Friedman Lab
Department of Pediatrics
Biochemistry and Molecular Genetics

Current research interests:
Regulation of C/EBP gene expression and gluconeogenesis; insulin receptor signaling and mechanisms of insulin resistance in human and mouse models of diabetes; fetal origins of adult obesity and diabetes.

PI
Jacob E. Friedman, Ph.D.
Jed.Friedman@uchsc.edu

Contact information:
(303) 724-3983

Purpose or description:
Our primary research interests are in the areas of insulin receptor signaling, hepatic gene regulation, and fetal origins of adult obesity and diabetes. Most recently, we have discovered that the nuclear transcription factor C/EBP b present in liver and adipose tissue, integrates carbohydrate and lipid metabolism during diabetes and acts as a nutrient sensor in hepatic cells. Using a combination of metabolic tracer metabolism in vivo and isolated tissues in vitro, we find that C/EBPb deletion protects mice from development of obesity and diabetes.  Currently, our major goals are to determine the adipose and liver-specific roles of C/EBPb in regulation of triglyceride metabolism using both germline (conditional knockout) and viral approaches to selectively inhibit C/EBPb in liver and other tissues in transgenic mice. In addition, we are using hepatic cell lines to understand how glucose and insulin triggers splicing of the inhibitory form of C/EBPb - Liver Inhibitory Protein (LIP) to control gluconeogenesis and lipogenesis.   We are also currently using a proteomic approach with the Mass-Spectroscopy facility to identify novel proteins and pathways controlled by C/EBPs.

Our clinical studies are focused on the cellular mechanisms of insulin receptor signal transduction 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 Pediatrics at UCD, 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. Recently, we identified specific intracellular serine-threonine kinases as possible candidates for inhibitors of insulin signal transduction and a novel pathway for insulin resistance. Using basic molecular techniques for studying isolated proteins in transgenic and in-vivo ovine fetal models, we have proposed a number of exciting new hypotheses for understanding the molecular interactions that promote the insulin resistance, which has a direct bearing on the health of pregnant women and their offspring.

Specialized facilities or techniques : Transgenic mouse metabolism in-vivo (insulin clamps) and in-vitro. Adenovirus production; Liver transfection (stable and transient). Human skeletal muscle fiber incubation in explants from patients undergoing c-section or elective surgery (muscle fiber incubation). Muscle culture.

Supported by:

• NIH-RO1-DK59767 "Regulation of Glucose Homeostasis by C/EBPb." Jacob E. Friedman, Principal Investigator,
• NIH RO1-DK062155 "Mechanisms of Insulin Resistance in GDM, Jacob E. Friedman, Principal Investigator,
• NIH-P30-DK48520 (James O. Hill) Clinical Nutrition Research Unit (CNRU) Program Grant. Jacob E. Friedman Metabolic Core Director, 07/01/02-12/30/05,
• ADA, "Role of TNFa in Insulin Resistance in Human Gestational Diabetes" Jacob E. Friedman, Principal Investigator,
• NIH RO1DK52138, "Fetal Glucose and Amino Acid Deprivation". 04/01/02 - 03/31/06, W.W. Hay, PI, Jacob E. Friedman, Co- Investigator , UCD department of Pediatrics.