Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance

C. Lipina, H. S. Hundal (Lead / Corresponding author)

    Research output: Contribution to journalReview article

    47 Citations (Scopus)

    Abstract

    Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.

    Original languageEnglish
    Pages (from-to)1596-1607
    Number of pages12
    JournalDiabetologia
    Volume54
    Issue number7
    DOIs
    Publication statusPublished - Jul 2011

    Keywords

    • Adipose tissue
    • Caveolae
    • Ceramide
    • Gangliosides
    • GM3
    • Skeletal muscle
    • Sphingomyelin
    • PKB/Akt
    • PROTEIN-KINASE-C
    • SKELETAL-MUSCLE CELLS
    • PLECKSTRIN HOMOLOGY DOMAIN
    • SATURATED FATTY-ACIDS
    • GANGLIOSIDE GM3
    • CERAMIDE SYNTHESIS
    • INDUCED APOPTOSIS
    • GLUCOSE-UPTAKE
    • IN-VIVO
    • DE-NOVO

    Cite this

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    abstract = "Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.",
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    Sphingolipids : agents provocateurs in the pathogenesis of insulin resistance. / Lipina, C.; Hundal, H. S. (Lead / Corresponding author).

    In: Diabetologia, Vol. 54, No. 7, 07.2011, p. 1596-1607.

    Research output: Contribution to journalReview article

    TY - JOUR

    T1 - Sphingolipids

    T2 - agents provocateurs in the pathogenesis of insulin resistance

    AU - Lipina, C.

    AU - Hundal, H. S.

    PY - 2011/7

    Y1 - 2011/7

    N2 - Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.

    AB - Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.

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    KW - Ceramide

    KW - Gangliosides

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    KW - Skeletal muscle

    KW - Sphingomyelin

    KW - PKB/Akt

    KW - PROTEIN-KINASE-C

    KW - SKELETAL-MUSCLE CELLS

    KW - PLECKSTRIN HOMOLOGY DOMAIN

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    KW - GANGLIOSIDE GM3

    KW - CERAMIDE SYNTHESIS

    KW - INDUCED APOPTOSIS

    KW - GLUCOSE-UPTAKE

    KW - IN-VIVO

    KW - DE-NOVO

    U2 - 10.1007/s00125-011-2127-3

    DO - 10.1007/s00125-011-2127-3

    M3 - Review article

    C2 - 21468641

    VL - 54

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    EP - 1607

    JO - Diabetologia

    JF - Diabetologia

    SN - 0012-186X

    IS - 7

    ER -