Kathleen L. Wyne, M.D., Ph.D.
RESEARCH INTERESTS
We have introduced into a chromosome of the rat a transgene that was designed to suppress the activity of an enzyme, carnitine palmitoyltransferase I (CPT I), selectively in the pancreatic beta cell. Our expectation was that this manipulation might produce a state of insulin overproduction and thus provide support for the recently proposed involvement of CPT I suppression as a key factor in glucose-mediated insulin secretion. To our surprise, animals carrying the transgene display the opposite characteristic, namely, a state of severe insulin deficiency that is caused by loss of pancreatic beta cells. This represents the first transgenic rat model of diabetes. The diabetes develops at ~ 4-8 weeks of age and, if not treated with insulin, the animals show persistent thirst and excessive urination due to the hyperglycemia, lose weight, stop growing and die young.
The cause of the insulin deficiency is not yet clear, although we know it is related to a gradual loss of beta cells beginning around 14 days of age without evidence of an autoimmune attack on the islets. This suggests that the transgene has altered a process that is not necessary for initial islet development but is essential for maintenance of normal islet structure and function. The problem in our transgenic rat (which differs from all other animal models of insulin deficiency) might stem from an alteration in beta cell fat metabolism or from disruption of a critically important gene. Our studies are aimed at distinguishing between these scenarios. At the very least will provide us with important new insights into the cell biology of the pancreatic islet. It may also prove to be relevant to an understanding of the cause of Type 1 diabetes in those individuals afflicted with the disease but in whom circulating islet antibodies have never been found which represents as many as 15% of patients with Type 1 diabetes.
EDUCATION
1979-1983 BA with honors in Biology, University of Chicago, Chicago, Illinois
1983-1985 MS in Human Biology, University of Chicago, Chicago, Illinois
1985-1988 Ph.D. in Pathology, University of Chicago, Chicago, Illinois
1988-1990 M.D., University of Chicago, Chicago, Illinois
PROFESSIONAL EXPERIENCE
1980-1983 Student Athletic Trainer, Department of Physical Education, University of
Chicago, Chicago, Illinois
1983 Junior Research Technician, Department of Pathology, University of Chicago, Chicago, Illinois
1986-1987 Teaching Assistant, Cell Pathology, University of Chicago, Chicago, Illinois
1990 Teaching Assistant, Physical Diagnosis, University of Chicago, Chicago, Illinois
1990-1993 Resident, Internal Medicine, Baylor College of Medicine, Houston, Texas
1993-1998 Fellow, Endocrinology, Diabetes and Metabolism, University of Texas Southwestern
Medical Center, Dallas, Texas
1995 Volunteer Physician - Olympic Training Center, Colorado Springs, Colorado
1998 Instructor, Division of Endocrinology, Diabetes and Metabolism, University of Texas
Southwestern Medical Center, Dallas, Texas
RESEARCH
1985 Master's Paper: Characterization of the Apolipoprotein E Secretion Product from Rat
Ovarian Granulosa Cells.
1988 Doctoral Thesis: The Regulation of Apolipoprotein E Synthesis in Rat Ovarian
Granulosa Cells.
PROFESSIONAL ORGANIZATIONS
American Medical Association
American College of Physicians
US Olympics Sports Medicine Society
BOARD CERTIFICATION
1993 American Board of Internal Medicine
1998 Endocrinology, Diabetes and Metabolism
PUBLICATIONS
1. Getz G, Driscoll D, Blix P, Diller P, Fox JC, Schreiber JR and Wyne KL. Dietary and hormonal regulation of apo E synthesis and secretion, 7th International Symposium on Atherosclerosis Melbourne, Australia, ed. by NH Fidge and PJ Nestel, Exerpta Medica, Amsterdam 1986, pp. 307.
2. Wyne KL, Schreiber JR, Larsen A and Getz G. Regulation of apolipoprotein E biosynthesis by cAMP and phorbol ester in rat ovarian granulosa cells. J Biol Chem 1989; 264:981-989.
3. Wyne KL, Schreiber JR, Larsen A and Getz G. Rat granulosa cell apolipoprotein E secretion: regulation by cell cholesterol. J Biol Chem 1989; 264:16530-16536.
4. Getz G, Mazzone T, Schreiber JR, Wyne KL and Olson L. Intracellular sterol and apo E biosynthesis. 10th International Symposium on Drugs Affecting Lipid Metabolism 1989;Houston, Texas.
