At birth, mammals transition from an environment that provides a continuous supply of nutrients to conditions that are characterized by periods of fasting. This change requires many physiological adaptations, including the functional maturation of pancreatic β-cells, but the mechanisms behind these adaptations have remained unclear. Now, in a new study, David Sabatini and Douglas Melton provide insight on the environmental signals that govern this process.
“Although in the lab we can produce millions of cells that highly resemble native β-cells, these stem cell-derived β-cells don’t secrete insulin as well as real β-cells in response to glucose,” expounds Douglas Melton, co-corresponding author on the study. “We therefore wanted to better understand how β-cells become functional after birth and try to mimic this transition.”
The researchers measured metabolite profiles in fetal and neonatal mouse blood. They observed that embryonic mice have higher serum amino acid and lower glucose levels than mice that are a week old and that embryonic islets secrete insulin in response to amino acids while adult islets gain responsiveness to glucose.
To understand the underlying mechanisms, the team examined the activity of the nutrient-sensing mTORC1 pathway. “In fetal β-cells the mTORC1 pathway is sensitive to amino acids, whereas in maturing β-cells the pathway becomes sensitive to glucose as well,” says Andrew Cangelosi, co-first author of the study.
The researchers observed that pluripotent stem cell-derived β-cells, just like fetal-derived β-cells, have a limited ability to activate mTORC1 in response to glucose. However, the cells could be induced to mature by exposing them to an adult or ‘adult-like’ nutrient environment. “Environmental nutrients are sensed by the mTORC1 pathway and contribute to cell maturation,” explains Sabatini.
These data could aid research in regenerative medicine. “Our work suggests that researchers can exploit nutrients and nutrient sensing to improve the functional maturation of stem cell-derived β-cells in vitro,” concludes co-first author Ronny Helman.
More work remains to be done to determine the role other nutrients and metabolites might have in regulating β-cell maturation.
Helman, A. et al. A nutrient-sensing transition at birth triggers glucose-responsive insulin secretion. Cell Metab. 31, 1004–1016 (2020)
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Kriebs, A. Understanding nutrient-sensing at birth. Nat Rev Endocrinol 16, 344 (2020). https://doi.org/10.1038/s41574-020-0373-5