# Endocrine islet β-cell subtypes with differential function are derived from biochemically distinct embryonic endocrine islet progenitors that are regulated by maternal nutrients

## TL;DR

This study shows that different types of beta cells in the pancreas develop from distinct embryonic progenitors, and maternal nutrition affects their function, which could help in preventing diabetes.

## Contribution

The study identifies biochemically distinct embryonic progenitors that give rise to functionally different beta-cell subtypes and links maternal nutrition to DNA methylation changes affecting these subtypes.

## Key findings

- Embryonic islet progenitors with distinct gene expression and DNA methylation produce functionally different beta-cell subtypes in adult mice.
- Maternal overnutrition reduces the proportion of high-function beta-cell progenitors by deregulating DNA methyl transferase 3a.
- The gene signature defining mouse beta-cell subtypes can also classify human beta cells, with reduced high-function subtypes in diabetic donors.

## Abstract

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.