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Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential1-5, thus understanding the mechanisms underlying this functional heterogeneity might allow novel regenerative approaches. Here we discovered Flattop (Fltp) as a biomarker that distinguishes proliferative from mature β-cells. Genetic lineage tracing revealed that these β-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- β-cells undergo compensatory proliferation, whereas Fltp-lineage+ β-cells account for islet cell hypertrophy commonly associated with cytotoxic stress. The expression of the Wnt/planar cell polarity (PCP) effector gene Fltp increases when naïve β-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs6-8. We show that dispersed early postnatal islet cells, insulinoma cells and human β-cells all have the intrinsic ability to form polarized pseudo-islets in 3D cultures. Compaction and polarization correlates with the induction of maturation markers and can be enhanced by Wnt/PCP pathway activation. Finally, we show that Fltp is not only a marker for mature β-cells, but is also functionally required for proper insulin secretion in mouse and human. We conclude that planar cell polarity and 3D architecture underlie functional β-cell heterogeneity and report that Fltp is a biomarker that separates proliferative from mature β-cells. These findings establish novel molecular underpinnings of β-cells and enable targeting of subpopulations for the regeneration of functional β-cell mass in diabetic patients. We performed gene expression microarray analysis on two FACS-sorted pancreatic islet cell populations: flattop-positive and flattop-negative.

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