BACH2 inhibition reverses β cell failure in type 2 diabetes models

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

doi:10.1172/jci153876

Cited by 54 publications

(57 citation statements)

References 60 publications

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“…The molecular mechanisms driving cellular reprogramming remain to be elucidated. Our findings strengthen the notion that FOXO1 participates in intestinal secretory lineage trans-differentiation, similar to its role in pancreatic β-cells (Son et al, 2021; Talchai et al, 2012b). Single cell RNA-seq of FoxO1-ablated cells also shows the reemergence of HOXP- and Olfm4-positive cells along with β-like cells, suggesting that committed secretory cells can revert to a stem- or fetal-like stage as a path to differentiate into β-like cells.…”

Section: Discussionsupporting

confidence: 88%

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Wang

Kuo

et al. 2022

Preprint

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Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing β-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgfβ that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

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Section: Discussionsupporting

confidence: 88%

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Wang

Kuo

et al. 2022

Preprint

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“…Outside of cancer, MR-based predictions have been validated in disease as different as Parkinson’s (Brichta et al, 2015), ALS (Mishra et al, 2020), alcohol dependency (Repunte-Canonigo et al, 2015), and Type II diabetes (Son et al, 2021), suggesting direct OncoLoop applicability to such contexts, as long as appropriate drug-perturbation data were available. Indeed, while human translation of drugs validated in a GEMM or PDX context has been reasonably effective in cancer, mouse models have largely failed to recapitulate the effect of drugs on human disease.…”

Section: Discussionmentioning

confidence: 99%

OncoLoop: A network-based precision cancer medicine framework

Vasciaveo

Zou

Almeida

et al. 2022

Preprint

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Prioritizing cancer treatment at the individual patient level remains challenging and performing co-clinical studies using patient-derived models in real-time is often unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework to predict drug sensitivity in both a human tumor and its highest-fidelity (cognate) model(s), for contextual in vivo validation, by leveraging perturbational profiles of clinically-relevant oncology drugs. As proof-of-concept, we applied OncoLoop to prostate cancer using a series of genetically engineered mouse models (GEMMs) that capture the broad spectrum of disease states, including metastatic, castration-resistant, and neuroendocrine prostate cancer. Interrogation of published cohorts revealed that most patients were represented by at least one cognate GEMM-derived tumor (GEMM-DT), based on Master Regulator (MR) conservation analysis. Drugs recurrently predicted to invert MR protein activity in patients and their cognate GEMM-DTs were successfully validated, including in two cognate allografts and one patient derived xenograft (PDX). OncoLoop is highly generalizable and can be extended to other cancers and other pathologies.

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“…The molecular basis of dedifferentiation remains to be fully elucidated [ 146 ], however, it has been shown that FoxO1 migrates to the nucleus in beta cells prior to dedifferentiation, maintaining the MODY network, including HNF1A and HNF4A [ 147 ]. The molecular basis of MODY-related genes causing diabetes and their involvement in dedifferentiation have rarely been investigated because of the difficulties in obtaining pancreatic tissue or beta cells from patients with MODY.…”

Section: Pancreas and Hnf1amentioning

confidence: 99%

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

Miyachi

Miyazawa

Ogawa

2022

IJMS

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Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells.

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BACH2 inhibition reverses β cell failure in type 2 diabetes models

Abstract: AC is founder, SAB member, and shareholder of DarwinHealth Inc., which has licensed the VIPER and metaVIPER software. DA is founder, director, and chairman of the SAB of Forkhead Biotherapeutics, corp. Columbia University is also a shareholder of DarwinHealth Inc.

Cited by 54 publications

References 60 publications

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

OncoLoop: A network-based precision cancer medicine framework

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

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