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 Rajesh Chheda, Kang Chen, David M. Kern, Chau My-Ta, Joshua M 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 Smith, Peter Nau, Yumi Imai, Ryan D. Sheldon, Eric B. Taylor, Daniel J. Lerner, Andrew W. Norris, Samuel Klein, Stephen G. Brohawn, Robert J. Kerns, Rajan Sah
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 I Cl,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.