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S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Sung Hee Um, Melanie Sticker-Jantscheff, Gia Cac Chau

    The Journal of Clinical Investigation
    |June 16, 2015
    PubMed

    Insights

    Loss of S6K1 in mice impairs pancreatic beta cell growth, potentially leading to type 2 diabetes. Restoring S6K1 in beta cells improved glucose tolerance, suggesting a direct role in diabetes development.

    Area of Science:

    • Endocrinology
    • Metabolic Diseases
    • Developmental Biology

    Background:

    • Type 2 diabetes mellitus (T2DM) is a global health issue marked by insulin resistance and beta cell dysfunction.
    • Ribosomal protein S6 kinase 1 (S6K1) is implicated in insulin sensitivity, with its loss potentially improving insulin resistance.
    • S6K1 deficiency has been linked to systemic insulin sensitivity, prompting interest in S6K1 inhibitors for T2DM treatment.

    Purpose of the Study:

    • To investigate the role of S6K1 in beta cell development and its potential link to intrauterine growth restriction (IUGR) and T2DM.
    • To determine if S6K1 deficiency causes an intrinsic defect in beta cells or is secondary to IUGR.
    • To explore the therapeutic potential of targeting S6K1 signaling in the context of T2DM development.

    Main Methods:

    • Utilized S6K1-deficient (S6K1-/-) mice to study the effects of S6K1 loss on beta cell growth, placental development, and IUGR.
    • Employed tetraploid embryo complementation to differentiate between placental effects and intrinsic beta cell defects.
    • Re-expressed S6K1 in the beta cells of S6K1-/- mice to assess its specific role in restoring function.

    Main Results:

    • S6K1 deficiency in mice resulted in decreased beta cell growth, IUGR, and impaired placental development.
    • Tetraploid embryo complementation rescued IUGR but did not restore beta cell size or insulin levels in S6K1-/- embryos, indicating an intrinsic beta cell defect.
    • Re-expression of S6K1 specifically in beta cells of S6K1-/- mice normalized embryonic beta cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, independent of IUGR.

    Conclusions:

    • Loss of S6K1 leads to an intrinsic defect in pancreatic beta cells, affecting their growth and function.
    • Reduced S6K1 signaling in beta cells during fetal development, potentially due to nutrient availability, may contribute to impaired beta cell growth and the later onset of T2DM.
    • Targeting S6K1 signaling within beta cells represents a potential therapeutic strategy for preventing or treating T2DM.

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