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Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets

Karl Bacos1, Alexander Perfilyev1, Alexandros Karagiannopoulos2

  • 1Epigenetics and Diabetes Unit, Department of Clinical Sciences and.

The Journal of Clinical Investigation
|January 19, 2023
PubMed

Insights

Researchers identified 395 genes with altered expression in pancreatic islets of individuals with type 2 diabetes (T2D). These gene expression changes contribute to beta cell dysfunction and T2D development.

Area of Science:

  • Endocrinology
  • Genetics
  • Molecular Biology

Background:

  • Type 2 diabetes (T2D) is characterized by impaired insulin secretion from pancreatic beta cells.
  • Identifying genetic factors influencing T2D pathophysiology is crucial for understanding disease mechanisms.

Purpose of the Study:

  • To identify novel candidate genes involved in T2D pathophysiology by analyzing gene expression in human pancreatic islets.
  • To investigate the functional relevance of identified genes in beta cell function and glucose homeostasis.

Main Methods:

  • Differential gene expression analysis in human pancreatic islets from ~300 individuals (T2D vs. non-diabetic).
  • Single-cell RNA-sequencing to determine gene expression in human beta cells.
  • Chromatin accessibility assays and association analysis with T2D single nucleotide polymorphisms (SNPs).
  • In vivo studies using mouse knockout models and functional validation of candidate genes (OPRD1, PAX5, SLC2A2) in beta cells.

Main Results:

  • 395 differentially expressed genes (DEGs) identified in T2D islets, including novel candidates (OPRD1, PAX5, TET1).
  • One-third of DEGs associated with HbA1c levels in individuals without diagnosed T2D, suggesting a predisposing role.
  • DEGs showed altered chromatin accessibility and association with T2D SNPs.
  • Mouse models confirmed the role of candidate genes in glucose homeostasis and body composition.
  • Functional studies revealed that altered OPRD1, PAX5, and SLC2A2 expression impairs insulin secretion, with PAX5-related impairment linked to mitochondrial dysfunction.
  • PAX5 identified as a potential transcriptional regulator of T2D-associated DEGs.

Conclusions:

  • Significant molecular alterations in human pancreatic islets contribute to beta cell dysfunction in T2D.
  • Identified DEGs, including novel candidates like PAX5, represent potential therapeutic targets for T2D.
  • PAX5 plays a critical role in beta cell function and may regulate multiple T2D-associated genes.
Keywords:
Beta cellsDiabetesEndocrinologyInsulinMetabolism

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