Impact of the circadian clock on α- and β-pancreatic islet cell gene transcription and function upon β-cell failure and regeneration

Circadian oscillation of biological processes has been described in light-sensitive organisms from bacteria to human beings, reflecting the existence of underlying intrinsic clocks. Our recent work suggests that α- and β-cellular clocks are oscillating with distinct phases in vivo and in vitro. These cellular oscillators impact critically on the temporal profiles of insulin and glucagon secretion, and on the transcriptional patterns of key functional genes in the islet cells. Parallel analysis of the molecular properties of α- and β-cell oscillators was conducted by establishing a mouse model expressing three reporters: one diagnostic for α-cells, one specific for β-cells, and third monitoring circadian gene expression. Rodent β-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. A model for studying β-cell regeneration following 70-80% ablation, proposed and characterized by the Dor’s lab, in combination with the triple reporter mouse strain developed by the Dibner’s lab, represents a unique and powerful tool for characterizing circadian oscillator upon hyperglycemic conditions, and during β-cell regeneration. Crossing these mice to genetic clock-deficient mouse strain will allow unraveling the impact of functional circadian clock on the regenerative capacity of β-cells. In vivo studies in genetic rodent models will be translated to the human model, employing human islet isolated from type 2 diabetic donors, synchronized in vitro. Molecular and functional analysis of the islet cellular clockwork upon type 2 diabetes conditions and during β-cell regeneration will be of high scientific importance and clinical relevance.

Participants
  • UNIGE Division of Endocrinology, Diabetes, Hypertension and Nutrition/Department of the Specialties of Medicine/Department of Cell Physiology and Metabolism/Faculty of Medicine
    • Dr. Charna Dibner
    • Dr. Volodymyr Petrenko
  • HUJI Department of Developmental Biology and Cancer Research/The Institute for Medical Research Israel-Canada/Hadassah Medical School
    • Prof. Yuval Dor
    • Dr. Miri Stolovich-Rain