5. Olson L, Wyne KL, Schmit V, Gong E, Getz G and Schreiber JR. The influence of lipoproteins on synthesis of apolipoprotein E by rat ovarian granulosa cells. In Regulatory Processes and Gene Expression in the Ovary, ed. G Gibori, Serono Symposium, 1990.
6. Jokkinen E, Landschulz KT, Wyne KL, Ho YK, Frykman P and Hobbs HH. Regulation of the VLDL receptor by thyroid hormone in rat skeletal muscle. J Biol Chem 1994; 269:26411-26418.
7. Wyne KL, Pathak RK, Seabra MC and Hobbs HH. Expression of the very low density lipoprotein receptor in endothelial cells. Arterioscler Thromb Vasc Biol 1996; 16:407-415.
8. Cao G, Garcia CK, Wyne KL, Schultz RA, Parker KL and Hobbs HH. Structure and localization of the human gene encoding SR-BI/CLA-1 - Evidence for transcriptional control by steroidogenic factor-1. J Biol Chem 1997; 272:33068-33076.
9. Wyne KL and Woollett, LA. Transport of Maternal LDL and HDL to the fetal membranes and placenta of the Golden Syrian Hamster is mediated by receptor-dependent and receptor-independent processes. J Lipid Res 1998; 39:518-530.
10. Stangl H, Cao G, Wyne KL and Hobbs HH. Scavenger receptor class B Type l-dependent stimulation of cholesteryl esterification by high density lipoproteins, low density lipoproteins and nonlipoprotein cholesterol. J Biol Chem, 1998; 273: 31002-31008.
11. Wyne KL and Bradshaw K. PCOS and insulin resistance: therapeutic considerations, Current Opinion in Endocrinology & Diabetes 1998; in press
ABSTRACTS
1. Wyne KL, Schreiber JR, Schmit V and Getz G. Regulation of apo E and apo E mRNA synthesis in rat ovarian granulosa cells, 68th Annual Meeting, Endocrine Society, Anaheim, CA, 1986.
2. Schreiber JR, Wyne KL, Larsen A and Getz G. Protein kinase C regulation of apolipoprotein E (apo E) and apo E mRNA synthesis by rat ovarian granulosa cells. 34th Annual Meeting, Society for Gynecologic Investigation, Atlanta, GA, 1987.
3. Wyne KL, Schreiber JR and Getz G. Regulation of apo E by phorbol ester in rat ovarian granulosa cells, 60th Annual Meeting, American Heart Association, Anaheim, CA, 1987.
4. Schreiber JR, Wyne KL, Larsen A and Getz G. Regulation of apolipoprotein E synthesis in rat ovarian granulosa cells, 70th Annual Meeting, Endocrine Society, New Orleans, LA, 1988.
5. Wyne KL, Getz G and Schreiber JR. Regulation of apolipoprotein E synthesis in an active steroidogenic cell, 8th International Congress of Atherosclerosis, Rome, Italy, 1988.
6. Wyne KL, Schreiber JR and Getz G. Regulation of apo E by lipoprotein in rat ovarian granulosa cells, 72nd Annual Meeting, Federation of American Societies for Experimental Biology, Las Vegas, NV, 1988.
7. Schreiber JR, Wyne KL and Getz G. Apo E synthesis by cultured human ovarian granulosa cells; regulation by hCG and cholesterol, 71st Annual Meeting, Endocrine Society, Seattle, WA, 1989.
8. Wyne KL and Hobbs HH. SR-Bl is an HDL receptor that mediates selective uptake of the cholesteryl esters from high density lipoprotein (HDL) and is regulated by cyclic AMP in human adrenal cells, 79th Annual Meeting, Endocrine Society, Minneapolis, MN, 1997.
9. Wyne KL, Savonen R, Bengtsson-Olivecrona G, Olivecrona T, and Hobbs HH. The VLDL Receptor is not a primary chylomicron receptor in the mouse, 79th Annual Meeting, Endocrine Society, Minneapolis, MN, 1997.
10. Wyne KL, Esser V, Comerford SA, Hammer RE and McGarry JD. A new genetic rat model of insulin-dependent diabetes without insulitis, 58th Annual Scientific Meetings and Sessions, American Diabetes Association, Chicago, IL, 1998.
11. Esser V, Wyne KL, Comerford SA, Hammer RE and McGarry JD. A new genetic rat model of severe insulin deficiency without insulitis, 34th Annual Meeting, European Association for the Study of Diabetes, Barcelona, Spain, 1998.
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