title: Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet.
abstract: Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and β-cell insulin content under nutrient overload.
authors.affiliation: Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.affiliation: School of Engineering, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Sakineh
authors.initials: S
authors.lastname: Esmaeili Mohsen Abadi
authors.affiliation: Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Nehal
authors.initials: N
authors.lastname: Malik
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Rausaria
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Imani-Nejad
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: McPherson
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schober
authors.affiliation: School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL, 62026, USA. Electronic address: gkwon@siue.edu.
authors.forename: Guim
authors.initials: G
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011162:Porphobilinogen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; C507544:dipyrromethene; D030421:Peroxynitrous Acid; D011162:Porphobilinogen
keywords: Diabetes; Glucose homeostasis; Insulin content; Insulin signaling; Islet architecture; Nitrotyrosine; Peroxynitrite