Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats.
Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of beta-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 beta-cell function. We hypothesized that enhancement of the cytoprotective and beta-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 ( approximately 26 vs. approximately 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 beta-cells (+120%) and in the islet beta-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin biosynthesis. In vitro studies using a beta-(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.
Pospisilik
J Andrew
JA
Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
Martin
Jennifer
J
Doty
Timothy
T
Ehses
Jan A
JA
Pamir
Nathalie
N
Lynn
Francis C
FC
Piteau
Shalea
S
Demuth
Hans-Ulrich
HU
McIntosh
Christopher H S
CH
Pederson
Raymond A
RA
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D004435:Eating / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000032:analysis; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011498:Protein Precursors / Q000008:administration & dosage / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011498:Protein Precursors; C055453:glucagon-like peptide 1 (7-36)amide; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D010729:Phosphoenolpyruvate Carboxykinase (GTP)