Jacob E (Jed) Friedman, Ph.D. Professor Department of Pediatrics, Biochemistry & Molecular Genetics Post-Doc Fellow, Dept of Biochemistry & Endocrinology, East Carolina Univ. SOM, Greenville, NC (1989-1991) University of Colorado Health Sciences Center Mail Stop 8106 Research Complex-1 South 12801 East 17th Ave Room 7127 Aurora, CO 80045 (303) 724-3983 (office) (303) 724-3920 (fax) jed.friedman@uchsc.edu

Research Interests:

Molecular Mechanisms for Insulin Resistance in GDM: Our clinical studies are focused on the cellular and molecular mechanisms of insulin resistance in obese women with Gestational Diabetes Mellitus (GDM). GDM is an enormous public health concern, as children from these pregnancies have demonstrated a dramatic rise in obesity and type II DM in young adulthood. Despite the dramatic increase in the incidence of GDM, and the long-term effects on the fetus, there are very few mechanistic data in the field of insulin resistance of GDM. Working with clinical investigators in the department of Ob-Gyn and women’s health at UCHSC, we utilize a novel incubated human muscle fiber system suitable for the study of muscle metabolism and signal transduction in-vitro. We have demonstrated that obese women with GDM have a unique insulin receptor defect that may underlie future risk for the development of type II DM. We identified specific intracellular serine-threonine kinases as possible candidates for inhibitors of insulin signal transduction and a novel pathway for insulin resistance. We are currently using Mass-Spectroscopy Core laboratories to carry out 2D/Mass-spec phosphopeptide mapping of the insulin receptor and IRS-1 to identify proteins that affect insulin signaling in human muscle during and 6 wks post-partum in human skeletal muscle biopsies.

Role of C/EBPb in development of diabetes and non-alcoholic fatty liver disease (NASH). We are interested in the regulation of fatty liver disease and gluconeogenesis in the liver. We are currently investigating the role of the nuclear transcription factor CCAAT/Enhancer Binding Protein b (C/EBP b) in carbohydrate and lipid metabolism and its role in ER stress and the imflammatory pathways leading to NASH. Using a combination ofmetabolic tracer metabolism in vivo and isolated tissues in vitro, we have shown that deletion of C/EBPb protects mice from diabetes and obesity by regulating key lipogenic and gluconeogenic genes, and through the inflammatory pathway. The major goal of this work is to create mice bearing a liver and brain-specific deletion for C/EBPb to determine its effect on food intake, hepatic lipid deposition and susceptibility to NASH. A secondary goal will be to examine the expression pattern of C/EBPb in archival liver biopsies from obese children with and without fatty liver disease.

Exploring the Fuel-Mediated Programming of Neonatal Growth in Non-Human Primates Despite the dramatic rise in the incidence of pediatric obesity, and the predicted effects of impaired glucose tolerance during pregnancy on childhood obesity, there are very few mechanistic data documenting the specific metabolic consequences of abnormal maternal insulin/glucose, leptin, or fatty acids on insulin resistance in the fetus. To address this issue we have begun a long-term project using adult Japanese Macaques subjected to a high fat diet during repeated pregnancies. Elevated hepatic triglycerides and HNF4a expression suggest that babies born from overweight mothers chronically consuming a high fat diet are born with early signs of liver steatosis and possibly the metabolic syndrome. The major goal of these studies is to determine the effect of maternal high fat feeding on the mechanisms for inflammation, steatosis, and excess gluconeogenesis observed in the fetal liver.

Selected Publications

1. Yamashita, H., Shao, J., Qiao, L., Pagliassotti, M., and J.E. Friedman. Effects of caloric restriction on fetal and postnatal hepatic insulin resistance in offspring from Spontaneous Gestational Diabetic Lepr db/+ mice. Pediatric Research, 53:411-418, 2003.

2. Barbour L.A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Bartke, A., J.E. Friedman and B. Draznin (2004). Human Placental Growth Hormone increases expression of the p85 regulatory subunit of PI 3-kinase and triggers insulin resistance in skeletal muscle, Endocrinology, 145(3):1144-50.2004 27.

3. Kirwan, J., Varastehpour, A., Jing, M., Presley, L., Shao, J., Friedman, J.E.*, and P. M. Catalano. Reversal of insulin resistance post-partum is linked to enhanced skeletal muscle insulin signaling. Journal of Clinical Endocrinology and Metabolism, 89(9):4678-84, 2004. *Corresponding Author.

4. Anderson, M., Qiao, L., Shao, J., Friedman, J.E., Devaskar, S., and Hay, WW. Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 288(2):R473-81, 2005.

5. Shao, J., Qiao, L., Janssen, R., Pagliassotti, M., and J.E. Friedman. Sustained hyperglycemia increases phosphoenolpyruvate carboxykinase gene expression and hepatocellular glucose production via elevated LAP/LIP Ratio. Diabetes, 54: 976-985, 2005.

6. Qiao, L., MacLean P., Schaack, J., Orlicky, D.J, Dairymont, C., Pagliassotti, M, Friedman J.E., and J. Shao. C/EBPa regulates human adiponectin gene transcription through an intronic enhancer. Diabetes 54:1744-1754, 2005.

7. Barbour, L., Fisher, S., Knotts, T., Rahman, M. Roper, M., Leitner, W., Govechenko, I., Cantley, L., Kahn, C.R., J.E. Friedman* and B. Draznin. Increased p85a is a potent negative regulator of skeletal muscle insulin signaling and induces in-vivo insulin resistance associated with growth hormone excess. Journal of Biological Chemistry, 2005 (In Press). *Corresponding Author.

Latest Publications in PubMed