A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

Area of Science:

• Metabolic adaptation in neonates
• Pancreatic beta cell function
• Nutrient sensing pathways

Background:

• The transition from in utero nutrient supply to postnatal feeding necessitates significant metabolic adjustments in newborns.
• Pancreatic beta cells are vital for metabolic homeostasis, but their adaptation to the neonatal nutritional environment is poorly understood.

Purpose of the Study:

• To investigate how pancreatic beta cells adjust their function in response to the drastic nutritional changes at birth.
• To identify the molecular mechanisms, particularly nutrient-sensing pathways, involved in neonatal beta cell adaptation.

Main Methods:

• Correlating beta cell function with the changing nutritional environment post-birth.
• Investigating the role of the mTORC1 pathway in mediating the shift in nutrient sensitivity.
• Experimenting with disrupting and manipulating mTORC1 nutrient sensitivity in mature and stem cell-derived beta cells.

Main Results:

• Beta cell insulin secretion shifts from amino acid-stimulated to glucose-stimulated post-birth.
• The mTORC1 pathway's nutrient sensitivity transitions, leading to intermittent activity and mediating this functional shift.
• Disrupting mTORC1 nutrient sensitivity in mature beta cells caused a reversion to an immature secretory state.
• Enhancing mTORC1 nutrient sensitivity in stem cell-derived beta cells in vitro significantly improved glucose-responsive insulin secretion.

Conclusions:

• Nutrient availability dynamically regulates pancreatic beta cell function through the mTORC1 pathway.
• This mTORC1-mediated adaptation is essential for enabling appropriate metabolic responses in newborns.
• Targeting mTORC1 nutrient sensitivity holds potential for improving beta cell function, particularly in regenerative medicine applications.