Glucose metabolism: key endogenous regulator of β-cell replication and survival

Authors

  • D. Dadon,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • S. Tornovsky-Babaey,

    1. Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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  • J. Furth-Lavi,

    1. Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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  • D. Ben-Zvi,

    1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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  • O. Ziv,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • R. Schyr-Ben-Haroush,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • M. Stolovich-Rain,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • A. Hija,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • S. Porat,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Z. Granot,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • N. Weinberg-Corem,

    1. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • Y. Dor,

    Corresponding author
    • Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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  • B. Glaser

    Corresponding author
    1. Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    • Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Correspondence to: Benjamin Glaser, Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

E-mail: beng@cc.huji.ac.il

Yuval Dor, Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.

E-mail: yuvald@ekmd.huji.ac.il.

Abstract

Recent studies in mice have shown that pancreatic β-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β-cell regeneration is based on the replication of fully differentiated, insulin-positive β-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual β-cell workload, defined as the amount of insulin that an individual β-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β-cells may allow for the development of effective regenerative therapies for diabetes.

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