Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression

A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between alpha-cell and beta-cell clocks. We performed a parallel analysis of the molecular properties of alpha-cell and beta-cell oscillators using a mouse model expressing three reporter genes: one labeling alpha cells, one specific for beta cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the alpha-cell and beta-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that alpha-cellular and beta-cellular clocks are oscillating with distinct phases in vivo and in vitro. Diurnal transcriptome analysis in separated alpha and beta cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian alpha-cell and beta-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.