Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Insulins | Review

Crosstalk between autophagy and insulin resistance: evidence from different tissues

Authors: Asie Sadeghi, Maryam Niknam, Mohammad Amin Momeni-Moghaddam, Maryam Shabani, Hamid Aria, Alireza Bastin, Maryam Teimouri, Reza Meshkani, Hamed Akbari

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.
Literature
1.
Brown JC, Harhay MO, Harhay MN. The value of anthropometric measures in nutrition and metabolism: comment on anthropometrically predicted visceral adipose tissue and blood-based biomarkers: a cross-sectional analysis. Nutr Metab Insights. 2019;12:1178638819831712.PubMedCentral
2.
Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):6275.PubMedCentral
3.
Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133–223.PubMedCentral
4.
Rondinone CM, Wang L-M, Lonnroth P, Wesslau C, Pierce JH, Smith U. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci. 1997;94(8):4171–5.PubMedCentral
5.
Kim Y-B, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Investig. 1999;104(6):733–41.PubMedCentral
6.
Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol. 2010;8(8): e1000465.PubMedCentral
7.
Se S, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.
8.
Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21(12):1443–55.
9.
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373–84.PubMed
10.
Sah SP, Singh B, Choudhary S, Kumar A. Animal models of insulin resistance: a review. Pharmacol Rep. 2016;68(6):1165–77.
11.
Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab. 2012;23(3):142–53.PubMedCentral
12.
Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab. 2010;21(10):589–98.PubMedCentral
13.
Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440(7086):944–8.PubMed
14.
Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal. 2005;7(7–8):1040–52.
15.
Hurrle S, Hsu WH. The etiology of oxidative stress in insulin resistance. Biomed J. 2017;40(5):257–62.PubMedCentral
16.
Han J, Back SH, Hur J, Lin Y-H, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15(5):481–90.PubMedCentral
17.
Boden G, Duan X, Homko C, Molina EJ, Song W, Perez O, et al. Increase in endoplasmic reticulum stress–related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes. 2008;57(9):2438–44.PubMedCentral
18.
Lane JD, Gallagher LE, Chan EY. Early signalling events of autophagy. Essays Biochem. 2013;55:1–15.
19.
Galluzzi L, Green DR. Autophagy-independent functions of the autophagy machinery. Cell. 2019;177(7):1682–99.PubMedCentral
20.
Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014;24(1):9–23.
21.
Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007;9(10):1102–9.
22.
Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017;61(6):585–96.PubMedCentral
23.
Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32(1):2–11.PubMedPubMedCentral
24.
Cao W, Li J, Yang K, Cao D. An overview of autophagy: mechanism, regulation and research progress. Bull Cancer. 2021;108:304.
25.
Melia TJ, Lystad AH, Simonsen A. Autophagosome biogenesis: from membrane growth to closure. J Cell Biol. 2020;219(6).
26.
27.
Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12(9):823–30.PubMedCentral
28.
Xie W, Zhou J. Aberrant regulation of autophagy in mammalian diseases. Biol Let. 2018;14(1):20170540.
29.
RostamiRad A, Ebrahimi SSS, Sadeghi A, Taghikhani M, Meshkani R. Palmitate-induced impairment of autophagy turnover leads to increased apoptosis and inflammation in peripheral blood mononuclear cells. Immunobiology. 2018;223(3):269–78.
30.
Alizadeh S, Mazloom H, Sadeghi A, Emamgholipour S, Golestani A, Noorbakhsh F, et al. Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients. J Physiol Biochem. 2018;74(3):369–79.
31.
Kovsan J, Blüher M, Tarnovscki T, Klöting N, Kirshtein B, Madar L, et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab. 2011;96(2):E268–77.
32.
Öst A, Svensson K, Ruishalme I, Brännmark C, Franck N, Krook H, et al. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med. 2010;16(7):235–46.PubMedCentral
33.
Clemente-Postigo M, Tinahones A, El Bekay R, Malagón MM, Tinahones FJ. The role of autophagy in white adipose tissue function: implications for metabolic health. Metabolites. 2020;10(5):179.PubMedCentral
34.
Frendo-Cumbo S, Tokarz VL, Bilan PJ, Brumell JH, Klip A. Communication between autophagy and insulin action: at the crux of insulin action-insulin resistance? Front Cell Dev Biol. 2021;9.
35.
Soussi H, Clément K, Dugail I. Adipose tissue autophagy status in obesity: expression and flux—two faces of the picture. Autophagy. 2016;12(3):588–9.
