Anthony J. Weinhaus, Ph.D.

Current Positions:
Instructor and Laboratory Director, Department of Genetics, Cell Biology and Development, University of Minnesota

Research Interests: 
My research interests are in islet biology. Before going to graduate school, I was involved in a study for the use of isolated pancreatic islets in transplantation to reverse diabetes. This work was done on rats and resulted in 6 publications.  I then had the opportunity to go to graduate school and work with Dr Bernard Tuch and a group that had transplanted human islets, isolated from fetal tissue, to diabetic patients. Although the islet grafts were eventually rejected, they did show signs of function and growth. My graduate work began on the isolation and culture of human islets, but moved onto the physiology of insulin secretion. Studies on human fetal islets showed that they were not glucose sensitive. This feature precluded the tissue as a viable source of donor tissue. The goal of my graduate work was to investigate the insulin secretory pathway, in order to determine if the cells could be made glucose sensitive through tissue culture. Studies on the development of the membrane ion channels involved in the insulin secretory pathway from fetal to adult islets from rat, pig and humans were published. My worked showed that the ion channels are fully functioning very early in gestation. Thus, the glucose-insensitivity was due to the proximal or glucose metabolism part of the pathway. However, If allowed to grow to full gestation, or if grown in tissue culture for the equivalent time, the tissue becomes glucose-sensitive and thus valuable for transplantation.

For post-doctoral work, I was interested in the biochemical study of the insulin secretory pathway. I came to Minneapolis to work with Dr Robert Sorenson who had a model for the up-regulation of insulin secretion. During pregnancy, or prolactin treatment (in vivo or in vitro), islets undergo a 2 to 8-fold increase in insulin secretion and cell division. I used this model to examine the role of glucose utilization and oxidation in insulin secretion. These studies led to the investigation of what turned out to be the most important and rate-limiting enzyme of glucose metabolism, glucokinase. I am currently concluding studies on the up-regulation of transcription and expression of glucokinase and have begun work on transcription factors involved in increasing promoter activity. I will continue to examine the very complicated network of transcription factors involved in the up-regulation of glucokinase and thus insulin secretion. Ultimately, this research has clinical application. The results may be used to develop a drug for the treatment of type-II (late-onset) diabetes. Currently, most of the drugs used in treatment of type-II target the ion channels involved in insulin secretion in order to up-regulate insulin secretion. Peptides used to target the up-regulation of glucokinase, in order to increase secretion, is a novel approach.

Publications:

Peer-Reviewed Publications:

1. Hegre O.D., Enriquez A.J., Weinhaus A.J., Marshall S., Serie J.R. Allotransplantability of neonatal rat islets in the BB/Wor rat. Diabetes 36: p.272-277. 1987.

2. Serie J.R., Hegre O.D., Eide C.R., Weinhaus A.J., Marshall S. The successful allotransplantation of neonatal rat islets across multiple combined major and minor histocompatibility barriers. Transplantation 44: p.739-741. 1987.

3. Hegre O.D., Enriquez A.J., Ketchum R.J., Weinhaus A.J., Serie J.R. Islet transplantation in spontaneously diabetic BB/ Wor rats. Diabetes 38: p.1148-1164. 1989.

4. Hegre O.D., Serie J.R., Weinhaus A.J., Ketchum R.J., Enqriquez A.J., Esteban M.M. Cultured neonatal islet transplants in alloxan-treated and spontaneously diabetic rats. Hormone and Metabolic Research 25: p.108-116, 1990.

5. Hegre O.D., Serie J.R., Enriquez A.J., Weinhaus A.J., Ketchum R.J., Sueppel K.L. Growth of neonatal islet graft following transplantation to the BB/ Wor rat. Hormone and Metabolic Research 25: p.142-147, 1990.

6. Esteban M.M., Weinhaus A.J., Sueppel K.L., Ketchum R.J., Marshall S., Serie J.R., Hegre O.D. Effect of third-party, MHC-incompatible allograft rejection on cultured islet allografts. Transplantation Proceedings 22 (2): p.836-837, 1990.

