Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

Gunasekar, S. K.; Xie, L.; Chheda, P. R.; Kang, C.; Kern, D. M.; My-Ta, C.; Kumar, A.; Maurer, J. M.; Gerber, E. E.; Grzesik, W. J.; Elliot-Hudson, M.; Zhang, Y.; Kulkarni, C. A.; Samuel, I.; Smith, J. K.; Nau, P.; Imai, Y.; Sheldon, R. D.; Taylor, E. B.; Lerner, D. J.; Norris, A. W.; Brohawn, S. G.; Kerns, R.; Sah, R.

doi:10.1101/2021.02.28.432901

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bioRxiv · 10.1101/2021.02.28.432901

Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

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Abstract

Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic {beta}-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, {beta}-cell insulin secretion and glycemic control - suggesting that SWELL1-LRRC8 complex dysfunction contributes to T2D pathogenesis. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and {beta}-cells in murine and human T2D. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-designed active derivatives (SN-40X) of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1-LRRC8 hexameric complex, restore SWELL1-LRRC8 protein, plasma membrane trafficking, signaling and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 and active SN-40X compounds restore glycemic control and prevents NAFLD by improving insulin-sensitivity and insulin secretion in murine T2D. These findings demonstrate that small molecule SWELL1 modulators restore SWELL1-dependent insulin-sensitivity and insulin secretion in T2D and may represent a first-in-class therapeutic approach for T2D and NAFLD.

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Gunasekar, S. K., Xie, L., Chheda, P. R., Kang, C., Kern, D. M., My-Ta, C., Kumar, A., Maurer, J. M., Gerber, E. E., Grzesik, W. J., Elliot-Hudson, M., Zhang, Y., Kulkarni, C. A., Samuel, I., Smith, J. K., Nau, P., Imai, Y., Sheldon, R. D., Taylor, E. B., Lerner, D. J., Norris, A. W., Brohawn, S. G., Kerns, R., Sah, R.. 2021-03-02. Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes. https://doi.org/10.1101/2021.02.28.432901

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