In collaboration with Dr. Christopher McIntosh, my laboratory is engaged in the study of mechanisms involved in control of insulin release; particularly the involvement of the gut hormones Glucose dependent Insulinotropic Polypeptide (GIP) [1] and Glucagon Like Peptide 1 (GLP-1) [2]. These hormones are known as incretins and the gut-pancreas connection is known as the enteroinsular axis. Using in vitro and in vivo experimental techniques, the enteroinsular axis is under investigation in normal and pathophysiological states of obesity and non insulin dependent diabetes mellitus (NIDDM). The mechanism of action of GIP on the pancreatic B cell is studied by means of insulin secretory models varying from isolated pancreatic islets, to the perfused pancreas and the intact animal. This action is further defined by studying GIP binding and activation of the islet receptor cloned in our laboratory [3, 4]. This work has the potential for establishing the active site of the GIP molecule [5, 6,7] and pathways of cellular actviation in health and disease. In that regard we have recently identified novel pathways by which GIP acts on the pancreatic insulin-secreting beta cell that may be involved in the regulation of islet cell differentiation and mitogenesis [8,9]. Insulin secretion is altered in human obesity and NIDDM. We have recently shown that the expression of the GIP receptor in a Vancouver strain of the obese Zucker rat has greatly reduced expression of the islet GIP receptors and reduced signal-transduction [10]. This study provides clues to the origins of the reduced sensitivity of incretins in human type 2 diabetes. Another aspect of our work on the enteroinsular axis focuses on the metabolism/inactivation of GIP and the related incretin GLP-1. These hormones are rapidly metabolized by the circulating enzyme dipeptidyl peptidase IV (DP IV) [11, 12]. We are developing methods for blocking the actions of DP IV with specific inhibitors which increases the circulating half life and glucose-lowering potency of both incretins. This has potential clinical significance as a therapeutic strategy for both type 1 and type 2 diabetes [13,14,15,16,17].

1.   Pederson R.A. GIP. In: Gut Peptides. Ed. J. Walsh, G. Dockray, Raven Press, pp. 217-259, 1993.

2.   Pederson R.A., Satkunarajah, M., McIntosh, C.H.S., Scrocchi, L., Flamez, D., Schuit, F., Drucker, D.J., Wheeler, M.B. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in Glucagon-like peptide-1 receptor -/- mice. Diabetes 47: 1046-1052, 1988.

3.   Wheeler MB, Gelling RW, McIntosh CHS, Georgiou Brown JC, Pederson RA. Functional cloning of the rat pancreatic islet glucose-dependent polypeptide receptor: ligand binding and intracellular signaling properties. Endocrinology 136: 4629-4639, 1995.

4.   Gelling RW, Wheeler MB, Xue J, Gyomorey S, Nain C, Pederson RA, and McIntosh CHS. Localization of the domains involved in ligand binding and activation of the glucose-dependent insulinotropic polypeptide receptor. Endocrinology 138:2640-2643, 1997.

5.   Gelling RW, Coy DH, Pederson RA, Wheeler MB, Hinke S, Kwan T, McIntosh CHS. GIP6-30 amide contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro. Regulatory Peptides 69: 151-154, 1997.

6.   Wheeler, M.B., Gelling, R.W., Hinke, S., Tu, B., Pederson, R.A., Lynn F., Ehses, J., and McIntosh, C.H.S. Characterization of the carboxyl-terminal domain of the glucose-dependent insulinotropic polypeptide (GIP) receptor. Journal of Biological Chemistry 274: 24593-24601, 1999.

7.   Hinke, S.A., Gelling, R.W., Manhart, S., Lynn, L., Pederson, R.A., Kuhn-Wache, K., Rosche, F., Demuth, H-U., Coy, D., and McIntosh, C.H.S. Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP). Biological Chemistry, 384: 403-407, 2003.

8.   Ehses, J.A., Pelech, S.L., Pederson, R.A. and McIntosh, C.H.S. Glucose-dependent Insulinotropic Polypeptide (GIP) activates the Raf-Mek1/2-ERK 1/2 module in the INS-1 beta cell line via a cyclic AMP/PKA/Rap1-mediated pathway. Journal of Biological Chemistry, 277:37088-37097, 2002.

9.   Lynn, F.C., Thompson, S.A., Pospisilik, J.A., Ehses, J.A., Hinke, S.A., Pamir, N., McIntosh, C.H.S. and Pederson, R.A. A novel pathway for regulation of glucose-dependent insulinotopic polypeptide (GIP) receptor express in beta cells. FASEB Journal, 17:19-93, 2003.

10.   Lynn, F.C., Pamir, N., Ng, E.H.C., McIntosh, C.H.S., and Pederson, R.A. Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes 50:1004-1011, 2001.

11.   Kieffer, T.J., McIntosh, C.H.S., Pederson, R.A. Degradation of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide 1 (tGLP-1) in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136: 3585-3596, 1995.

12.   Pauly RP, Rosche R, Wermann M, McIntosh CHS, Pederson RA, Demuth H-U. Investigation of glucose-dependent insulinotropic polypeptide (1-42) degradation in vitro by dipeptidylpeptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF). J. Biol. Chem. 271: 23222-23229, 1996.

13.   Pederson, R.A., White, H., Schenzig, D., Pauly, R., McIntosh, C.H.S., and Demuth, H-U. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase inhibitor isoleucine thiazolidide. Diabetes 47:125-3-58, 1998.

14.   Pauly, R.P., Demuth, H-U., Rosche, F., Schmidt, J., White, H., Lynn, F., McIntosh, C.H.S., and Pederson, R.A. Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD 26) inhibitor Ife-thiazolidide. Metabolism 48:385-389, 1999.

15.   Pospisilik, J.A., Stafford, S.G., Demuth, H.-U., Brownsey, R., Parkhouse, W., Finegood, D.T., McIntosh, C.H.S. and Pederson, R.A. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 51:943-950, 2002.

16.   Pospisilik, J.A., Stafford, S.G., Demuth, H.-U., McIntosh, C.H.S. and Pederson, R.A. Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat. Diabetes 51:2677-2683, 2002.

17.   Pospisilik, J.A., Martin, J., Doty, T., Ehses, J., Pamir, N., Lynn, F.C., Piteau, S., Demuth, H.-U., McIntosh, C.H.S., and Pederson, R.A. Dipeptidyl peptidase IV inhibitor treatment stimulates beta cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 52:741-750, 2003.