Identification of proliferative and mature beta-cells in the islet of Langerhans

Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential, 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 beta-cell subpopulations with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that these beta-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- beta-cells undergo compensatory proliferation, whereas Fltp-lineage+ beta-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 naive beta-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger mouse and human beta-cell maturation. Finally, we show that Fltp is not necessary for beta-cell development, proliferation, or maturation, but is required for proper glucose-stimulated insulin secretion in mature beta-cells. We conclude that 3D architecture and Wnt/PCP signaling underlie functional beta-cell heterogeneity and induce beta-cell maturation. The identification of Fltp as a biomarker for mature beta-cells establish novel molecular underpinnings of beta-cells and enable targeting of subpopulations for the regeneration of functional beta-cell mass in diabetic patients. We performed gene expression microarray analysis on 15 samples from FACS-sorted pancreatic islet cell populations. Here we provide two of these populations, flattop-positive (n=3) and flattop-negative (n=2), as part of this bigger dataset.