Biology subjects

Samuel, I.

Publications and source records attributed to Samuel, I..

2 recordsLinked to original sources

bioRxiv2023

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice

Bariatric surgery is an effective obesity treatment, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. Here, we investigated the role of somatostatin (Sst) in bariatric surgery outcomes using a mouse model of sleeve gastrectomy (SG). Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally, and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of Glp1. Mathematical modeling of the feedback inhibition between Sst and Glp1 showed that Sst exerts its maximal effect on Glp1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of Glp1 compared with heterozygous SG-operated controls. Accordingly, SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months, had higher Glp1 levels, regained less weight, and improved glycemia compared to saline- treated SG-operated controls. Our results suggest that Sst signaling inhibition enhances and maintains the long-term favorable metabolic outcomes of bariatric surgery.

physiology↗

bioRxiv2021

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

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.

physiology↗