Professors Raymond Pederson and Christopher McIntosh, Physiology Department, University of British Columbia – collaborators and scientific advisors to probiodrug research GmbH, Halle (Saale), Germany
Vancouver, Canada // Halle (Saale), Germany //
The Pederson/McIntosh laboratories have been engaged in the study of mechanisms involved in the control of insulin release; particularly the roles played by the gut hormones Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide 1 (GLP-1). These hormones are known as incretins. Using a variety of experimental techniques ranging from the whole animal to studies at the molecular level, the action of incretins on insulin secretion and the regulation of blood sugar levels has been investigated in health and disease states of obesity and diabetes.
The mechanism of action of GIP and GLP-1 on the pancreatic insulin-secreting cell is studied with insulin secretory models ranging from isolated beta cells to the intact animal. These actions are being further defined at the molecular level by studying hormone interaction with, and activation of, cloned incretin receptors. This work has the potential for establishing the way in which GIP and GLP-1 molecules activate the insulin secreting cell in health and disease. Another aspect of the work on incretin actions focuses on the metabolism/inactivation of GIP and the related incretin GLP-1 in the circulation. These hormones are rapidly metabolized by the circulating enzyme dipeptidyl peptidase IV (DP IV).
Pederson and McIntosh established collaborative links with Hans-Ulrich Demuth, Halle, Germany in 1995 to study the physiological consequences of blocking the actions of DP IV with specific inhibitors in order to increase the circulating half life and glucose-lowering potency of both incretins. This proved to be a fruitful collaboration as the laboratory in Halle (Saale), Germany, was, and is recognized as one of the world’s leaders in the study of the biochemistry of protein degrading enzymes with particular reference to the development of specific inhibitors of the prolyl oligopeptidase enzyme family. It was established that specific DP IV inhibitors were effective in inhibiting circulating levels of DP IV in experimental animals and, as a consequence, enhanced the insulin-releasing and glucose-lowering actions of incretins released after food stimulation. Subsequently, it was demonstrated that orally administered DP IV-inhibiting drugs had a marked glucose lowering action in an animal model of Type II (maturity onset) diabetes (the most prevalent form of diabetes).
This work has generated a great deal of interest among researchers, highlighting DP IV inhibitory drugs as potential therapeutic agents in the treatment of diseases characterized by high blood sugar (hyperglycemia) e.g. obesity and Type II diabetes. Recently, the collaborative research with probiodrug GmbH (co-founded by Drs. Demuth and Glund) has focused on one DP IV inhibitor, P32/98. These efforts resulted a number of common publications and patent applications since 1996.
The collaborative work of the Vancouver laboratories with the scientists at probiodrug GmbH will continue to elucidate the details of events that occur subsequent to DP IV inhibition in the body, e.g. effects of long term treatment with P32/98 on insulin secretion and blood sugar levels, the time course of the incretin-sparing effects of DP IV inhibition, and the minimum effective doses of P32/98 required to lower blood glucose levels in hyperglycemic states. R.A. Pederson and C.H.S. McIntosh advice probiodrug GmbH during preclinical and clinical studies of P32/98 and related developments.