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

Nat Commun. 2022 Feb 10;13(1):784. doi: 10.1038/s41467-022-28435-0.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Cryoelectron Microscopy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose / metabolism
  • Glycemic Control / methods*
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Liver / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Signal Transduction
  • Transcriptome


  • Insulin
  • LRRC8A protein, mouse
  • Membrane Proteins
  • Glucose