Modeling diabetic alpha cell dysfunction using stem cell-derived alpha cells

Area of Science:

• Endocrinology
• Cell Biology
• Diabetes Research

Background:

• Pancreatic alpha cell dysfunction is central to diabetes pathophysiology.
• Diabetic alpha cells exhibit glucagon hypersecretion, altered proglucagon processing, and transcriptomic changes.
• A lack of in vitro human alpha cell models hinders research into these defects.

Purpose of the Study:

• To investigate the impact of endoplasmic reticulum (ER) stress on stem cell-derived alpha (SC-α) cells.
• To establish a functional in vitro model for studying diabetic alpha cell phenotypes.
• To identify potential therapeutic targets for correcting alpha cell dysfunction.

Main Methods:

• Induction of ER stress in stem cell-derived alpha (SC-α) cells.
• Measurement of glucagon and related peptide secretion (glicentin, GLP-1).
• Analysis of transcriptomic profiles and key pathway expression (MAFB, glycolysis, oxidative phosphorylation).
• Treatment of SC-α cells with sunitinib, a tyrosine kinase inhibitor.

Main Results:

• ER stress in SC-α cells induced glucagon hypersecretion.
• ER stress increased glicentin secretion and glucagon-like peptide-1 (GLP-1) expression.
• ER stress led to a diabetic transcriptional state, downregulating MAFB and metabolic pathways.
• Sunitinib treatment protected SC-α cells from ER stress-induced glucagon hypersecretion.

Conclusions:

• ER stress in SC-α cells recapitulates key features of diabetic alpha cell dysfunction.
• The SC-α cell model provides a platform for studying diabetes pathophysiology.
• Sunitinib shows potential in protecting against ER stress-mediated alpha cell dysfunction.