In Utero Exposure to a High Fat Diet: Epigenomic Programming of Metabolic Disease

At present most of our studies are focused on two members of the glucose transporter gene family,GLUT4 and GLUT8. GLUT4 is insulin and exercise responsive and is the major glucose transporter expressed in cardiac and skeletal muscle and adipose tissue. Glucose homeostasis depends mainly on controlled changes in glucose transport in insulin-responsive tissues such as muscle and adipose cells. By using techniques such as recombinant DNA methods, immunofluorescence microscopy, chimeric gene transfections, and transgenic and knockout mouse models, we study the role of GLUT4 in normal glucose homeostasis and in disease states (e.g. diabetes mellitus and obesity) .and its target in trafficking within these cells. By integrating the findings from this type of multidisciplinary study we ultimately hope to be able to make practical applications in the field of gene therapy and treatment of diabetes mellitus, a disease which affects more than 16 million Americans.

GLUT8 is a newly identified member of the glucose transporter gene family which is expressed in many tissues (including testis, brain, liver, placenta and various tumor cells) in addition to GLUT4-expressing tissues (e.g. heart, adipose, muscle). GLUT8 is upregulated in several tissues in response to GLUT4 ablation and may represent a novel anti-diabetic target. We are also studying the potential role of GLUT8 in tumor cell growth and metabolism which may lead to novel chemotherapeutic modalities. We have shown that GLUT8 protein expression is significantly upregulated in human endometrial adenocarcinoma and in rodent mammary tumors. GLUT8 expression was highest in the most aggressive human tumors which may provide a growth advantage as glucose is the primary fuel used by tumor cells. Present studies are directed toward understanding the regulation of GLUT8 in normal and disease states (e.g. diabetes mellitus and cancer). Gene targeting experiments in mouse will be important for defining the role of GLUT8 in normal development and glucose homeostasis.

In contrast to our studies on insulin action and glucose uptake we are also studying the glucagon receptor. Glucagon is a peptide hormone that functions to elevate serum glucose levels (in opposition to insulin). We have cloned the glucagon receptor gene and studied its regulation by hormones and nutrients. We are currently studying the role of the glucagon receptor in the pathophysiology of diabetes mellitus using gene knockout and transgenic mouse models developed in our laboratory. Novel insight has been gained from these studies which demonstrate a role for glucagon action in normal development of the pancreatic islet.

Additionally, gene knockout studies have provided proof of concept that pharmacologic inhibition of hepatic glucagon action can lower fasting glycemia and may be useful in treating hepatic insulin resistance in diabetic individuals.

Hosted by: Amy Davidoff, Ph.D. and Karen Houseknecht, Ph.D.