Whole-Organism Chemical Screening Identifies Modulators of Pancreatic β-Cell Function

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Beta-cell dysfunction and loss are central to diabetes pathogenesis.
• Novel therapeutic strategies targeting beta-cell function and mass are crucial for diabetes treatment.

Purpose of the Study:

• To identify novel small molecules that modulate beta-cell function and glucose metabolism using a high-throughput in vivo screen.
• To explore potential therapeutic targets for diabetes by screening for compounds that enhance insulin expression and secretion.

Main Methods:

• A large-scale in vivo screen of 4,640 small molecules in a zebrafish model to identify modulators of beta-cell function.
• Analysis of insulin promoter activation kinetics to determine direct modulators.
• Evaluation of gluconeogenic gene expression (pck1) to assess functional response.
• Testing of identified compounds, including Kv1.3 inhibitors, in adult zebrafish and a mouse model of hyperglycemia.

Main Results:

• Identified 84 small molecules that stimulate insulin expression and reduce glucose levels.
• Confirmed direct mode of action for 32 insulin stimulators.
• Observed coordinated upregulation of pck1 expression in response to insulin stimulators.
• Kv1.3 inhibitors demonstrated efficacy in increasing beta-cell mass and function across different models, including larval zebrafish, adult zebrafish, and a mouse model.

Conclusions:

• Whole-organism screening is an effective strategy for identifying novel modulators of beta-cell function and glucose metabolism.
• Kv1.3 inhibitors represent a promising therapeutic avenue for diabetes, showing effects on beta-cell mass and function.
• The study identified new small molecules and pathways that could lead to innovative diabetes therapies.