7. Weinhaus A.J., Poronnik P., Cook D.I., Tuch B.E. Insulin secretagogues, but not glucose, stimulate and increase in [Ca2+] I in the fetal rat b-cell. Diabetes 44: p.118-124. 1995.

8. Tuch B.E., Simpson A.M., Smith M.S.R., Waugh P., Weinhaus  A.J., Tu J, Rose M. Basic biology of pig fetal pancreas and its use as an allograft. In "Fetal Islet Transplantation." C.M. Peterson (ed.). Plenum Pub. Corp., New York, 1995.

9. Weinhaus A.J., Stout L.E., Sorenson R.L. Glucokinase, Hexokinase, glucose transporter 2 and glucose metabolism in islets during pregnancy and prolactin treated islets in vitro: Mechanisms for up-regulation of islets. Endocrinology 137 (5): p. 1640-1649. 1996.

10. Kowluru, A., Seavey S.E., Sorenson R.L., Weinhaus A.J., Nesher R., Li G., Rabaglia M.E., Vadakekalam J., Metz S.A. GTP-dependent stimulation of the membrane association and carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure b-cells: Evidence for an essential role in nutrient-induced insulin secretion. Journal of Clinical Investigations 98 (2): p.540-555. 1996.

11. Weinhaus A.J., Poronnik P., Tuch B.E., Cook D.I. Mechanisms of arginine-induced increase in cytosolic calcium concentration in the Beta-cell line NIT-1. Diabetologia, 40 (4): p.374-382, 1997.

12. Weinhaus A.J., Bhagroo N.V., Brelje TC, Sorenson R.L. Role of cAMP in Up-Regulation of Insulin Secretion during the Adaptation of Islets of Langerhans to Pregnancy. Diabetes 47:1426-1435, 1998

13. Weinhaus A.J., Bhagroo N.V., Brelje TC, Sorenson R.L. Dexamethasone counteracts the effect of prolactin on islet function: Implications for islet regulation in late pregnancy. Endocrinology 141: 1384-1393, 2000

Manuscripts submitted for Publication:

1. Weinhaus A.J., Poronnik P., Cook D.I., Tuch B.E. Physiological analysis of the fetal development of the insulin secretory response by the human islet b-cell. Manuscript in preparation.

2. Weinhaus A.J., Brelje TC, Sorenson RL. Prolactin directly Up-regulates glucokinase expression in islets leading to enhanced insulin secretion. Manuscript in preparation.

Peer Reviewed Abstracts:

1. Weinhaus A.J., Ketchum R.J., Hegre O.D. The preparation of enriched epithelial cells from the human fetal pancreas. Proceedings of Methods in Islet Transplantation Research International Workshop, Bad Nauheim, FRG. 1989.

2. Hulinsky I., Weinhaus A.J., Silinik M. DNA synthesis of cultured neonatal rat pancreatic islets. Pancreatic Beta Cell - 14th International Diabetes Federation Congress, Cambridge, Mass.: p. 41. 1991.

3. Hulinsky I., Weinhaus A.J., Silinik M. DNA synthesis in cultured neonatal rat islets-a comparison of two methods. Proceedings of the 9th International Congress of Endocrinology, Nice: p.341. 1992.

4. Weinhaus A.J., Tuch B.E., Poronnik P., Cook D.I. Effects of physiological stimuli on intracellular calcium in the transgenic b-cell line, NIT-1. Proceedings of the Australian Physiological and Pharmacological Society 23: p.213. 1992.

5. Weinhaus A.J., Tuch B.E., Poronnik P., Cook D.I. Effects of physiological stimuli on intracellular calcium in the transgenic b-cell line, NIT-1. Proceedings of the Endocrine Society of Australia 35: p.109. 1992.

6. Weinhaus A.J., Tuch B.E., Poronnik P., Cook D.I. ATP-sensitive potassium and voltage-activated calcium channels are functional in fetal rat pancreatic b-cells. Proceedings of the Australian Diabetes Society, Dunedin, New Zealand: p.46. 1993.