36.
Kovsan J, Blüher M, Tarnovscki T, Klöting N, Kirshtein B, Madar L, et al. Altered autophagy in human adipose tissues in obesity. Endocr Rev. 2010;31(6):945–6.
37.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.
38.
Jansen H, Van Essen P, Koenen T, Joosten L, Netea M, Tack C, et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology. 2012;153(12):5866–74.
39.
Codogno P, Meijer AJ. Autophagy: a potential link between obesity and insulin resistance. Cell Metab. 2010;11(6):449–51.
40.
Jung CH, Jun CB, Ro S-H, Kim Y-M, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992–2003.PubMedCentral
41.
Hemmings BA, Restuccia DF. Pi3k-pkb/akt pathway. Cold Spring Harb Perspect Biol. 2012;4(9): a011189.PubMedCentral
42.
Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK, et al. Autophagy regulates adipose mass and differentiation in mice. J Clin Investig. 2009;119(11):3329–39.PubMedCentral
43.
Zhang Y, Goldman S, Baerga R, Zhao Y, Komatsu M, Jin S. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci. 2009;106(47):19860–5.PubMedCentral
44.
Cai J, Pires KM, Ferhat M, Chaurasia B, Buffolo MA, Smalling R, et al. Autophagy ablation in adipocytes induces insulin resistance and reveals roles for lipid peroxide and Nrf2 signaling in adipose-liver crosstalk. Cell Rep. 2018;25(7):1708–17.PubMedCentral
45.
Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des. 2008;14(12):1225–30.
46.
Kang Y-H, Cho M-H, Kim J-Y, Kwon M-S, Peak J-J, Kang S-W, et al. Impaired macrophage autophagy induces systemic insulin resistance in obesity. Oncotarget. 2016;7(24):35577.PubMedCentral
47.
Liu K, Zhao E, Ilyas G, Lalazar G, Lin Y, Haseeb M, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy. 2015;11(2):271–84.PubMedCentral
48.
Lavallard VJ, Meijer AJ, Codogno P, Gual P. Autophagy, signaling and obesity. Pharmacol Res. 2012;66(6):513–25.
49.
Zhang Y, Zeng X, Jin S. Autophagy in adipose tissue biology. Pharmacol Res. 2012;66(6):505–12.
50.
Zhang C, He Y, Okutsu M, Ong LC, Jin Y, Zheng L, et al. Autophagy is involved in adipogenic differentiation by repressing proteasome-dependent PPARγ2 degradation. Am J Physiol-Endocrinol Metab. 2013;305(4):E530–9.PubMedCentral
51.
Baerga R, Zhang Y, Chen P-H, Goldman S, Jin SV. Targeted deletion of autophagy-related 5 (atg5) impairs adipogenesis in a cellular model and in mice. Autophagy. 2009;5(8):1118–30.
52.
Dunlop EA, Tee AR. The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. Biochem Soc Trans. 2013;41(4):939–43.
53.
Zhang X, Wu D, Wang C, Luo Y, Ding X, Yang X, et al. Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism. Autophagy. 2020;16(9):1668–82.
54.
Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim Y-N, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19(1):83–92.
55.
Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137: 111315.
56.
McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 2018;27(2):439–49.PubMedCentral
57.
Pua HH, Guo J, Komatsu M, He Y-W. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol. 2009;182(7):4046–55.
58.
Ashrafi G, Schwarz T. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20(1):31–42.PubMed
59.
Tsilingiris D, Tzeravini E, Koliaki C, Dalamaga M, Kokkinos A. The role of mitochondrial adaptation and metabolic flexibility in the pathophysiology of obesity and insulin resistance: an updated overview. Curr Obes Rep. 2021;10(3):191–213.
60.
Maixner N, Kovsan J, Harman-Boehm I, Blüher M, Bashan N, Rudich A. Autophagy in adipose tissue. Obes Facts. 2012;5(5):710–21.
61.
Yin J-J, Li Y-B, Wang Y, Liu G-D, Wang J, Zhu X-O, et al. The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death. Autophagy. 2012;8(2):158–64.
62.
Li H, Zhou B, Xu L, Liu J, Zang W, Wu S, et al. The reciprocal interaction between autophagic dysfunction and ER stress in adipose insulin resistance. Cell Cycle. 2014;13(4):565–79.
63.
