title: Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin.
abstract: The aims of the present study were to assess whether sustained HO-1 expression could moderate or prevent diabetes in an animal model of the disease and, if so, to examine the possible mechanisms involved. Our results showed that HO-1 expression and HO activity were upregulated in the pancreas of non-obese diabetic (NOD) mice by the weekly administration of cobalt protoporphyrin (CoPP). Blood glucose levels in CoPPtreated mice decreased to normal, but continuously increased in untreated controls. Beta-cell numbers were preserved in the islets of CoPP-treated mice, whereas no beta cells were found in untreated diabetic mice. The number of CD11c(+) dendritic cells was significantly decreased in the pancreas of CoPP-treated NOD mice, but this effect was reversed by the inhibition of HO activity. Increased levels of HO-1 produced a new pancreatic phenotype, as reflected by increases in phosphorylated AKT, BcL-xL and RSK levels, and decreases in O(2)- and 3-NT levels. These novel findings provide a link between the increase in HO-1 activity, with its concurrent enhanced production of carbon monoxide (CO) and bilirubin, a decrease in infiltrated CD11c(+) dendritic cells and an increase in anti-apoptotic proteins, including RSK and BcL-xL, in the interdiction of the diabetic state.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Stephen
authors.initials: S
authors.lastname: Peterson
authors.forename: Daniel
authors.initials: D
authors.lastname: Husney
authors.forename: Muneo
authors.initials: M
authors.lastname: Inaba
authors.forename: Kequan
authors.initials: K
authors.lastname: Guo
authors.forename: Eri
authors.initials: E
authors.lastname: Terada
authors.forename: Toshisuke
authors.initials: T
authors.lastname: Morita
authors.forename: Kiran
authors.initials: K
authors.lastname: Patil
authors.forename: Attallah
authors.initials: A
authors.lastname: Kappas
authors.forename: Susumu
authors.initials: S
authors.lastname: Ikehara
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000378:metabolism* / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D018845:CD11 Antigens / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D019255:NADPH Oxidases / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018845:CD11 Antigens; D007328:Insulin; D011524:Protoporphyrins; D051020:bcl-X Protein; D006418:Heme; C007095:cobaltiprotoporphyrin; D002248:Carbon Monoxide; D005934:Glucagon; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051057:Proto-Oncogene Proteins c-akt; D001663:Bilirubin