7. Weinhaus A.J., Tuch B.E., Poronnik P., Cook D.I. ATP-sensitive potassium and voltage-activated calcium channels are functional in fetal rat pancreatic b-cells. Coast Medical Association Meetings, Sydney. 1993.

8. Weinhaus A.J., Poronnik P., Cook D.I., Tuch B.E. Functional ATP-sensitive potassium and voltage-activated calcium channels in the glucose-insensitive human fetal b-cell. Proceedings of the Australian Diabetes Association, Brisbane. 1994.

9. Weinhaus A.J., Poronnik P., Cook D.I., Tuch B.E. Functional ATP-sensitive potassium and voltage-activated calcium channels in the glucose-insensitive fetal rat b-cell. Proceedings of the 15th International Diabetes Federation Congress, Kobe, Japan. 1994.

10. Weinhaus A.J., Poronnik P., Cook D.I., Tuch B.E. Functional ATP-sensitive potassium and voltage-activated calcium channels in the glucose-insensitive human fetal b-cell. Pancreatic Beta-cell- 15th International Diabetes Federation Congress, Kyoto, Japan. 1994.

11. Sorenson RL, Stout LE, Zhu Q, Weinhaus A.J. Increased levels of glucokinase and hexokinase activities in rat islets from pregnancy. 31st Annual Meeting of the European Association for the Study of Diabetes, Stockholm, Sweden. 1995.

12. Sorenson RL, Stout LE, Zhu Q, Weinhaus A.J. Glucokinase, hexokinase and glucose metabolism in rat islets during pregnancy. Third International Meeting of the Pancreatic Islet Study Group, Sigtuna, Sweden. 1995.

13. Sorenson RL, Stout LE, Weinhaus A.J. Glucokinase, hexokinase, glucose transporter 2 and glucose metabolism in islets during pregnancy and prolactin treated islets in vitro: Mechanisms for long-term up-regulation of islets. 56th Annual Scientific Session of the American Diabetes Association, San Francisco. Volume 45, supplement 2: p. 59A.1996

14. Weinhaus AJ, Sorenson RL. Lactogen Treatment Leads to Increased cAMP Production: A Mechanism for Long-Term Up-regulation of Islets during pregnancy. Diabetes Research in Minnesota Conference, 31st Annual. St. Paul MN, 1997.

15. Weinhaus A.J., Bhagroo N.V., Sorenson R.L. Prolactin Treatment Leads to Increased c-AMP Production in Islets: A Mechanism for Long-Term Up-regulation of Insulin Secretion.  79th Annual Endocrine Society Meetings, Minneapolis MN. 1997

16. Weinhaus A.J., Bhagroo N.V., Sorenson R.L. Dexamethasone Inhibits Prolactin-Induced Up-regulation of Islet Function. 57th Annual Scientific Session of the American Diabetes Association, Boston. Volume 45, supplement 1: p.218A. 1997.

17. Weinhaus AJ, Bhagroo NV, Brelje TC, Sorenson RL. Role of cAMP in Lactogen-Induced Up-regulation of Insulin Secretion: Adaptation of Islets to Pregnancy. 58th Annual Scientific Session of the American Diabetes Association, Chicago, Ill, 1998.

18. Weinhaus AJ, Bhagroo NV, Brelje TC, Sorenson RL. Prolactin directly Up-regulates glucokinase expression in islets leading to enhanced insulin secretion. 59th Annual Scientific Session of the American Diabetes Association, San Diego, CA, 1999.

19. Weinhaus AJ, Brelje TC, Sorenson RL. Prolactin regulation of glucokinase gene expression. 36th Annual Meeting of the European Association for the Study of Diabetes, Jerusalem, Isreal, 2000.

20. Weinhaus AJ, Brelje TC, Sorenson RL. Prolactin regulation of glucokinase gene expression. Annual meeting of the EASD Islet Study Group, Eilat, Isreal, 2000.