학술논문
Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Document Type
article
Author
Gunasekar, Susheel K; Xie, Litao; Kumar, Ashutosh; Hong, Juan; Chheda, Pratik R; Kang, Chen; Kern, David M; My-Ta, Chau; Maurer, Joshua; Heebink, John; Gerber, Eva E; Grzesik, Wojciech J; Elliot-Hudson, Macaulay; Zhang, Yanhui; Key, Phillip; Kulkarni, Chaitanya A; Beals, Joseph W; Smith, Gordon I; Samuel, Isaac; Smith, Jessica K; Nau, Peter; Imai, Yumi; Sheldon, Ryan D; Taylor, Eric B; Lerner, Daniel J; Norris, Andrew W; Klein, Samuel; Brohawn, Stephen G; Kerns, Robert; Sah, Rajan
Source
Nature Communications. 13(1)
Subject
Language
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.