Endocrine islet β-cell subtypes with differential function are derived from biochemically distinct embryonic...

Endocrine islet b cells comprise heterogenous cell subsets. Yet when/how these subsets are produced and how stable they are remain unknown. Addressing these questions is important for preventing/curing diabetes, because lower numbers of b cells with better secretory function is a high risk of this disease. Using combinatorial cell lineage tracing, scRNA-seq, and DNA methylation analysis, we show here that embryonic islet progenitors with distinct gene expression and DNA methylation produce b-cell subtypes of different function and viability in adult mice. The subtype with better function is enriched for genes involved in vesicular production/trafficking, stress response, and Ca²⁺-secretion coupling, which further correspond to differential DNA methylation in putative enhancers of these genes. Maternal overnutrition, a major diabetes risk factor, reduces the proportion of endocrine progenitors of the b-cell subtype with better-function via deregulating DNA methyl transferase 3a. Intriguingly, the gene signature that defines mouse b-cell subtypes can reliably divide human cells into two sub-populations while the proportion of b cells with better-function is reduced in diabetic donors. The implication of these results is that modulating DNA methylation in islet progenitors using maternal food supplements can be explored to improve b-cell function in the prevention and therapy of diabetes.