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BACH2 inhibition reverses β cell failure in type 2 diabetes models
Jinsook Son, … , Domenico Accili, Andrea Califano
Jinsook Son, … , Domenico Accili, Andrea Califano
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e153876. https://doi.org/10.1172/JCI153876.
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Research Article Endocrinology Metabolism Article has an altmetric score of 10

BACH2 inhibition reverses β cell failure in type 2 diabetes models

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Abstract

Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet–specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.

Authors

Jinsook Son, Hongxu Ding, Thomas B. Farb, Alexander M. Efanov, Jiajun Sun, Julie L. Gore, Samreen K. Syed, Zhigang Lei, Qidi Wang, Domenico Accili, Andrea Califano

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Figure 3

T2D-enriched subclusters in human islets.

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T2D-enriched subclusters in human islets.
(A) Bar plots presenting the p...
(A) Bar plots presenting the percentage of ND or T2D cells in each subcluster. A dashed line represents the proportion of cells from ND or T2D islets analyzed by scRNA-Seq. P values were derived from Fisher’s exact test. (B) Single cells from human ND and T2D islets were projected onto 2D t-SNE space based on protein activity inferred from islet-specific regulatory networks. ND cells are shown in gray and T2D cells are shown in red as background. T2D cells in T2D-enriched clusters, MI+2 (T2D-β-like) and MI–4 and MI–5 (both T2D-α-like), were color coded as indicated.

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