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Discovering human diabetes-risk gene function with genetics and physiological assays

Author

Listed:
  • Heshan Peiris

    (Stanford University School of Medicine)

  • Sangbin Park

    (Stanford University School of Medicine)

  • Shreya Louis

    (Stanford University School of Medicine)

  • Xueying Gu

    (Stanford University School of Medicine)

  • Jonathan Y. Lam

    (Stanford University School of Medicine)

  • Olof Asplund

    (Lund University Diabetes Centre)

  • Gregory C. Ippolito

    (University of Texas at Austin)

  • Rita Bottino

    (Allegheny Health Network)

  • Leif Groop

    (Lund University Diabetes Centre)

  • Haley Tucker

    (University of Texas at Austin)

  • Seung K. Kim

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.

Suggested Citation

  • Heshan Peiris & Sangbin Park & Shreya Louis & Xueying Gu & Jonathan Y. Lam & Olof Asplund & Gregory C. Ippolito & Rita Bottino & Leif Groop & Haley Tucker & Seung K. Kim, 2018. "Discovering human diabetes-risk gene function with genetics and physiological assays," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06249-3
    DOI: 10.1038/s41467-018-06249-3
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