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

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, Macaulay Elliot-Hudson, Yanhui Zhang, Phillip Key, Chaitanya A. Kulkarni, Joseph W. Beals, Gordon I. Smith, Isaac Samuel, Jessica K. Smith, Peter Nau, Yumi Imai, Ryan D. Sheldon, Eric B. Taylor, Daniel J. Lerner, Andrew W. Norris, Samuel Klein, Stephen G. Brohawn, Robert Kerns and Rajan Sah ()
Additional contact information
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
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
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
Robert Kerns: University of Iowa, College of Pharmacy
Rajan Sah: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-25

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28435-0

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