SR-135, a peroxynitrite decomposing catalyst, enhances β-cell function and survival in B6D2F1 mice fed a high fat diet.
Peroxynitrite has been implicated in β-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogs, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al., 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances β-cell function and survival under nutrient overload.
Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Michael
M
Johns
Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Robert
R
Fyalka
Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Jennifer A
JA
Shea
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
William L
WL
Neumann
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Smita
S
Rausaria
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Eliwaza Naomi
EN
Msengi
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Maryam
M
Imani-Nejad
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Harry
H
Zollars
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Timothy
T
McPherson
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Joseph
J
Schober
Department of Kinesiology and Health Education, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States.
Joshua
J
Wooten
School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026, United States. Electronic address: gkwon@siue.edu.
Guim
G
Kwon
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011162:Porphobilinogen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C559046:bis(hydroxyphenyl)dipyrromethene; D030421:Peroxynitrous Acid; D008345:Manganese; D011162:Porphobilinogen
Apoptosis; Diabetes; Insulin; Nitrotyrosine; Pancreatic β-cell; Peroxynitrite