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Wang L, Yu J, Zhou Q, et al. TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver. Cell Metab. 2021;34(1):158-170.e5doi: 10.1016/j.cmet.2021.11.013.
Wang, L., Yu, J., Zhou, Q., Wang, X., Mukhanova, M., Du, W., Sun, L., Pajvani, U. B., & Accili, D. (2022). TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver. Cell metabolism, 34(1), 158-170.e5. https://doi.org/10.1016/j.cmet.2021.11.013
Wang, Liheng, et al. "TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver." Cell metabolism vol. 34,1 (2022): 158-170.e5. doi: https://doi.org/10.1016/j.cmet.2021.11.013
Wang L, Yu J, Zhou Q, Wang X, Mukhanova M, Du W, Sun L, Pajvani UB, Accili D. TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver. Cell Metab. 2022 Jan 04;34(1):158-170.e5. doi: 10.1016/j.cmet.2021.11.013. Epub 2021 Dec 15. PMID: 34914893; PMCID: PMC8732315.
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Cell Metab. 2022 Jan 04;34(1):158-170.e5. doi: 10.1016/j.cmet.2021.11.013. Epub 2021 Dec 15.

TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver.

Cell metabolism

Liheng Wang, Junjie Yu, Qiuzhong Zhou, Xiaobo Wang, Maria Mukhanova, Wen Du, Lei Sun, Utpal B Pajvani, Domenico Accili

Affiliations

  1. Department of Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Electronic address: [email protected].
  2. Department of Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
  3. Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
  4. Department of Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
  5. Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
  6. Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
  7. Department of Medicine, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Electronic address: [email protected].

PMID: 34914893 PMCID: PMC8732315 DOI: 10.1016/j.cmet.2021.11.013

Abstract

Increased hepatic glucose production (HGP) contributes to hyperglycemia in type 2 diabetes. Hormonal regulation of this process is primarily, but not exclusively, mediated by the AKT-FoxO1 pathway. Here, we show that cAMP and dexamethasone regulate the high-mobility group superfamily member TOX4 to mediate HGP, independent of the insulin receptor/FoxO1 pathway. TOX4 inhibition decreases glucose production in primary hepatocytes and liver and increases glucose tolerance. Combined genetic ablation of TOX4 and FoxO1 in liver has additive effects on glucose tolerance and gluconeogenesis. Moreover, TOX4 ablation fails to reverse the metabolic derangement brought by insulin receptor knockout. TOX4 expression is increased in livers of patients with steatosis and diabetes and in diet-induced obese and db/db mice. In the latter two murine models, knockdown Tox4 decreases glycemia and improves glucose tolerance. We conclude that TOX4 is an insulin receptor-independent regulator of HGP and a candidate contributor to the pathophysiology of diabetes.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: TOX2, transcription regulation, HGP, type 2 diabetes

Conflict of interest statement

Declaration of interests The authors declare no competing interests. D.A. is a founder, director, and chair of the SAB of Forkhead Biotherapeutics, Corp.

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