HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online-Only Appendix Figures All Versions of this Article: db07-1639v1 db07-1639v2 57/5/1331    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kim, S.-J. Articles by McIntosh, C. H.S. PubMed PubMed Citation Articles by Kim, S.-J. Articles by McIntosh, C. H.S. Social Bookmarking                What's this?

Inhibition of Dipeptidyl Peptidase IV With Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin-Induced Diabetic Mice

¹ Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
² Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Corresponding author: Dr. C.H.S. McIntosh, Department of Cellular and Physiological Sciences, the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, B.C., V6T 1Z3, Canada. E-mail: mcintoch{at}interchange.ubc.ca

Abbreviations: AMC, aminomethylcoumarin; AUC, area under the curve; DPP-IV, dipeptidyl peptidase-IV; [¹⁸F]FHBG, 9-(4-[¹⁸F]-fluoro-3-hydroxymethylbutyl)-guanine; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GSIS, glucose-stimulated insulin secretion; IPGTT, intraperitoneal glucose tolerance test; m.o.i., multiplicity of infection; PET, positron emission tomography; rAD-TK, recombinant adenovirus expressing HSV1-Sr39TK; ROI, region of interest; STZ, streptozotocin

OBJECTIVE—Dipeptidyl peptidase-IV (DPP-IV) inhibitors have been introduced as therapeutics for type 2 diabetes. They partially act by blocking degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus increasing circulating levels of active hormones. In addition to their insulinotropic actions, GLP-1 and GIP also promote β-cell proliferation and survival, and DPP-IV inhibitors exert similar effects in rodent type 2 diabetes models. The study objective was to establish whether DPP-IV inhibitor treatment prolonged survival of transplanted islets and to determine whether positron emission tomography (PET) was appropriate for quantifying the effect of inhibition on islet mass.

RESEARCH DESIGN & METHODS—Effects of the DPP-IV inhibitor MK0431 (sitagliptin) on glycemic control and functional islet mass in a streptozotocin (STZ)-induced type 1 diabetes mouse model were determined with metabolic studies and microPET imaging.

RESULTS—The type 1 diabetes mouse model exhibited elevated plasma DPP-IV levels that were substantially inhibited in mice on an MK0431 diet. Residual β-cell mass was extremely low in STZ-induced diabetic mice, and although active GLP-1 levels were increased by the MK0431 diet, there were no significant effects on glycemic control. After islet transplantation, mice fed normal diet rapidly lost their ability to regulate blood glucose, reflecting the suboptimal islet transplant. By contrast, the MK0431 group fully regulated blood glucose throughout the study, and PET imaging demonstrated a profound protective effect of MK0431 on islet graft size.

CONCLUSIONS—Treatment with a DPP-IV inhibitor can prolong islet graft retention in an animal model of type 1 diabetes.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?