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Divergent Effects of Sulforaphane on Basal and Glucose-Stimulated Insulin Secretion in β-Cells: Role of Reactive Oxygen Species and Induction of Endogenous Antioxidants

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Abstract

Purpose

Oxidative stress is implicated in pancreatic β-cell dysfunction, yet clinical outcomes of antioxidant therapies on diabetes are inconclusive. Since reactive oxygen species (ROS) can function as signaling intermediates for glucose-stimulated insulin secretion (GSIS), we hypothesize that exogenously boosting cellular antioxidant capacity dampens signaling ROS and GSIS.

Methods

To test the hypothesis, we formulated a mathematical model of redox homeostatic control circuit comprising known feedback and feedforward loops and validated model predictions with plant-derived antioxidant sulforaphane (SFN).

Results

SFN acutely (30-min treatment) stimulated basal insulin secretion in INS-1(832/13) cells and cultured mouse islets, which could be attributed to SFN-elicited ROS as N-acetylcysteine or glutathione ethyl ester suppressed SFN-stimulated insulin secretion. The mathematical model predicted an adapted redox state characteristic of strong induction of endogenous antioxidants but marginally increased ROS under prolonged SFN exposure, a state that attenuates rather than facilitates glucose-stimulated ROS and GSIS. We validated the prediction by demonstrating that although 24-h treatment of INS-1(832/13) cells with low, non-cytotoxic concentrations of SFN (2–10 μM) protected the cells from cytotoxicity by oxidative insult, it markedly suppressed insulin secretion stimulated by 20 mM glucose.

Conclusions

Our study indicates that adaptive induction of endogenous antioxidants by exogenous antioxidants, albeit cytoprotective, inhibits GSIS in β-cells.

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Abbreviations

AC:

Antioxidant capacity

ARE:

Antioxidant response element

BSA:

Bovine serum albumin

CM-H2DCFDA:

5-(and-6)-chloromethyl-2’ 7’-dichlorodihydrofluorescein diacetate, acetyl ester

DEM:

Diethylmaleate

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

GCLC:

γ-glutamate cysteine ligase catalytic subunit

GSH-EE:

Glutathione ethyl ester

GSIS:

Glucose-stimulated insulin secretion

H2O2 :

Hydrogen peroxide

HMOX-1:

Heme oxygenase 1

NAC:

N-acetylcysteine

NQO1:

NAD(P)H: quinone oxidoreductase 1

Nrf2:

Nuclear factor erythroid 2-related factor 2

ROS:

Reactive oxygen species

SFN:

Sulforaphane

SRXN1:

Sulfiredoxin 1

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

tBHQ:

Tert-butylhydroquinone

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Acknowledgments and Disclosures

Jingqi Fu and Qiang Zhang contributed equally to this work. This work was supported in part by the National Institutes of Health Grants DK76788 (to J.P.) and ES016005 (to J.P.) and the DOW Chemical Company (to M.E.A.). The content is solely the responsibility of the authors. All authors have agreed to its content and there are no financial or other conflicts of interest. J.F., B.Y., Q.Z., C.G.W, H.Z., M.E.A. and J.P. are/were employees of The Hamner Institutes for Health Sciences. The Hamner is a 501(c)3 not-for-profit organization that has a diverse research portfolio that includes funding from the American Chemistry Council, a trade association that represents chemical manufacturers.

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Authors and Affiliations

  1. Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, Durham, North Carolina, 27709, USA

    Jingqi Fu, Qiang Zhang, Courtney G. Woods, Hongzhi Zheng, Bei Yang, Melvin E. Andersen & Jingbo Pi

  2. College of Basic Medical Science, China Medical University, Shenyang, 110001, China

    Bei Yang

  3. Department of Environmental Health, School of Public Health, Fudan University, Shanghai, 200032, China

    Weidong Qu

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  1. Jingqi Fu
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Fu, J., Zhang, Q., Woods, C.G. et al. Divergent Effects of Sulforaphane on Basal and Glucose-Stimulated Insulin Secretion in β-Cells: Role of Reactive Oxygen Species and Induction of Endogenous Antioxidants. Pharm Res 30, 2248–2259 (2013). https://doi.org/10.1007/s11095-013-1013-8

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