Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review)

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Abstract

Type 2 diabetes mellitus (T2DM) is a major chronic disease that is characterized by pancreatic β-cell dysfunction and insulin resistance. Autophagy is a highly conserved intracellular recycling pathway and is involved in regulating intracellular homeostasis. Transcription factor Forkhead box O1 (FoxO1) also regulates fundamental cellular processes, including cell differentiation, metabolism and apoptosis, and proliferation to cellular stress. Increasing evidence suggest that autophagy and FoxO1 are involved in the pathogenesis of T2DM, including β-cell viability, apoptosis, insulin secretion and peripheral insulin resistance. Recent studies have demonstrated that FoxO1 improves insulin resistance by regulating target tissue autophagy. The present review summarizes current literature on the role of autophagy and FoxO1 in T2DM. The participation of FoxO1 in the development and occurrence of T2DM via autophagy is also discussed.

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Pathophysiology of Type 2 Diabetes Mellitus

Unai Galicia-Garcia, Asier Benito-Vicente, Shifa Jebari … (2020)

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

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Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.

Ying Zhao, Jing Yang, Wenjuan Liao … (2010)

Autophagy is characterized by the sequestration of bulk cytoplasm, including damaged proteins and organelles, and delivery of the cargo to lysosomes for degradation. Although the autophagic pathway is also linked to tumour suppression activity, the mechanism is not yet clear. Here we report that cytosolic FoxO1, a forkhead O family protein, is a mediator of autophagy. Endogenous FoxO1 was required for autophagy in human cancer cell lines in response to oxidative stress or serum starvation, but this process was independent of the transcriptional activity of FoxO1. In response to stress, FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD(+)-dependent histone deacetylase, and the acetylated FoxO1 bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death. This FoxO1-modulated cell death is associated with tumour suppressor activity in human colon tumours and a xenograft mouse model. Our finding links the anti-neoplastic activity of FoxO1 and the process of autophagy.

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Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.

Ling Yang, Ping Li, Suneng Fu … (2010)

Autophagy is a homeostatic process involved in the bulk degradation of cytoplasmic components, including damaged organelles and proteins. In both genetic and dietary models of obesity, we observed a severe downregulation of autophagy, particularly in Atg7 expression levels in liver. Suppression of Atg7 both in vitro and in vivo resulted in defective insulin signaling and elevated ER stress. In contrast, restoration of the Atg7 expression in liver resulted in dampened ER stress, enhanced hepatic insulin action, and systemic glucose tolerance in obese mice. The beneficial action of Atg7 restoration in obese mice could be completely prevented by blocking a downstream mediator, Atg5, supporting its dependence on autophagy in regulating insulin action. Our data demonstrate that autophagy is an important regulator of organelle function and insulin signaling and that loss of autophagy is a critical component of defective insulin action seen in obesity. Copyright 2010 Elsevier Inc. All rights reserved.

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Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): July 2021

Publication date (Electronic): 02 May 2021

Publication date PMC-release: 02 May 2021

Volume: 22

Issue: 1

Electronic Location Identifier: 707

Affiliations

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China

Author notes

Correspondence to: Professor Yanbo Li, Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, 23 You Zheng Street, Harbin, Heilongjiang 150001, P.R. China liyanbo34567@ 123456163.com

Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; Atg, autophagy-related gene; ERS, endoplasmic reticulum stress; FoxO1, Forkhead box O1; GLP-1, glucagon-like peptide-1; G6Pase, glucose-6-phosphatase; miR, microRNA; mTOR, mammalian target of rapamycin; Pdx1, pancreatic and duodenal homeobox 1; PEPCK, phosphoenolpyruvate carboxykinase; ROS, reactive oxygen species; SIRT1, sirtuin 1; T2DM, type 2 diabetes mellitus; 3-MA, 3-methyladenine

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Publisher ID: ETM-0-0-10139

DOI: 10.3892/etm.2021.10139

PMC ID: 8120662

PubMed ID: 34007316

SO-VID: 640a3e0d-289f-4340-a315-0021d4ac8c06

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 14 September 2020

Date accepted : 09 February 2021

Funding

Funding: The present review was supported by the National Natural Science Foundation of China (grant no. 81770820).

Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review)

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Karger: Nutrition and Dietetics

Most cited references 78

Pathophysiology of Type 2 Diabetes Mellitus

Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity.

Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.

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