FTY720 preserved islet <i>β</i>‐cell mass by inhibiting apoptosis and increasing survival of <i>β</i>‐cells in db/db mice

Moon, Hosik; Chon, Jinyoung; Joo, Jin-Deok; Kim, Dae Woo; In, Janghyeok; Lee, Hae-Jin; Park, Jaesik; Choi, Jin‐Woo

doi:10.1002/dmrr.2341

Cited by 29 publications

(26 citation statements)

References 30 publications

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“…In this context, it should be mentioned that in an animal model of diabetic mice, administration of FTY720, which binds after activation to all S1P receptors except S1P 2 , prevents the development of T2D. Indeed, oral administration of FTY720 to db/db mice normalizes fasting blood glucose by increasing β‐cell mass and blood insulin levels without affecting insulin sensitivity (41, 42). These studies are congruent with our in vitro data indicating that FTY720‐P protects MIN6 cells from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-phosphate counteracts insulin signaling in pancreatic β-cells via the sphingosine 1-phosphate receptor subtype 2

Japtok¹,

Schmitz²,

Fayyaz³

et al. 2015

The FASEB Journal

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Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic β-cells but also regulate β-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by β-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D.

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Section: Discussionmentioning

confidence: 99%

Sphingosine 1-phosphate counteracts insulin signaling in pancreatic β-cells via the sphingosine 1-phosphate receptor subtype 2

Japtok¹,

Schmitz²,

Fayyaz³

et al. 2015

The FASEB Journal

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“…25 graft destruction (Fu et al, 2002;Maki et al, 2002;Suzuki et al, 1998;Tsuji et al, 2012;Yang et al, 2003). Interestingly, fingolimod also increased beta-cell survival and improved their regeneration in vivo in hyperglycemic db/db mice (Moon et al, 2013;Zhao et al, 2012).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Huwiler

Zangemeister‐Wittke

2018

Pharmacology & Therapeutics

170

134

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The immunomodulatory drug fingolimod (FTY720, Gilenya) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P subtype by induction of receptor downregulation. Since S1P is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.

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“…In support of this possibility, elevation of the S1P level by inhibiting SPL activity has been demonstrated to improve regeneration of pancreas [90] and skeletal muscles [91]. …”

Section: Novel Potential Approaches To Enhancing the Responsivenesmentioning

confidence: 99%

The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells

Ratajczak

Suszyńska

Borkowska

et al. 2013

Expert Opinion on Therapeutic Targets

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Introduction A common feature of many types of cells is their responsiveness to chemotactic gradients of factors for which they express the corresponding receptors. The most studied chemoattractants so far are peptide-based growth factors and a family of cytokines endowed with strong chemotactic properties, called chemokines. However, additional evidence has accumulated that, in addition to these peptide-based chemoattractants, an important role in cell migration is played by bioactive lipids. Areas covered Solid evidence has accumulated that two bioactive phosphorylated sphingolipids that are derivatives of sphingolipid metabolism, namely sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are potent chemoattractants for a variety of cells. In this review, we will discuss the effect of these two phosphorylated sphingolipids on the trafficking of normal and malignant cells, and, in particular, we will focus on their role in trafficking of normal hematopoietic stem/progenitor cells. Unlike other mediators, S1P under steady state conditions maintain a steep gradient between interstitial fluid and peripheral blood and lymph across the endothelial barrier, which is important in the egress of cells from bone marrow. Both S1P and C1P may be upregulated in damaged tissues, which may result in reversal of this gradient. Expert opinion S1P and C1P are important regulators of the trafficking of normal and malignant cells, and modification of their biological effects will have important applications in optimizing stem cell mobilization and homing, tissue organ/regeneration, and preventing cancer metastasis.

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FTY720 preserved islet β‐cell mass by inhibiting apoptosis and increasing survival of β‐cells in db/db mice

Abstract: We concluded that early intervention with FTY720 in db/db mice can prevent development of diabetes through preserving β-cell mass by inhibiting apoptosis and increasing survival of islet β-cells.

Cited by 29 publications

References 30 publications

Sphingosine 1-phosphate counteracts insulin signaling in pancreatic β-cells via the sphingosine 1-phosphate receptor subtype 2

Sphingosine 1-phosphate counteracts insulin signaling in pancreatic β-cells via the sphingosine 1-phosphate receptor subtype 2

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells

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