of the PI3K/AKT pathway, a pathway selectively inhibited by metabolite-induced activation of stress MAPK. The selective loss of insulin’s anti-atherosclerotic actions is proposed to cause endothelial dysfunction and to accelerate atherosclerosis associated with diabetes and the metabolic syndrome. Specific areas of research include: