McIntosh

My research focuses on the modes of action of gastrointestinal hormones involved in the regulation of insulin secretion and fat metabolism, and the pathophysiological consequences of altered function in obesity and non-insulin dependent diabetes mellitus (NIDDM). This consists of the following areas of study:

A.  The GIP receptor and its signal transduction mechanisms
GIP (gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide) is synthesized in the intestine and has two well characterized biological actions: inhibition of acid secretion (enterogastrone action) and the stimulation of insulin release (incretin effect) (1). We have cloned the pancreatic GIP receptor (2-3), and are studying the specific domains involved in ligand binding and signal-transduction using receptor chimeras (4) and point-mutated and truncated forms (5) of the receptor produced by site-directed mutagenesis. The possibility that there are different receptor subtypes in other tissues, which are involved in different actions, is also being investigated. We have recently identified a novel new pathway by which GIP acts on the pancreatic insulin-secreting beta cell that may be involved in the regulation of islet cell differentiation and mitogenesis.

B.  Changes in responsiveness to incretins in obesity and non-insulin dependent diabetes mellitus
Insulin secretion is altered in human obesity and NIDDM. Animal models of these conditions are being studied to determine the origin of altered responsiveness to GIP in these animals (7). 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 GIP receptor and reduced signal-transduction (8). Such studies should provide clues as to the origins of the reduced sensitivity to incretins in the human disorders.

C.  The metabolism of incretins in normal and disease states
There is currently great interest in using incretins in the treatment of NIDDM in humans. We are defining the biologically active region of the GIP molecule (12-14) and attempting to develop long acting analogs. In addition, the alternative strategy of inhibiting DP IV, and thus increasing endogenous incretins, is being studied. In the studies with Probiodrug, Germany, one of these inhibitors has been shown to dramatically improve glucose tolerance in diabetic rats (14, 15), and is currently undergoing clinical trials.

The above studies involve extensive collaboration with Dr. Raymond Pederson in the Department of Cellular & Physiological Sciences, and Hans-Ulrich Demuth, Probiodrug, Halle, Germany.

Jia, X., Brown, J.C., Pederson, R.A. and McIntosh, C.H.S. The effects of glucose dependent insulinotropic polypeptide and glucagon-like peptide 1(7-36) on insulin secretion. American Journal of Physiology 268: E645-E651, 1995.

Wheeler, M.B., Gelling, R.W., McIntosh, C.H.S., Georgiu, J., Brown, J.C., and Pederson, R.A. Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide (GIP) receptor. Endocrinology 136: 4629-4639, 1995.

Jia, X., Elliott R., Kwok, Y.N., Pederson, R.A. and McIntosh, C.H.S. Altered glucose dependence of glucagon-like peptide 1(7-36)-induced insulin secretion from the Zucker (fa/fa) rat pancreas. Diabetes 44: 495-500, 1995.

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.

McIntosh, C.H.S., Wheeler, M.B., Gelling, R.W., Brown, J.C. and Pederson, R.A. GIP receptors and signal-transduction mechanisms. Acta Physiologica Scandinavica 157: 361-365, 1996.

Pauly, R.P. Rosche, F., Wermann, M., McIntosh, C.H.S., Pederson, R.A. and Demuth H-U. Investigation of GIP1-42 and GLP-1 7-36 degradation in vitro by dipeptidyl peptidase IV (DP IV) using Matrix-Assisted Laser Desorption/Ionization – Time of Flight Mass Spectometry (MALDI-TOF MS): a novel kinetic approach. Journal of Biological Chemistry 271: 23222-23229, 1996.

Morrow, G.W., Kieffer, T., McIntosh, C.H.S., MacGillivray, R.T.A., Brown, J.C. and Pederson, R.A. The insulinotropic region of gastric inhibitory polypeptide; fragment analysis suggests the bioactive site lies between residues 19 and 30. Canadian Journal of Physiology 74: 65-72, 1996.

Gelling, R.W., Wheeler, M.B., Xue, J., Gyomorey, S., Nian, C., Pederson, R.A., McIntosh, C.H.S. Localization of the domains involved in ligand binding and activation of the glucose-dependent insulinotropic polypeptide receptor. Endocrinology 138: 2640-2643, 1997.

Gelling, R.W., Coy, D., Pederson, R.A., Wheeler, M.B., O’Dorisio T., Hinke, S., McIntosh, C.H.S. 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.

Pederson R.A., White H., Schlenzig D., Schmidt J., McIntosh, C.H.S., Demuth H.-U. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV (DP IV) inhibitor, Ile-thiazolidide. Diabetes 47: 1253-1258, 1998.

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.

Hinke, S. A., Pospisilik,J.A., Demuth, H.-U., Mannhart, S., Kühn-Wache, K., Hoffmann, T., Nishimura, E., Pederson, R. A. and McIntosh, C.H.S. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. Journal of Biological Chemistry 275: 3827-3834, 2000.

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.

Hinke, A.A., Manhart, S., Pamir, N., Demuth, H.-U., Gelling, R.W., Pederson, R.A. and McIntosh, C.H.S. Identification of a bioactive domain in the amino-terminus of glucose-dependent insulinotropic polypeptide (GIP) Biochimica Biophysica Acta 364: 1-13, 2001.

Ehses, J.A., Lee, S.T., Pederson, R.A. and McIntosh, C.H.S. A new pathway for glucose-dependent insulinotropic polypeptide (GIP) receptor signalling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion. Journal of Biological Chemistry276(26): 23667-73, 2001.

Hinke SA, Manhart S, Kühn-Wache K, Nian C, Demuth H-U, Pederson RA & McIntosh C.H.S. [Ser2]- and [Ser(P)2]-incretin analogs: Comparison of dipeptidyl peptidase IV resistance and biological activities in vitro and in vivo. Journal of Biological Chemistry 279:3998-4006, 2004.

Hinke SA, Manhart S, Speck M, Pederson RA, Demuth H-U & McIntosh C.H.S. In depth analysis of the N-terminal bioactive domain of gastric inhibitory polypeptide. Life Sciences 75:1857-1870, 2004.

McIntosh C.H.S., Demuth H-U, Pospisilik JA & Pederson RA. Dipeptidyl peptidase IV (DP IV) Inhibitors: How do they work as new antidiabetic agents? Regulatory Peptides 128:159-165, 2005.

Kim S-J, Winter K, Nian C, Tsuneoka M, Koda Y & McIntosh, C.H.S. Glucosedependent Insulinotropic Polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1 and down-regulation of bax expression. Journal of Biological Chemistry 280:22297-22307, 2005.

Kim S-J, Choi WS, Han JSM, Warnock G, Fedida D & McIntosh C.H.S. A novel mechanism for the suppression of a voltage-gated potassium channel by glucose-dependent insulinotropic polypeptide. Protein kinase A-dependent endocytosis. Journal of Biological Chemistry 280: 28692-28700, 2005.

Demuth H-U, McIntosh C.H.S. & Pederson RA. Type 2 diabetes-Therapy with dipeptidyl peptidase IV inhibitors. Biochimica Biophysica Acta 1751: 33-44, 2005.