Ebselen Treatment Prevents Islet Apoptosis, Maintains Intranuclear Pdx-1 and MafA Levels, and Preserves β-Cell Mass and Function in ZDF Rats

被引:67
|
作者
Mahadevan, Jana [1 ,2 ]
Parazzoli, Susan [1 ,2 ]
Oseid, Elizabeth [1 ,2 ]
Hertzel, Ann V. [3 ]
Bernlohr, David A. [3 ]
Vallerie, Sara N. [1 ,2 ]
Liu, Chang-qin [1 ,2 ]
Lopez, Melissa [1 ,2 ]
Harmon, Jamie S. [1 ,2 ]
Robertson, R. Paul [1 ,2 ,3 ]
机构
[1] Univ Washington, Pacific Northwest Diabet Res Inst, Seattle, WA 98195 USA
[2] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA
[3] Univ Minnesota, Dept Biochem & Mol Biol, Minneapolis, MN USA
基金
美国国家卫生研究院;
关键词
HIGH GLUCOSE-CONCENTRATIONS; INSULIN GENE-TRANSCRIPTION; BLIND CLINICAL-TRIAL; DIABETIC FATTY RAT; GLUTATHIONE-PEROXIDASE; OXIDATIVE STRESS; CHRONIC EXPOSURE; PANCREATIC-ISLETS; HIT CELLS; ANTIOXIDANT;
D O I
10.2337/db13-0357
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We reported earlier that -cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of -cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent -cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA(1c) levels with no effects on body weight. Ebselen doubled -cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal -cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on -cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of -cell mass and function in humans undergoing the onset of type 2 diabetes.
引用
收藏
页码:3582 / 3588
页数:7
相关论文
共 3 条
  • [1] Ebselen, a Glutathione Peroxidase Mimetic, Prevents Fasting Hyperglycemia, Loss of Insulin Secretion, Increases β-Cell Mass, and Preserves Intranuclear MafA and PDX-1 in ZDF Rats
    Mahadevan, Jana
    Parazzoli, Susan D.
    Oseid, Elizabeth A.
    Harmon, Jamie S.
    Hericks, Allison
    Lynch, Eric D.
    Kil, Jonathan
    Robertson, R. Paul
    [J]. DIABETES, 2011, 60 : A273 - A273
  • [2] Chronic treatment with taspoglutide, a once-weekly human GLP-1 analogue, prevents beta cell apoptosis, islet inflammation and fibrosis in ZDF rats
    Uhles, S.
    Funk, J.
    Brecheisen, M.
    Benardeau, A.
    Tobalina, L.
    Wollheim, C. B.
    Sewing, S.
    Migliorini, C.
    Sebokova, E.
    [J]. DIABETOLOGIA, 2010, 53 : S73 - S73
  • [3] Pancreatic and Duodenal Homeobox Protein 1 (Pdx-1) Maintains Endoplasmic Reticulum Calcium Levels through Transcriptional Regulation of Sarco-endoplasmic Reticulum Calcium ATPase 2b (SERCA2b) in the Islet β Cell
    Johnson, Justin S.
    Kono, Tatsuyoshi
    Tong, Xin
    Yamamoto, Wataru R.
    Zarain-Herzberg, Angel
    Merrins, Matthew J.
    Satin, Leslie S.
    Gilon, Patrick
    Evans-Molina, Carmella
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (47) : 32798 - 32810