H. Henry Dong Assistant professor
PhD. Uppsala University, Sweden 1995
Email: dongh@pitt.edu
Research Interests:
Obesity, particularly intra-abdominal fat accumulation, is associated with insulin resistance that is defined as a significantly diminished state of responsiveness of the body to normal plasma insulin concentrations. To overcome insulin resistance in peripheral tissue, the pancreas tends to release more insulin via a compensatory mechanism, which over time leads to deterioration and loss of the ability of the pancreas to overcome progressively increased insulin resistance and eventually results in overt type 2 diabetes. Despite tremendous efforts to elucidate the molecular basis of insulin resistance, a unifying idea to account for the pathophysiology of insulin resistance in obesity and type 2 diabetes is still lacking. A major objective of this lab is to characterize the role of forkhead transcription factors in glucose and lipid metabolism in relation to the pathophysiology of insulin resistance. We identify and characterize Foxo target genes in metabolism to define the molecular mechanism by which Foxo factors regulate glucose and lipid metabolism in response to insulin action. These studies are expected to gain insight into the molecular events that link insulin resistance to metabolic aberrations, providing a knowledge base for the design and development of small molecule drugs for better clinical management of diabetic dyslipidemia in obesity and type 2 diabetes.
Insulin Gene Therapy for Type 1 Diabetes
Type 1 diabetes is caused by the lack of insulin production in the pancreas. Insulin gene therapy is being developed as an alternative insulin replacement therapy for it offers great potential for achieving long-term blood glucose control without causing immune rejection. Here the insulin gene is delivered through a gene vehicle to the liver, such that insulin will be produced in liver cells and released into the blood stream. We have provided proof-of-principle that sustained insulin production at a basal level in the liver is sufficient to prevent the development of ketoacidosis in the urine and relieve diabetes symptoms in diabetic animals. To improve this procedure, we propose to control insulin production to achieve insulin release in a glucose-dependent manner. In other words, we will use the natural glucose and insulin response mechanisms in the liver to generate a regulated system, in which insulin production will be stimulated when blood sugar is high and suppressed when blood sugar is low. Our hypothesis is that this highly regulated system will provide control of blood sugar without low blood sugar episodes caused by production of too much insulin. We will test this system in diabetic animals for its safety and efficacy in blood sugar control.
Islet Neovascularization and Islet Transplantation
Successful islet transplantation depends on infusion of sufficiently large amounts of islets (11,000 islets/kg), of which only about 30% islet mass becomes stably engrafted. Rapid and adequate vascularization is crucial for islet survival and function. Delay in vascularization tends to deprive islets of oxygen and nutrients, resulting in islet cell death. In addition, insufficient vascularization is attributable to early graft failure. To overcome this limitation, we propose to express angiogenic molecules in islet cells prior to transplantation to promote angiogenesis in islet grafts and enhance graft vascularization. We would like to characterize at molecular levels the mechanism of islet graft vascularization and provide a molecular basis for future development of angiogenic therapies to achieve rapid and adequate islet vascularization post transplantation. While the Edmonton protocol for islet transplantation generally requires 2-4 cadaveric pancreata per recipient, enhanced islet vascularization by angiogenic therapies is expected to improve the donor/recipient ratio in islet transplantation with better transplantation outcome at a reduced cost of islets.
Recent Publications
Qu S., Su D., Altomonte J., Kamagate A., He J., Perdomo G., Tse T., Jiang Y., and Dong HH. PPAR- mediates the hypolipidemic action of fibrates by antagonizing FoxO1. Am J Physiol Endocrin & Metab. 292:E421-434. 2007.
Qu S., Altomonte J., Perdomo G., He J., Fan Y., Kamagate A., Meseck M. and Dong HH. Aberrant FoxO1 function is associated with impaired hepatic metabolism. Endocrinoloyg. 147:5641-5652. 2006
Zhang N., Su D, Qu S, Tse T, Bottino R, Balamurugan AN, Xu J, Bromberg JS and Dong HH. Sirolimus is associated with reduced islet engraftment and impaired -cell function. Diabetes 55:2429-2436. 2006.
Zhang, N., Bertera, S., Qu, S., He, J., Bottino, R., Bromberg, J. and Dong, H. Therapeutic angiogenesis for islet revascularization. Current Medicinal Chemistry-Immunology, Endocrine and metabolic Agents. 6:155-166. 2006.
Zhang, N., Qu, S., Xu, J., Bromberg, J. and Dong, H. Inhibition of angiogenesis is associated with reduced islet engraftment in diabetic recipient Mice. Transplantation Proceedings. 37:4452-4457. 2005.
Dong, H., Maddux, B.A., Altomonte, J., Meseck, M., Accili, D., Terkeltaub, R., Johnson, K., Youngren, J. and Goldfine, I.D. 2005. Increased Hepatic Levels of the insulin receptor inhibitor, PC-1/NPP1, induce glucose intolerance. Diabetes. 54:367-372. 2005.
Altomonte, J., Cong, L., Harbaran, S., Richter, A., Xu, J., Meseck, M. and Dong, H. (2004). Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J. Clin. Invest. 114:1493-1503. 2004.
Zhang, N., Richter, A., Suriawinata, J., Harbaran, S., Altomonte, J., Cong, L., Zhang, H., Song, K., Meseck, M., Bromberg, J., and Dong, H. (2004). Elevated VEGF production in islets improves islet graft vascularization. Diabetes. 53:963-970. 2004.
Altomonte, J., Richter, A., Harbaran, S., Nakae, J., Meseck, M., Accili, D. and Dong, H. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am. J. Physiol. 285. E718-728. 2003.
Puigserver P, Rhee J, Donovan J, Yoon J.C., walkey C.J., Oriente F, Kitamura Y., Altomonte J., Dong H., Accili D. and Spiegelman B.M.. Insulin-dependent hepatic gluconeogenesis through Foxo1/PGC1 interaction. Nature. 423, 550-555. 2003.
Zhang N, K. Anthony, K. Shinozaki, J. Altomonte, Z. Bloomgarden and H Dong. Angiogenic gene transfer for improving islet graft Vascularization. Gene Ther. Mol. Biol. 7, 153-165. 2003.
Altomonte, J., Harbaran, S., Richter, A. and Dong, H. Fat depot-specific expression of adiponectin is impaired in Zucker fatty rats. Metabolism. 52, 958-963. 2003.
