Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes

Okamoto, Mitsuhiro; Yamaoka, Mami; Takei, Masahiro; Ando, Tomomi; Taniguchi, Shigeki; Ishii, Isao; Tohya, Kazuo; Ishizaki, Toshimasa; Niki, Ichiro; Kimura, Toshihide

doi:10.1016/j.bbrc.2013.11.023

Cited by 48 publications

(42 citation statements)

References 27 publications

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“…Cth-deficient mice developed normally but exhibited high-fat diet-induced metabolic defects (15,21). Indeed, when the mice were fed normal chow, the hepatic CysSSH level in Cth-deficient mice was comparable with that of wild-type mice (Supplementary Figure S6A).…”

Section: Resultsmentioning

confidence: 99%

Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

et al. 2016

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The 2-methylthio (ms2) modification at A37 of tRNAs is critical for accurate decoding, and contributes to metabolic homeostasis in mammals. However, the regulatory mechanism of ms2 modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms2 modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms2 modification, which was rescued by the application of an exogenous CysSSH donor. Using a unique and stable isotope-labeled CysSSH donor, we show that CysSSH was capable of specifically transferring its reactive sulfur atom to the cysteine residues of ms2-modifying enzymes as well as ms2 modification. Furthermore, the suppression of CysSSH production impaired insulin secretion and caused glucose intolerance in both a pancreatic β-cell line and mouse model. These results demonstrate that intracellular CysSSH is a novel sulfur source for ms2 modification, and that it contributes to insulin secretion.

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Section: Resultsmentioning

confidence: 99%

Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

et al. 2016

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“…Under diabetic conditions, activation of the hepatic CBS/CSE system was associated with a significant reduction in plasma homocysteine levels (Jacobs et al 1998;Wijekoon et al 2005;Noll et al 2011) and increased H 2 S biosynthesis in the pancreas and liver (Yusuf et al 2005). Increased H 2 S biosynthesis may have vasculoprotective effects in type 1 diabetes (Yusuf et al 2005) and may serve to protect pancreatic islets from glucose-induced cytotoxicity (Kaneko et al 2009;Taniguchi et al 2011;Okamoto et al 2013). However, Zhang et al (2013) reported that H 2 S increased gluconeogenesis, reduced glucose consumption, and impaired glycogen storage in hepatocytes.…”

Section: Insulin Resistancementioning

confidence: 96%

The CBS/CSE system: a potential therapeutic target in NAFLD?

Siow

2015

Can. J. Physiol. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum liver disorder diagnosed in patients without a history of alcohol abuse. NAFLD is growing at alarming rates worldwide. Its pathogenesis is complex and incompletely understood. The cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) system regulates homocysteine and cysteine metabolism and contributes to endogenous hydrogen sulfide (H2S) biosynthesis. This review summarizes our current understanding of the hepatic CBS/CSE system, and for the first time, positions this system as a potential therapeutic target in NAFLD. As will be discussed, the CBS/CSE system is highly expressed and active in the liver. Its dysregulation, presenting as alterations in circulating homocysteine and (or) H2S levels, has been reported in NAFLD patients and in NAFLD-associated co-morbidities such as obesity and type 2 diabetes. Intricate links between the CBS/CSE system and a number of metabolic and stress related molecular mediators have also emerged. Various dysfunctions in the hepatic CBS/CSE system have been reported in animal models representative of each NAFLD spectrum. It is anticipated that a newfound appreciation for the hepatic CBS/CSE system will emerge that will improve our understanding of NAFLD pathogenesis, and give rise to new prospective targets for management of this disorder.

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“…To study the possible role of H 2 S in this process, 6-month-old CSE À/À mice were fed for 8 weeks with a high-fat diet in order to induce hyperglycaemia (Okamoto et al 2013). The mice developed impaired glucose tolerance and decreased insulin content in their pancreatic cells as compared to their wild-type counterparts.…”

Section: Diabetesmentioning

confidence: 99%

H2S Synthesizing Enzymes: Biochemistry and Molecular Aspects

Huang

Moore

2015

Handbook of Experimental Pharmacology

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Hydrogen sulfide (H2S) is a biologically active gas that is synthesized naturally by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthetase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are constitutively present in a wide array of biological cells and tissues and their expression can be induced by a number of disease states. It is becoming increasingly clear that H2S is an important mediator of a wide range of cell functions in health and in disease. This review therefore provides an overview of the biochemical and molecular regulation of H2S synthesizing enzymes both in physiological conditions and their modulation in disease states with particular focus on their regulation in asthma, atherosclerosis and diabetes. The importance of small molecule inhibitors in the study of molecular pathways, the current use of common H2S synthesizing enzyme inhibitors and the relevant characteristics of mice in which these enzymes have been genetically deleted will also be summarized. With a greater understanding of the molecular regulation of these enzymes in disease states, as well as the availability of novel small molecules with high specificity targeted towards H2S producing enzymes, the potential to regulate the biological functions of this intriguing gas H2S for therapeutic effect can perhaps be brought one step closer.

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Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes

Cited by 48 publications

References 27 publications

Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion

The CBS/CSE system: a potential therapeutic target in NAFLD?

H2S Synthesizing Enzymes: Biochemistry and Molecular Aspects

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