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

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.

Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8

“…The overall architecture and subunit folding are the same in all of the LRRC8 structures that have been determined ( Deneka et al, 2021 , 2018 ; Gunasekar et al, 2022 ; Kasuya et al, 2018 ; Kefauver et al, 2018 ; Kern et al, 2019 ; Nakamura et al, 2020 ). The overall architecture of LRRC8 assembles into a hexamer ( Figure 1A ).…”

“…Identification of LRRC8 as the molecular entity of VRAC has also accelerated our understanding of the physiological and medical aspects of the LRRC8-mediated VRAC current ( Osei-Owusu et al, 2018 ; Chen et al, 2019 ; Figueroa and Denton, 2022 ). For example, the LRRC8-mediated VRAC current is implicated in adipocyte development ( Zhang et al, 2017 ), insulin secretion ( Zhang et al, 2017 ; Kang et al, 2018 ; Stuhlmann et al, 2018 ; Gunasekar et al, 2022 ), and sperm development ( Bao et al, 2018 ; Lück et al, 2018 ). VRAC in hippocampal astrocytes transports glutamates to regulate synaptic transmission and neuronal excitability ( Yang et al, 2019 ).…”

“…Due to recent advances in cryo-EM, the first structure of LRRC8 was reported in 2018, only 4 years after the identification of LRRC8 as the molecular entity of VRAC ( Deneka et al, 2018 ). Since then, six studies reported the LRRC8 structures to date ( Kasuya et al, 2018 ; Kefauver et al, 2018 ; Kern et al, 2019 ; Nakamura et al, 2020 ; Deneka et al, 2021 ; Gunasekar et al, 2022 ). In this review, we describe the structural and functional features of the LRRC8 protein family that were elucidated by those studies and discuss the possible directions of further research in this field.…”

“…These sybody-bound MmLRRC8A structures provided mechanistic insights into the allosteric modulation in the intracellular leucine-rich repeat (LRR) region. In 2022, the TM region structures of MmLRRC8A homo-hexamer in nanodiscs in complex with SN-407, a DCPIB analog, were determined by cryo-EM ( Gunasekar et al, 2022 ). The DCPIB analog-bound MmLRRC8A homo-hexamer structures provided the structural basis for optimizing chemical compounds targeting the channel pore of LRRC8.…”

“…The extracellular, TM, and intracellular regions have six-fold or three-fold (pseudo six-fold) symmetry in the LRRC8A structures ( Deneka et al, 2018 , Deneka et al, 2021 ; Kasuya et al, 2018 ; Kefauver et al, 2018 ; Kern et al, 2019 ; Gunasekar et al, 2022 ) and two-fold (pseudo six-fold) symmetry in the LRRC8D structure ( Nakamura et al, 2020 ). In contrast, the symmetry of the LRR region is variable, suggesting its conformational flexibility.…”