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Single-cell RNA Sequencing and Analysis of Human Pancreatic Islets
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IAPP-induced beta cell stress recapitulates the islet transcriptome in type 2 diabetes
Montgomery Blencowe1,2, Allison Furterer3,4, Qing Wang3
1Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
Diabetologia
|September 23, 2021
Summary
Toxic oligomers of islet amyloid polypeptide (IAPP) contribute to type 2 diabetes. This study reveals IAPP toxicity drives islet inflammation and dedifferentiation, identifying key transcriptional drivers for potential therapeutic targets.
Area of Science:
- Endocrinology
- Molecular Biology
- Genomics
Background:
- Type 2 diabetes is characterized by islet amyloid and toxic oligomers of islet amyloid polypeptide (IAPP).
- Understanding the islet response to IAPP toxicity and its transcriptional drivers is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate if IAPP toxicity induces an islet response comparable to human type 2 diabetes.
- To identify the key transcriptional drivers of this response.
Main Methods:
- Evaluated islet transcriptomes in transgenic mice expressing human or rodent IAPP, or human calpastatin.
- Utilized RNA sequencing, differential expression, and gene co-expression network analysis.
- Compared mouse islet transcriptomes with those from humans with prediabetes or type 2 diabetes.
Main Results:
- Islet transcriptomes in humans with prediabetes and type 2 diabetes are highly similar.
- Overexpression of human IAPP, but not rodent IAPP, induced islet inflammation and decreased expression of beta cell identity genes.
- Identified STAT3, NF-κB, ESR1, CTNNB1, COL3A1, NID1, and ZNF800 as key mediators of islet injury.
Conclusions:
- IAPP-mediated beta cell injury contributes to islet inflammation and dedifferentiation in type 2 diabetes.
- Inhibiting IAPP toxicity represents a potential therapeutic strategy for type 2 diabetes.
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