Review
Lessons from neonatal β-cell epigenomic for diabetes prevention and treatment

https://doi.org/10.1016/j.tem.2022.03.002Get rights and content

Highlights

  • Expansion of β-cell mass during suckling period relies on epigenetic program connected to specific signaling pathways of humoral factors.

  • Maternal milk, innate immunity, and intestinal microbiota are keys for the control of the epigenetic mechanisms governing cell cycle entry pathways during the lactating period.

  • Nutritional switch during suckling–weaning transition induces a change in the epigenetic pathways leading to the growth arrest and β-cell maturation.

  • Pathways involved in postnatal constitutive and adaptive β-cell replication are reactivated during pregnancy and obesity.

  • In diabetes, activation of epigenetic pathways involved in neonate β-cell proliferation is impaired.

  • Understanding how to manipulate these pathways can be foreseen as a possible therapeutic treatment option to restore the lost β-cell mass in diabetes.

Pancreatic β-cell expansion and functional maturation during the birth-to-weaning period plays an essential role in the adaptation of plasma insulin levels to metabolic needs. These events are driven by epigenetic programs triggered by growth factors, hormones, and nutrients. These mechanisms operating in the neonatal period can be at least in part reactivated in adult life to increase the functional β-cell mass and face conditions of increased insulin demand such as obesity or pregnancy. In this review, we will highlight the importance of studying these signaling pathways and epigenetic programs to understand the causes of different forms of diabetes and to permit the design of novel therapeutic strategies to prevent and treat this metabolic disorder affecting hundreds of millions of people worldwide.

Section snippets

β-Cells during the suckling period: functionally immature but optimized for proliferation

Since the proliferative capacity of β-cells in adults is limited, expansion of insulin-secreting cells during the suckling period is critical to generate enough cells to control blood glucose levels throughout life. In rodents, the expansion of the β-cell mass (BCM) results from increased β-cell size and replication [3,4], but also from duct cell differentiation that accounts for 30–50% of the insulin-secreting cells produced during the first postnatal month [5,6]. In human, the BCM is largely

Epigenetic programming of β-cell proliferation and metabolism during the suckling period

Adaptation to maternal milk nutrition requires profound modifications in gene expression. This is achieved through reprogramming of the DNA and RNA methylation profile as well as in changes in histone methylation, acetylation, phosphorylation, or ubiquitylation. These epigenetic mechanisms are crucial for activating the expression of genes controlling metabolism and proliferation of immature β-cell during the breastfeeding period [32,33]. In immature β-cells, the expression of genes involved in

Nutritional switch during the suckling–weaning transition promotes β-cell maturation

Full β-cell maturation is achieved upon weaning [50], when infants switch from maternal breastmilk feeding, rich in fat and poor in carbohydrates, to solid and carbohydrate-enriched food. This is associated with changes in the gastrointestinal tract enabling the digestion and absorption of solid foods. During weaning, β-cells acquire the ability to sense changes in blood glucose levels and metabolize glucose to produce metabolic signals that trigger exocytosis of insulin-containing granules.

The epigenomic code of neonatal β-cells as a paradigm for adaptative proliferation under conditions of increased insulin demand

After weaning, the BCM remains relatively stable. However, under conditions of increased insulin demand an expansion of the ΒCM can be observed [61]. Obesity and pregnancy are associated with a diminished sensitivity of insulin target tissues. Thus, expansion of the BCM is pivotal for providing enough insulin and preserving normoglycemia [62,63]. BCM expansion in obesity and pregnancy necessitates a reduction in the expression of CDK inhibitors and a rise in the level of different cyclins, an

Translating the knowledge of neonatal β-cell physiology into therapy

Restoration of a functional BCM sufficient to compensate for insulin resistance is crucial for achieving long-term glycemic control in diabetes (Box 3). Thus, targeting the epigenetic mechanisms controlling β-cell replication and maturation is an attractive strategy to prevent and treat T2D. Some current medications that stimulate insulin secretion, including sulfonylurea and GLP-1 receptor agonists (GLP-1RA) promote changes in DNA methylation [79,80]. The modifications of the DNA methylome

Concluding remarks and future perspectives

Here, we highlighted the signals and epigenetic pathways governing early postnatal β-cell proliferation and maturation. These pathways can be at least in part reactivated in adulthood to allow the adaptation of β-cells to metabolic conditions of increased insulin demand. Several questions remain (see Outstanding questions), including the connection between the mitogenic pathways and epigenetic mechanisms, and the impact of long-term reactivation of these pathways on insulin secretion. We

Acknowledgments

This work was supported by Centre National de la Recherche Scientifique (CNRS), I-SITE ULNE ‘Sustain’ Betaprotect, the Hauts-de-France region via Start-AIRR Dermaseptine B2, the CPER P4S ‘Photonics for Society’ and by a grant from the Swiss National Science Foundation (310030-1884473 to R.R.). We warmly thank Chris Donnelly for his quality work on the graphics of the figures.

Declaration of interest

The authors declare no competing interests.

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