Pancreatic β cell identity requires continual repression of non–β cell programs
Giselle Domínguez Gutiérrez, … , Klaus H. Kaestner, Lori Sussel
Giselle Domínguez Gutiérrez, … , Klaus H. Kaestner, Lori Sussel
Published December 12, 2016
Citation Information: J Clin Invest. 2017;127(1):244-259. https://doi.org/10.1172/JCI88017.
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Research Article Metabolism

Pancreatic β cell identity requires continual repression of non–β cell programs

Abstract

Loss of β cell identity, the presence of polyhormonal cells, and reprogramming are emerging as important features of β cell dysfunction in patients with type 1 and type 2 diabetes. In this study, we have demonstrated that the transcription factor NKX2.2 is essential for the active maintenance of adult β cell identity as well as function. Deletion of Nkx2.2 in β cells caused rapid onset of a diabetic phenotype in mice that was attributed to loss of insulin and downregulation of many β cell functional genes. Concomitantly, NKX2.2-deficient murine β cells acquired non–β cell endocrine features, resulting in populations of completely reprogrammed cells and bihormonal cells that displayed hybrid endocrine cell morphological characteristics. Molecular analysis in mouse and human islets revealed that NKX2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of a functional, monohormonal β cell identity by directly activating critical β cell genes and actively repressing genes that specify the alternative islet endocrine cell lineages. This study demonstrates the highly volatile nature of the β cell, indicating that acquiring and sustaining β cell identity and function requires not only active maintaining of the expression of genes involved in β cell function, but also continual repression of closely related endocrine gene programs.

Authors

Giselle Domínguez Gutiérrez, Aaron S. Bender, Vincenzo Cirulli, Teresa L. Mastracci, Stephen M. Kelly, Aristotelis Tsirigos, Klaus H. Kaestner, Lori Sussel

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Figure 4

Nkx2.2ΔBeta islet cells exhibit ultrastructural alterations compatible with a disrupted secretory granule identity and morphology, accompanied by ER stress.

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Nkx2.2ΔBeta islet cells exhibit ultrastructural alterations compatible w...
(A–E) Transmitted electron microscopy (TEM) of pancreatic islets reveals a combination of insulin and either glucagon- or somatostatin-like granules in the same cell in Nkx2.2ΔBeta (ΔBeta) mice. Magenta lines outline individual β cells. (B and C) Granule identity is indicated by colored arrows: glucagon (blue), insulin (yellow), and somatostatin (green). (D) Framed insets indicate regions magnified in B (yellow-framed inset shows an insulin granule; blue-framed inset shows a glucagon granule) and C (green-framed inset shows a somatostatin granule). (E) Representative image of a β cell from Nkx2.2ΔBeta islets with severely altered secretory granules. (F) Quantification of individual granule identity in hybrid β cells from Nkx2.2ΔBeta mice (n = 93 hybrid β cells with a total of 10,533 granules counted). (G) Quantification of individual granule identity in hybrid α cells from Nkx2.2ΔBeta mice (n = 31 hybrid α cells with 3,297 total granules counted). (H–K) TEM images of single cells from control and Nkx2.2ΔBeta mice. (H) Representative image of normal-looking rough endoplasmic reticulum (RER) in control islets (arrowheads). (I and J) Islet cells from Nkx2.2ΔBeta mice show enlarged RER cisternae (red-stroked arrows) and increased free ribosomes not associated with RER (blue-stroked arrows). (K) β Cells in Nkx2.2ΔBeta mice contained large populations of insulin granules that exhibited an altered crystallization pattern (red-stroked arrows), and numerous coalescent granules (inset, arrowheads).