Joslin Investigator Details

A Harvard Medical School Affiliate

Welcome to the Joslin Research Website


	Joslin Investigator:

George L. King, MD

Investigator Specifics:

Professional Details:

CV not available

Member of Section:

Core Director:

Current Fellows, Students, or Lab Members:

Pedro Geraldes, PhD

Junko Hiraoka-Yamamoto

In-Kyung Jeong, M.D., Ph. D.

Munehiro Kitada

Chenzhong Li, M.D., Ph. D.

Past Fellows, etc.:

Emi Arikawa

Net Evcimen

Michio Hayashi

Henry He

Justine Hsu

Keiji Isshiki

Judith Jacobs

Zhen Jiang

Naomichi Katai

Tatsuya Kuroki

Keiko Naruse

Yuzuru Oshiro

Naotaka Sekiguchi

Gary Shen

Konstantinos Sotiropoulos

Kiyoshi Suzuma

Kerrie Way

Kunimasa Yagi

Michiko Yamagata

Yutaka Yasuda

Junqinq Zhang

Investigators

Adjunct Investigators

Fellows & Team Members

DERC Cores

Research Sections

Joslin Resources

George L King, MD

Director of Research

Joslin Diabetes Center

Section Head: Vascular Cell Biology

Joslin Diabetes Center

Professor of Medicine

Harvard Medical School

1/1/2001 -

Protein Kinase C

Dr. King and his team study the molecular mechanisms by which hyperglycemia may lead to vascular dysfunction and long-term diabetic complications. They have shown that hyperglycemia activates protein kinase C (PKC) and have discovered some of the many cellular activities that occur when PKC is activated. Since PKC regulates many important vascular functions, such as permeability and cellular reproduction, these researchers believe that the hyperglycemia induced activation of PKC leads to vascular dysfunction in diabetes. For example, PKC triggers a chain of cellular events that leads to inhibition of sodium-potassium ATPase, increases synthesis of TGFb, fibronectin and Type IV collagen, and changes in blood flow. These effects can be brought back toward normal by use of a protein kinase C inhibitor. PKC activation also regulates the production and action of vascular endothelial growth factor (VEGF), which triggers vascular cell growth, as well as the production of other genes.

To test the theory that PKC activation is involved in causing vascular complications, Dr. King and his team are developing genetically altered mice that produce excessive amounts of PKC. They have identified a highly selective protein kinase C inhibitor that can be given orally to inhibit PKC activity. Data published recently in Science from these researchers suggest that a PKC inhibitor can correct blood vessel abnormalities in the retina, as well as in the kidney, of diabetic animals. These studies, completed in conjunction with researchers from Eli Lilly and Company, now are entering human trials. The role of Vitamin E in preventing vascular complications is also being explored by Dr. King and his colleagues, since they found that Vitamin E can prevent increases in the levels of diacylglycerol and PKC in vascular cells triggered by diabetes or high blood glucose levels.

In their continuing research on the role of vascular endothelial growth factor (VEGF) in the development of diabetic eye disease, Dr. King and his colleagues are investigating what cellular events generate the production of VEGF and how VEGF receptors in the blood vessels of the retina are regulated. In addition, these researchers are studying how VEGF stimulates the reproduction of endothelial cells. They have found that this growth factor can activate PKC and are studying the effect of VEGF on blood vessels in the retina.

Dr. King's studies on how insulin and other hormones regulate the contraction and dilation of blood vessels are important to understanding insulin resistance and vascular complications in people with diabetes, since insulin resistance at one level of the blood vessel could cause either dilation or constriction, depending on the tissue involved. Their current studies suggest that insulin signaling in vascular cells is different than signaling which occurs in non-vascular cells. For example, endothelial cells in the blood vessels can internally transport insulin across the cell without being broken down. In addition, in vascular endothelial cells insulin receptors interact mainly with IRS-2 rather than IRS-1. Dr. King's group is also studying the interaction between insulin and vasoactive hormones such as endothelin and angiotensin.

Dr. King's recent work appears to suggest that insulin can regulate the expression of the gene that causes the hormone endothelin to be produced in the vascular endothelial cells. It also is possible that endothelin can alter insulin action in blood vessels. These researchers' data clearly show that insulin and endothelin can affect each others' action. Besides basic studies on the molecular biology and cell biology level, Dr. King's group is interested in knowing how these interactions affect the functioning of vascular cells. Using glucose clamp studies, possible interactions between insulin and ET-1 also are being characterized in humans and animals. Dr. King and his colleagues also collaborate and interact with the Section on Eye Research, especially in the biophysical studies to measure retinal blood flow and its regulation by various PKC inhibitors, insulin and vasoactive hormones.

Selected References:

Nishio, Y., Warren, C., Buczek-Thomas, J.A., Rulfs, J., Koya, D., Aiello, L.P., Feener, E.P., Miller, T.B. Jr., Denis, J.W., King, GL., Identification and Characterization of a Gene Regulating Enzymatic Glycosylation Which Is Induced by Diabetes and Hyperglycemia Specifically in Rat Cardiac Tissue, J Clin Invest., 1995, 96: 1759-1767.

Ishii, H., Jirousek, M.R., Koya, D., Takagi, C., Xia, P. , Clermont, A., Bursell, S.-E., Kern, T.S., Ballas, L.M., Feener, E.P., King, G.L., Amelioration of Vascular Dysfunction in Diabetic Rats by an Oral PKC Beta Inhibitor, Science, 1996, 272: 728-731.

Xia, P., Aiello, L.P., Ishii, H., Jiang, Z., Park, D.J., Robinson, G.S., Takagi, H., Newsome, W.P., Jirousek, M.R., King, G.L., Characterization of Vascular Endothelial Growth FactorÕs (VEGF) Effect on the Activation of Protein Kinase C (PKC), Its Isoforms and Endothelial Cell Growth, J Clin Invest., 1996, 98: 2018-2026.

Biographical Sketch:

Dr. King is Research Director at Joslin Diabetes Center, Professor of Medicine at Harvard Medical School and heads the Section on Vascular Cell Biology at Joslin. He received his medical degree from Duke Medical School and completed his residency training at University of Washington Affiliated Hospitals in Seattle, WA. Before coming to Joslin, Dr. King was a clinical and research associate at the National Institutes of Health. He is the recipient of numerous awards, including the Donald Silver Excellence in Research Award from the Juvenile Diabetes Foundation, the Cogan Award from the Association for Research in Vision and Ophthalmology, the Boehringer Mannheim-JDF Excellence in Diabetes Care Research Award, and the Alcon Award for vision research.

To contact by email: George King