Department of Medicine at University of Pittsburgh

Academic Resources

Other Resources

Division of Endocrinology and Metabolism
200 Lothrop Street
E1140 BST
Pittsburgh, PA 15213
Administrative/Research Office: (412) 648-9770
Patient/Clinical Inquiries: (412) 586-9700

Laboratory of Donald K. Scott PhD

Donald K. Scott PhD
Saint Louis University, 1991

My laboratory is focused on understanding how nutrients, such as glucose, control cellular phenotype. Our work is important for learning about the underlying molecular mechanisms of diabetes and aging. We are currently working in three different model systems: liver, pancreatic beta cells, and T lymphocytes.

The liver of a fasting animal produces glucose (via glycogenolysis and gluconeogenesis) to maintain plasma glucose levels so that the brain can continue to function normally. In a refed animal, the liver makes a remarkable transformation from an organ that produces glucose to an organ that consumes glucose. This switch in function is accompanied by a dramatic, coordinated change in gene expression that is mediated by both insulin and glucose (e.g., genes regulating glycolysis and fat synthesis go up, genes regulating gluconeogenesis go down). An increase in glucose metabolism generates signaling metabolites that alter the metabolic phenotype of the cell leading to increased glucose utilization and decreased glucose output (please see the Figure). Importantly, this metabolic reprogramming, and its concomitant alterations in gene expression, do not take place normally in diabetes. A natural starting place to understand how the liver coordinates this change in phenotype is to study transcription factors that control the expression of metabolic genes. We have focused on c-Myc, a transcription factor that is involved in proliferation, apoptosis and metabolism. Using a recombinant adenovirus that expresses an antisense c-myc mRNA, and therefore depletes liver cells of the c-Myc protein, we found that c-Myc is required for glucose regulated gene expression. In the near future we will study the metabolic consequences of altering hepatic c-Myc levels in vivo.

In the pancreatic beta cell, glucose metabolism is used to sense plasma glucose concentrations so that the appropriate amount of insulin is secreted to maintain glucose homeostasis. This process is accompanied by changes in the expression of genes involved in glucose metabolism and insulin secretion. Furthermore, glucose-regulated gene expression is aberrant in diabetes. We have found that c-Myc is required for glucose regulated gene expression in these cells as well. We are also studying how glucose activates the carbohydrate response element binding protein (ChREBP, see the figure below).

Fluorescent-tagged ChREBP in an INS-1-derived 832/13 beta cell

A new project in the lab is the study of glucose regulated gene expression in T lymphocytes. Lymphocytes display a large increase in glucose uptake and glycolysis after activation by mitogens. This is accompanied by large increases in the expression of glycolytic enzyme genes - so there is an obvious similarity between activated lymphocytes and the liver and beta cell systems, but the former system has not been studied in any detail. What is particularly interesting is that the increased glucose flux and glycolytic enzyme induction is impaired and delayed in the elderly and therefore may contribute to the immune dysfunction seen in the oldest old. We are studying the role of SP1 and other transcription factors in the coordinated regulation of gene expression in lymphocytes.

We are using a variety of methodologies to understand the coordinated regulation of gene expression by glucose, including in vivo and in vitro adenovirus gene delivery, transgenic animals, chromatin immunoprecipitation, nuclear run-ons, real time RT-PCR, Western blots and several variations of gene arrays. A better understanding of these coordinating transcription factors, how these factors interact with and their role in glucose homeostasis and immunological wellbeing will provide new opportunities for designing pharmaceutical and gene therapies for diabetes and for promoting healthy aging.

Summer 2005: Back Row: Kim Pedersen, David Eckert, Chris Doumen, Marcel Charbonnet, Pili Zhang. Front Row: Rebecca Shea, Sharell Bindom, Susan Burke, Don Scott. To view earlier lab photos, click here.

Recent Publications

1. Collier, J.J., Doan, T-T., Daniels, M.C., Schurr, J. Kolls, J., Scott, D.K. 2003. c-Myc is required for the glucose-mediated induction of metabolic enzyme genes. J. Biol Chem 278: 6588–6595.

2. Scott, D.K., Collier, J.J., Doan, T-T.T., Bunnell, A.S., Daniels, M.C., O'Doherty, R.M. 2003. A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression. Cell. Mol. Biochem. 254: 327-337.

3. Van de Casteele, M., Kefas, B.A., Cai, Y., Heimberg, H., Scott, D.K., Henquin, J.-C., Pipeleers, D., Jonas, J.-C. 2003. Prolonged reduction in glucose signal induces apoptosis of rat pancreatic beta cells through induction of c-myc. Biochem. Biophys. Res. Comm. 312: 937-944.

4. Cohen, J.C., Scott, D.K., Miller, J., Howley, P., Zhou, P., Larson, J.E. 2004. Transient in utero knockout (TIUKO) of C-MYC affects late lung and intestinal development in the mouse. BMC Dev Biol. Apr 16; 4(1):4.

5. Collier, J.J., Scott, D.K. 2004. Sweet changes: glucose homeostasis can be altered by manipulating genes controlling hepatic glucose metabolism. Mol. Endocrinol.18: 1051-1063.

6. Collier, J.J., White, S.M.,Dick, G.M., Scott, D.K. 2004. Phosphatidylinositol 3-kinase inhibitors reveal a unique mechanism off enhancing insulin secretion in 832/13 rat insulinoma cells. Biochem. Biophys. Res. Comm. 324:1018-1023.

7. Hsu, H-C., Scott, D.K., Zhang, P., Zhou, J., Yang, P., Wu, Q., Ravussin, E., Jazwinski, M.S., and Mountz, J.D. 2006. CD8 T-cell Immune Phenotype of Successful Aging Mech Ageing Dev. 127:231-9.

8. Pedersen, K.B., Zhang, P., Doumen, C., Charbonnet, M., Lu, D., Newgard, C.B., Haycock, J.W., Lange, A.J., and Scott, D.K. 2007. The promoter for the gene encoding the catalytic subunit of rat glucose-6-phosphatase contains two distinct glucose-responsive regions. (AJP Endo and Metab 292: E788-801).

9. Collier, J.J., Zhang, P., Pedersen, Burke, S.J., K.B., Haycock, J.W., and Scott, D.K. 2007. c-Myc and ChREBP contribute to glucose-regulated gene expression in INS-1-derived 832/13 pancreatic beta cells. (In Press, AJP Endo and Metab). (link to pdf?)

10. Alonso, L.C., Yokoe, T., Zhang, P., Scott, D.K., Seung, K.K., O’Donnell, C., and Garcia-Ocana, A. 2007. Glucose infusion induces compensatory β-cell replication in mice. (In Press, Diabetes).

Lab Photos