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Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

Author

Listed:
  • Susheel K. Gunasekar

    (Washington University School of Medicine)

  • Litao Xie

    (Washington University School of Medicine)

  • Ashutosh Kumar

    (Washington University School of Medicine)

  • Juan Hong

    (Washington University School of Medicine)

  • Pratik R. Chheda

    (University of Iowa, College of Pharmacy)

  • Chen Kang

    (Washington University School of Medicine)

  • David M. Kern

    (University of California Berkeley
    University of California Berkeley)

  • Chau My-Ta

    (Northwestern University)

  • Joshua Maurer

    (Washington University School of Medicine)

  • John Heebink

    (Washington University School of Medicine)

  • Eva E. Gerber

    (University of California Berkeley
    University of California Berkeley)

  • Wojciech J. Grzesik

    (University of Iowa)

  • Macaulay Elliot-Hudson

    (University of Iowa)

  • Yanhui Zhang

    (Xiamen University)

  • Phillip Key

    (Washington University School of Medicine)

  • Chaitanya A. Kulkarni

    (University of Iowa, College of Pharmacy)

  • Joseph W. Beals

    (Center for Human Nutrition, Washington University School of Medicine)

  • Gordon I. Smith

    (Center for Human Nutrition, Washington University School of Medicine)

  • Isaac Samuel

    (University of Iowa, Carver College of Medicine)

  • Jessica K. Smith

    (University of Iowa, Carver College of Medicine)

  • Peter Nau

    (University of Iowa, Carver College of Medicine)

  • Yumi Imai

    (University of Iowa)

  • Ryan D. Sheldon

    (University of Iowa)

  • Eric B. Taylor

    (University of Iowa)

  • Daniel J. Lerner

    (BioGenerator Labs)

  • Andrew W. Norris

    (University of Iowa)

  • Samuel Klein

    (Center for Human Nutrition, Washington University School of Medicine)

  • Stephen G. Brohawn

    (University of California Berkeley
    University of California Berkeley)

  • Robert Kerns

    (University of Iowa, College of Pharmacy)

  • Rajan Sah

    (Washington University School of Medicine)

Abstract

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

Suggested Citation

  • Susheel K. Gunasekar & Litao Xie & Ashutosh Kumar & Juan Hong & Pratik R. Chheda & Chen Kang & David M. Kern & Chau My-Ta & Joshua Maurer & John Heebink & Eva E. Gerber & Wojciech J. Grzesik & Macaula, 2022. "Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28435-0
    DOI: 10.1038/s41467-022-28435-0
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    References listed on IDEAS

    as
    1. Chloe L Edridge & Alison J Dunkley & Danielle H Bodicoat & Tanith C Rose & Laura J Gray & Melanie J Davies & Kamlesh Khunti, 2015. "Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-20, June.
    2. Dawid Deneka & Marta Sawicka & Andy K. M. Lam & Cristina Paulino & Raimund Dutzler, 2018. "Structure of a volume-regulated anion channel of the LRRC8 family," Nature, Nature, vol. 558(7709), pages 254-259, June.
    3. Chen Kang & Litao Xie & Susheel K. Gunasekar & Anil Mishra & Yanhui Zhang & Saachi Pai & Yiwen Gao & Ashutosh Kumar & Andrew W. Norris & Samuel B. Stephens & Rajan Sah, 2018. "SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

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