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George L. King, M.D.

Director of Research

Dr. King is the Director of Research and Head of the Section on Vascular Cell Biology at Joslin, as well as a Professor of Medicine at Harvard Medical School. He received his medical degree from Duke Medical School, completed residency training at the University of Washington Affiliated Hospitals, in Seattle, and then completed training as both a Research Associate and a Clinical Associate at the National Institutes of Health. He has been at Joslin and Harvard Medical School since 1981.

Dr. King has received numerous awards, including the Cogan Award from the Association for Research and Vision and Ophthalmology, the Stadie Memorial Award and Lectureship from the Philadelphia Affiliate of the American Diabetes Association, the Alcon Award for Vision Research and the Annual Award for Excellence in Research from the Japan Society of Diabetic Complications. Dr. King also was named Honorary Professor and Director of the Fu Dan Institute of Endocrinology and Diabetology at Fu Dan University, Shanghai, China.

Complications of vascular diabetes can affect many organs, but the most serious involve the eye, kidney, arteries, heart and nerves. The laboratory of Dr. King studies the molecular mechanisms by which hyperglycemia and insulin resistance may lead to vascular dysfunction and long-term complications of diabetes and insulin resistance.

In 1989, Dr. King’s laboratory proposed that activation of protein kinase C—especially the beta (PKC-beta) and delta (PKC-delta) isoforms—is the major signaling pathway by which hyperglycemia causes pathologies in the retina, kidney and cardiovascular systems. In a series of studies using cultured vascular cells from the retina, renal glomeruli and arteries, Dr. King’s laboratory demonstrated that hyperglycemia can activate PKC to induce vascular pathologies. Dr. King’s laboratory also characterized an isoform-selective inhibitor to PKC-beta, which, in diabetic animal models, prevents and stops the early changes of diabetic retinopathy, nephropathy and cardiovascular dysfunction.

From studies using PKC-beta and delta isoform transgenic or knockout animals, much evidence shows that various glucose metabolites, such as oxidants and glycation proteins, also can activate PKC-beta and delta isoforms in capillary and cardiovascular tissues, leading to vascular biochemical and pathological lesions. From this research evolved several years of collaboration with Eli Lilly to design the PKC inhibitor drug ruboxistaurin—with the goal of receiving approval from the Food and Drug Administration for use in treating diabetic eye disease.

Currently Dr. King’s laboratory is exploring the targets of PKC-beta and delta isoform activation in various vascular tissues, including retinal vascular cells, cardiomyocytes, arterial vascular cells, renal mesangial cells and podocytes. These targets involve extracellular matrix proteins, enzymes such as eNOS, and NADPH oxidase, cytokines and growth factors such as VEGF, TGF-beta, CTGF and endothelin, as well as transcription factors. Recently, Dr. King’s laboratory has reported that PKC delta activation by hyperglycemia can activate two independent signaling cascades, one NF-κB and the other is a tyrosine phosphatase (SHP-1) to reduce apoptosis of retinal and renal cells important in the initiation of diabetic retinopathy and nephropathy.

The second area of study concerns insulin’s role in regulating cardiovascular function in physiological and pathophysiological states. Insulin resistance is an important risk factor for cardiovascular diseases not only in people with diabetes, but also in those who have high blood pressure or lipid abnormalities or are obese.

Dr. King’s laboratory has shown that at the molecular and biochemical levels, insulin can regulate many vascular and cellular functions, including the enzyme activities of eNOS and HO-1, the expression of cytokines such as VEGF and endothelin and the migration and growth of smooth muscle cells. His laboratory postulated that insulin in the normal state can have anti-atherogenic actions. However, the loss of insulin’s normal action, in combination with the elevation of insulin levels found in insulin-resistant states, can lead to pro-atherogenic conditions in large blood vessels. These studies show an insulin-resistant or diabetic state causes a selective loss of insulin’s action with regard to one specific signaling pathway—IRS–PI 3-kinase–Akt—which mediates many of insulin’s anti-atherogenic actions, such as production of nitric oxide (NO) to dilate blood vessels and the expression of VEGF to improve heart perfusion and HO-1 for endogenous anti-oxidative stress actions.

Clinically, Dr. King is leading a comprehensive study to identify protective factors in a large group of Type 1 diabetic patients with diabetes duration over 50 years, called the Medalist Study. Over 40% of the Medalist diabetic patients do not have significant complications, even after 50-85 years of diabetes. Studies using molecular, genetic, biological and physiological methods are ongoing to identify these protective factors against the adverse effects of hyperglycemia of diabetes.

Selected References

Geraldes P, Hiaroka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med. 2009 Nov;15(11):1298-306. Epub 2009 Nov 1.

He Z, Opland DM, Way KJ, Ueki K, Bodyak N, Kang PM, Izumo S, Kulkarni RN, Wang B, Liao R, Kahn CR, King GL. Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia Arterioscler Thromb Vasc Biol 26:787-793, 2006.

He Z, Way KJ, Arikawa E, Chou E, Opland DM, Clermont A, Isshiki K, Ma RC, Scott JA, Schoen FJ, Feener EP, King GL. Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium. J Biol Chem 280:15719-15726, 2005.

Chou E, Suzuma I, Way K, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL. Decreased cardiac expression of vascular endothelial growth factor (VEGF) and its receptors in insulin resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 105:373-379, 2002.

Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC ß inhibitor. Science 272:728-731, 1996.

 


 

Page last updated: April 23, 2014