Thomas B. Farb

Eli Lilly (United States)

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Krister Bokvist

Sanofi (Germany)

James Ficorilli

Eli Lilly (United States)

Alexander M. Efanov

Eli Lilly (United States)

Samreen K. Syed

Eli Lilly (United States)

Raghavendra G. Mirmira

Indiana University – Purdue University Indianapolis

Sarah A. Tersey

Indiana University – Purdue University Indianapolis

David G. Barrett

Eli Lilly (United States)

Francis S. Willard

Eli Lilly (United States)

Martin Brenner

University of Vienna

Kara S. Orr

Indiana University – Purdue University Indianapolis

Cooperative Institutions

Fondazione Umberto Di Mario

125

Eli Lilly (United States)

Indiana University – Purdue University Indianapolis

Indiana University School of Medicine

Indianapolis Zoo

Monash University

University of Copenhagen

Indiana University

Weatherford College

Eli Lilly (Spain)

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BACH2 inhibition reverses β cell failure in type 2 diabetes models

Journal of Clinical Investigation (2021)

Jinsook Son Hongxu Ding Thomas B. Farb Alexander M. Efanov Jiajun Sun

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.

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10.1172/jci153876

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Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress

Free Radical Biology and Medicine (2016)

Katia Lejnev Lena Khomsky Krister Bokvist Shani Mistriel-Zerbib Tahel Naveh

10.1016/j.freeradbiomed.2016.09.011

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Ectonucleotidase NTPDase3 is abundant in pancreatic β-cells and regulates glucose-induced insulin secretion

AJP Endocrinology and Metabolism (2013)

Samreen K. Syed Audra L. Kauffman Lisa S. Beavers James T. Alston Thomas B. Farb

Extracellular ATP released from pancreatic β-cells acts as a potent insulinotropic agent through activation of P2 purinergic receptors. Ectonucleotidases, a family of membrane-bound nucleotide-metabolizing enzymes, regulate extracellular ATP levels by degrading ATP and related nucleotides. Ectonucleotidase activity affects the relative proportion of ATP and its metabolites, which in turn will impact the level of purinergic receptor stimulation exerted by extracellular ATP. Therefore, we investigated the expression and role of ectonucleotidases in pancreatic β-cells. Of the ectonucleotidases studied, only ENTPD3 (gene encoding the NTPDase3 enzyme) mRNA was detected at fairly abundant levels in human and mouse pancreatic islets as well as in insulin-secreting MIN6 cells. ARL67156, a selective ectonucleotidase inhibitor, blocked degradation of extracellular ATP that was added to MIN6 cells. The compound also decreased degradation of endogenous ATP released from cells. Measurements of insulin secretion in MIN6 cells as well as in mouse and human pancreatic islets demonstrated that ARL67156 potentiated glucose-dependent insulin secretion. Downregulation of NTPDase3 expression in MIN6 cells with the specific siRNA replicated the effects of ARL67156 on extracellular ATP hydrolysis and insulin secretion. Our results demonstrate that NTPDase3 is the major ectonucleotidase in pancreatic β-cells in multiple species and that it modulates insulin secretion by controlling activation of purinergic receptors.

Pancreatic Islets

P2Y receptor

Purinergic Signalling

10.1152/ajpendo.00328.2013

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Citations (33)