title: PTGS-2-PTGER2/4 signaling pathway partially protects from diabetogenic toxicity of streptozotocin in mice.
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) E(2) 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). PGE(2) 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 PGE(2) 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.
authors.affiliation: Department of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Vennemann
authors.forename: Anemone
authors.initials: A
authors.lastname: Gerstner
authors.forename: Niklas
authors.initials: N
authors.lastname: Kern
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros Bouzas
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D017353:Gene Deletion; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone