Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Type 2 diabetes (T2D) pathogenesis involves complex cellular interactions within pancreatic islets.
• Non-beta cells, including alpha, delta, and other cell types, play crucial roles in islet function and metabolic regulation.

Purpose of the Study:

• To investigate the role and heterogeneity of non-beta cells in the early stages of type 2 diabetes.
• To understand how non-beta cell transcriptional diversity influences intra-islet crosstalk and beta cell function.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of islet cells from obese, diabetes-susceptible (NZO) and resistant (OB) mouse strains on a diabetogenic diet.
• Comparative analysis of islet cell transcriptomes, including identification of subpopulations and differentially expressed genes.
• Validation using human islet datasets from individuals at various stages of type 2 diabetes.

Main Results:

• Identified heterogeneous subpopulations in alpha cells, delta cells, and macrophages, with 133 mapping to human diabetes genes.
• Observed distinct alpha and delta cell profiles in susceptible (NZO) versus resistant (OB) mice, indicating differential stress and maturation.
• Found a higher abundance of macrophages in resistant (OB) mice, with significant communication with beta cells, potentially mediated by IL-15 and STAT3 activation.

Conclusions:

• Transcriptional heterogeneity of non-beta cells significantly impacts intra-islet communication.
• Non-beta cell dysregulation contributes to beta cell dysfunction in type 2 diabetes.
• Macrophage abundance and communication dynamics are altered in diabetes-susceptible individuals.