PTGS-2–PTGER2/4 Signaling Pathway Partially Protects From Diabetogenic Toxicity of Streptozotocin in Mice

  1. Rolf M. Nüsing1
  1. 1Department of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany
  2. 2Department of Pediatrics, Philipps University, Marburg, Germany
  3. 3Department of Pharmacology, Kyoto University, Kyoto, Japan
  4. 4Minase Research Institute, ONO Pharmaceuticals, Osaka, Japan
  1. Corresponding author: Rolf M. Nüsing, r.m.nuesing{at}med.uni-frankfurt.de.

Abstract

Prostanoids are suggested to participate in diabetes pathology, but their roles are controversially discussed. The purpose of the current study was to examine the role of cyclooxygenase (prostaglandin synthase [PTGS]) enzymes and prostaglandin (PG) E2 signaling pathways in streptozotocin (STZ)-induced type 1 diabetes. Blood glucose, insulin, and survival rate were studied in mice with targeted disruption of the genes for PTGS and PGE receptors (PTGERs). PGE2 was found as the main prostanoid formed by the pancreas. Contrarily to PTGS-1, deficiency of PTGS-2 activity significantly amplified STZ effect, causing dramatic loss of insulin production and rise in blood glucose and death rate. STZ metabolism was unaffected by PTGS deficiency. Diabetogenicity of STZ in PTGER1−/−, PTGER2−/−, PTGER3−/−, and PTGER4−/− mice was comparable to control mice. In striking contrast, combined knockout of PTGER2 and PTGER4 by blocking PTGER4 in PTGER2−/− mice strongly enhanced STZ pathology. Treatment of PTGS-2−/− and wild-type mice with PTGER2/PTGER4 agonists partially protected against STZ-induced diabetes and restored β-cell function. Our data uncover a previously unrecognized protective role of PTGS-2–derived PGE2 in STZ-induced diabetes mediated by the receptor types PTGER2 and PTGER4. These findings offer the possibility to intervene in early progression of type 1 diabetes by using PTGER-selective agonists.

  • Received October 5, 2011.
  • Accepted February 21, 2012.

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This Article

  1. Diabetes
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