Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28435-0
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Funding
- NCI [P30CA086862]
- NIH [P30 DK 020579, T32 GM008365, P30 DK056341, UL1 TR000448, T32 HL130357]
- University of Iowa Center for Biocatalysis and Bioprocessing
- John L. & Carol E. Lach Chair in Drug Delivery Technology
- New York Stem Cell Foundation
- NIGMS [GM123496, GM128263]
- McKnight Foundation Scholar Award
- Rose Hill Innovator Award
- Sloan Research Fellowship
- NIH NIDDK [R01DK115791, R01DK106009, R01DK126068, R01DK127080, R43 DK121598, R44 DK126600]
- Leadership Entrepreneurship Acceleration Program (LEAP) from the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship at Washington University in St. Louis
- Roy J. Carver Trust
- University of Iowa
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SWELL1 channel modulators represent a novel therapeutic approach for treating Type 2 diabetes and associated liver steatosis by enhancing insulin sensitivity and secretion. These modulators improve SWELL1-dependent systemic metabolism and hold promise for future treatment of diabetes and nonalcoholic fatty liver disease.
Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice. Type 2 diabetes is associated with insulin resistance, impaired pancreatic beta-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs beta-cell insulin secretion and glycemic control. Here, we show that I-Cl,I-SWELL and SWELL1 protein are reduced in adipose and beta-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.
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