Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates β-Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats
- J. Andrew Pospisilik1,
- Jennifer Martin1,
- Timothy Doty1,
- Jan A. Ehses1,
- Nathalie Pamir1,
- Francis C. Lynn1,
- Shalea Piteau1,
- Hans-Ulrich Demuth2,
- Christopher H.S. McIntosh1 and
- Raymond A. Pederson1
- 1Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada
- 2Probiodrug AG, Halle (Saale), Germany
Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of β-cell growth, differentiation, and cell survival to well-documented, potent insulinotropic effects. Unfortunately, the therapeutic potential of these hormones is limited by their rapid enzymatic inactivation in vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance circulating incretin levels, has proved effective in the treatment of type 2 diabetes both in humans and in animal models, stimulating improvements in glucose tolerance, insulin sensitivity, and β-cell function. We hypothesized that enhancement of the cytoprotective and β-cell regenerative effects of GIP and GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type 1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated animals displayed increased weight gain (230%) and nutrient intake, decreased fed blood glucose (∼26 vs. ∼20 mmol/l, respectively), and a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l, respectively). Marked improvements in oral glucose tolerance, suggesting enhanced insulin secretory capacity, were corroborated by pancreas perfusion and insulin content measurements that revealed two- to eightfold increases in both secretory function and insulin content after 7 weeks of treatment. Immunohistochemical analyses of pancreatic sections showed marked increases in the number of small islets (+35%) and total β-cells (+120%) and in the islet β-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, β-cell survival, and insulin biosynthesis. In vitro studies using a β-(INS-1) cell line showed a dose-dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1, supporting a role for the incretins in eliciting the in vivo results. These novel findings provide evidence to support the potential utility of DP IV inhibitors in the treatment of type 1 and possibly late-stage type 2 diabetes.
Address correspondence and reprint requests to Dr. R.A. Pederson, Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. E-mail:.
Received for publication 11 July 2002 and accepted in revised form 18 November 2002.
H.U.D. is a Chief Executive Officer, the Chief Scientific Officer, and a shareholder in Probiodrug, a pharmaceutical company in the process of developing a DP IV inhibitor treatment for diabetes and its complications. R.A.P. and C.H.S.M. are members of a scientific advisory panel to Probiodrug and receive consulting fees for their participation and receive grant/research support from Probiodrug to support studies on the drug candidate P32/98 and its utility in treating diabetes and its complications.
DP IV, dipeptidyl peptidase IV; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; IDGTT, intraduodenal glucose tolerance test; IR, immunoreactive; OGTT, oral glucose tolerance test; PDX-1, pancreatic-duodenum homeobox-1; PP, pancreatic polypeptide; SOM, somatostatin; STZ, streptozotocin.