Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects

Area of Science:

• Endocrinology
• Genomics
• Metabolic Diseases

Background:

• Pancreatic islets are crucial for glucose homeostasis and implicated in type 2 diabetes (T2D).
• Limited understanding of specific human islet cell type alterations in T2D.
• Previous studies suggest beta-cell loss in T2D, but comprehensive single-cell data is lacking.

Purpose of the Study:

• To comprehensively profile human islet cell types across non-diabetic, pre-diabetic, and T2D states.
• To identify cell type-specific gene expression changes in T2D.
• To nominate candidate causal genes for T2D pathophysiology and beta-cell dysfunction.

Main Methods:

• Single-cell transcriptome profiling of 245,878 human islet cells from 48 donors.
• Cell-cluster analysis to identify distinct cell types and subpopulations.
• Integration of multi-omics data (genetics, proteomics) and mouse model phenotypes.

Main Results:

• Identified 14 distinct islet cell types present in all donors.
• Observed ~25-30% reduction in beta-cells in T2D, with increased senescent beta-cells.
• Discovered 511 differentially expressed genes in T2D beta-cells, including vitamin A metabolism genes impacting viability.
• Nominated 58 candidate causal T2D genes, such as PDZK1 and GRAMD2B, affecting beta-cell mass.

Conclusions:

• This study provides a valuable genomic resource for T2D research and understanding human islet dysfunction.
• Identified novel T2D-associated genes and pathways, offering new therapeutic targets.
• Highlights the importance of beta-cell alterations and senescence in T2D pathogenesis.