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Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity
Jonnell C Small1,2, Aidan Joblin-Mills3, Kaycee Carbone1
1Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States.
Abstract:
Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.
Insights
Researchers screened thousands of compounds to find small molecules that protect pancreatic beta cells from glucolipotoxicity, a key factor in type 2 diabetes. Ten promising kinase inhibitors were identified to preserve beta cell viability.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Type 2 diabetes is characterized by progressive beta-cell failure and loss of beta-cell mass.
- Obesity-associated hyperglycemia and elevated free fatty acids cause beta-cell glucolipotoxicity, with no current therapies targeting this in obese patients.
- Identifying novel therapeutic targets is crucial for preserving beta-cell function.
Purpose of the Study:
- To identify small molecules that protect pancreatic beta cells from glucolipotoxicity.
- To discover potential therapeutic agents for type 2 diabetes by screening for compounds that enhance beta-cell survival.
Main Methods:
- A high-throughput screen of 20,876 compounds was conducted using the INS-1E rat insulinoma cell line under glucolipotoxic conditions (elevated glucose and palmitate).
- Compounds demonstrating protective effects on INS-1E cell viability were further analyzed for known biological targets.
- Promising candidates were validated in dissociated human islets to assess their efficacy in reducing glucolipotoxicity-induced beta-cell death.
Main Results:
- 312 glucolipotoxicity-protective small molecules were identified, with 17 selected for further investigation based on known targets.
- 16 of these compounds were kinase inhibitors, including inhibitors of cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2).
- Ten compounds (KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, GSK2126458) successfully reduced glucolipotoxicity-induced beta-cell death in human islets by decreasing caspase activation, mitochondrial depolarization, and calcium flux.
Conclusions:
- This study identified novel small molecules, primarily kinase inhibitors, that protect beta cells from glucolipotoxicity.
- These findings offer a promising foundation for developing new treatments to preserve beta-cell viability in type 2 diabetes patients.
- Targeting kinase pathways presents a viable strategy for combating beta-cell loss in the context of obesity and type 2 diabetes.
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