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

Abstract

Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic β-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, β-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 β-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.

A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC)

“…Our lab has only begun to better understand how native VRAC may be modulated by small-molecule compounds utilizing the robust YFP-quenching assays previously established as a functional readout of chloride channel activity [ 72 , 82 ]. Others have used cryo-EM to identify putative binding sites of small-molecule VRAC inhibitors and using the gained structural insight to develop even more potent channel blockers [ 12 , 22 ]. Protein engineering approaches have generated LRRC8 chimeras that may serve as a complementary approach to identify putative binding sites of known VRAC modulators [ 83 ].…”

“…In pancreatic beta cells, VRAC enhances insulin secretion following glucose uptake suggesting the channel could be a novel drug target for type 2 diabetes. In support of this idea, Sah and colleagues recently reported that a small molecule that enhances the stability of VRAC in the cell membrane promotes glucose responsiveness and insulin release from beta cells [ 22 ]. Whether or not a frank activator of VRAC would have similar effects is not yet known.…”