Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in β-Cell Maturation Process

Mar 4, 2018Diabetes

Development of the Pancreatic Islet's Internal Clock Helps Beta Cells Mature After Birth

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Abstract

The islet circadian clock emerges during the early postnatal period and is essential for diurnal insulin secretion.

Circadian clock function in pancreatic islets is linked to the maturation of β-cells.
The establishment of global behavioral circadian rhythms influences the function of the islet circadian clock.
Increased expression of the circadian transcription factor BMAL1 is observed during islet cell maturation.
Deletion of BMAL1 disrupts the normal development of glucose-stimulated insulin secretion.
The postnatal development of the islet circadian clock may play a crucial role in β-cell maturation.

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Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown. To address this, we studied wild-type Sprague-Dawley as well asluciferase transgenic (:LUC) rats to determine circadian clock function, clock protein expression, and diurnal insulin secretion during islet development and maturation process. We additionally studied β-cell-specific-deficient mice to elucidate a potential role of this key circadian transcription factor in β-cell functional and transcriptional maturation. We report that emergence of the islet circadian clock) occurs during the early postnatal period,) depends on the establishment of global behavioral circadian rhythms, and) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose-stimulated insulin secretion and the associated transcriptional network. Postnatal development of the islet circadian clock contributes to early-life β-cell maturation and should be considered for optimal design of future β-cell replacement strategies in diabetes. Period1Per1Bmal1 1 2 3

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Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in β-Cell Maturation Process

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