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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 I_Cl,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.

SUBMITTER: Gunasekar SK

PROVIDER: S-EPMC8831520 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Gunasekar Susheel K SK Xie Litao L Kumar Ashutosh A Hong Juan J Chheda Pratik R PR Kang Chen C Kern David M DM My-Ta Chau C Maurer Joshua J Heebink John J Gerber Eva E EE Grzesik Wojciech J WJ Elliot-Hudson Macaulay M Zhang Yanhui Y Key Phillip P Kulkarni Chaitanya A CA Beals Joseph W JW Smith Gordon I GI Samuel Isaac I Smith Jessica K JK Nau Peter P Imai Yumi Y Sheldon Ryan D RD Taylor Eric B EB Lerner Daniel J DJ Norris Andrew W AW Klein Samuel S Brohawn Stephen G SG Kerns Robert R Sah Rajan R

Nature communications 20220210 1

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 I<sub>Cl,SWELL</sub> and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry ...[more]

PMID: 35145074

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Project description:BackgroundPatients with gallstone disease (GSD) often have highly co-occurrence with metabolic syndrome (MetS) and Nonalcoholic fatty liver disease (NAFLD) both associated with insulin resistance (IR). Meanwhile, highly prevalence of NAFLD was found in patients who received cholecystectomy. However, the associations of GSD with MetS, NAFLD is inconsistent in the published literature. And risk of cholecystectomy on NAFLD is unclear.MethodsWe searched the Medline EMBASE and WOS databases for literature that met our study topic. To be specific, studies with focus on associations between GSD and MetS/NAFLD, and risk evaluation on cholecystectomy and NAFLD incidence were enrolled for further analysis. The random effect model was used to calculate the combined relative ratio (RR) and odds ratio (OR)and 95% confidence interval (CI).ResultsSeven and six papers with focus on connections between GSD and NAFLD/MetS prevalence. Correspondingly, seven papers with focus on risk of cholecystectomy on NAFLD occurrence were also enrolled into meta-analysis. After pooling the results from individual study, patients with GSD had higher risk of MetS (OR:1.45, 95%CI: 1.23-1.67, I2 = 41.1%, P=0.165). Risk of GSD was increased by 52% in NAFLD patients (pooled OR:1.52, 95%CI:1.24-1.80). And about 32% of increment on NAFLD prevalence was observed in patients with GSD (pooled OR: 1.32, 95%CI:1.14-1.50). With regard to individual MetS components, patients with higher systolic blood pressure were more prone to develop GSD, with combined SMD of 0.29 (96%CI: 0.24-0.34, P<0.05). Dose-response analysis found the GSD incidence was significantly associated with increased body mass index (BMI) (pooled OR: 1.02, 95%CI:1.01-1.03) in linear trends. Patients who received cholecystectomy had a higher risk of post-operative NAFLD (OR:2.14, 95%CI: 1.43-2.85), P<0.05). And this impact was amplified in obese patients (OR: 2.51, 95%CI: 1.95-3.06, P<0.05).ConclusionOur results confirmed that controls on weight and blood pressure might be candidate therapeutic strategy for GSD prevention. And concerns should be raised on de-novo NAFLD after cholecystectomy.

Dataset Information

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

Publications

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

Similar Datasets

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