A single-cell and bulk transcriptome meta-analysis reveals RYR2 as a key biomarker and potential regulator in Type 2 Diabetes

Intracellular calcium release channels, including ryanodine receptors (RYRs) and inositol trisphosphate receptors (ITPRs), regulate calcium signalling essential for insulin secretion by pancreatic islet β-cells. However, alterations in their expression in type 2 diabetes (T2D) remain unclear. Here, we screened 1.3 million single-cell RNA sequencing transcriptomes and performed a meta-analysis of 464,713 transcriptomes from human islet α-, β-, or δ-cells across 22 independent studies from n=235 individuals with, at risk of, or without diabetes. We identified RYR2 as the predominant RYR isoform in human pancreatic islet β-cells, with significantly increased expression in T2D, compared to prediabetes and non-diabetes states. Bulk RNA sequencing of n=381 human islet samples from our own and publicly available datasets confirmed RYR2 abundance and enrichment of RYR2-212 (ENST00000714022.1) splice variant in human islets. These findings suggest that elevated β-cell RYR2 expression may contribute to islet dysfunction in T2D, identifying RYR2 as a candidate biomarker and potential therapeutic target to guide personalised strategies for diabetes management.