Behl T, Sehgal A, Bala R, Chadha S. Understanding the molecular mechanisms and role of autophagy in obesity. Mol Biol Rep. 2021;48:2881.
64.
Zhou L, Zhang J, Fang Q, Liu M, Liu X, Jia W, et al. Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance. Mol Pharmacol. 2009;76(3):596–603.PubMedCentral
65.
Zhang N, Cao M-M, Liu H, Xie G-Y, Li Y-B. Autophagy regulates insulin resistance following endoplasmic reticulum stress in diabetes. J Physiol Biochem. 2015;71(2):319–27.
66.
Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900–17.PubMedCentral
67.
Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.PubMed
68.
Ferhat M, Funai K, Boudina S. Autophagy in adipose tissue physiology and pathophysiology. Antioxid Redox Signal. 2019;31(6):487–501.PubMedCentral
69.
Lim Y-M, Lim H, Hur KY, Quan W, Lee H-Y, Cheon H, et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun. 2014;5(1):1–14.
70.
Nakahira K, Haspel JA, Rathinam VA, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.
71.
Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, et al. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J Biol Chem. 2011;286(11):9587–97.PubMedCentral
72.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.PubMed
73.
Jung HS, Lee MS. Role of autophagy in diabetes and mitochondria. Ann N Y Acad Sci. 2010;1201(1):79–83.
74.
Gan L, Liu Z, Luo D, Ren Q, Wu H, Li C, et al. Reduced endoplasmic reticulum stress-mediated autophagy is required for leptin alleviating inflammation in adipose tissue. Front Immunol. 2017;8:1507.PubMedCentral
75.
Javaid HMA, Ko E, Joo EJ, Kwon SH, Park J-H, Shin S, et al. TNFα-induced NLRP3 inflammasome mediates adipocyte dysfunction and activates macrophages through adipocyte-derived lipocalin 2. Metabolism. 2023;142: 155527.
76.
Cambi MPC, Baretta GAP, Magro DDO, Boguszewski CL, Ribeiro IB, Jirapinyo P, et al. Multidisciplinary approach for weight regain—how to manage this challenging condition: an expert review. Obes Surg. 2021;31(3):1290–303.
77.
Zhang Y, Sowers JR, Ren J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol. 2018;14(6):356–76.
78.
Alrushud AS, Rushton AB, Kanavaki AM, Greig CA. Effect of physical activity and dietary restriction interventions on weight loss and the musculoskeletal function of overweight and obese older adults with knee osteoarthritis: a systematic review and mixed method data synthesis. BMJ Open. 2017;7(6): e014537.PubMedCentral
79.
Webb VL, Wadden TA. Intensive lifestyle intervention for obesity: principles, practices, and results. Gastroenterology. 2017;152(7):1752–64.
80.
Halling JF, Pilegaard H. Autophagy-dependent beneficial effects of exercise. Cold Spring Harb Perspect Med. 2017;7(8): a029777.PubMedCentral
81.
Kim KH, Lee M-S. Autophagy—a key player in cellular and body metabolism. Nat Rev Endocrinol. 2014;10(6):322–37.
82.
He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481(7382):511–5.PubMedCentral
83.
Han X, Turdi S, Hu N, Guo R, Zhang Y, Ren J. Influence of long-term caloric restriction on myocardial and cardiomyocyte contractile function and autophagy in mice. J Nutr Biochem. 2012;23(12):1592–9.PubMedCentral
84.
Jiang Y, Huang W, Wang J, Xu Z, He J, Lin X, et al. Metformin plays a dual role in MIN6 pancreatic β cell function through AMPK-dependent autophagy. Int J Biol Sci. 2014;10(3):268.PubMedCentral
85.
Hussain Z, Khan JA. Food intake regulation by leptin: Mechanisms mediating gluconeogenesis and energy expenditure. Asian Pac J Trop Med. 2017;10(10):940–4.
86.
Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, et al. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes. 2015;64(1):36–48.PubMed
87.
Sun F, Chai S, Li L, Yu K, Yang Z, Wu S, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res. 2015;2015.
88.
Tomlinson B, Hu M, Zhang Y, Chan P, Liu Z-M. Investigational glucagon-like peptide-1 agonists for the treatment of obesity. Expert Opin Investig Drugs. 2016;25(10):1167–79.
89.
Nowrouzi-Sohrabi P, Rezaei S, Jalali M, Ashourpour M, Ahmadipour A, Keshavarz P, et al. The effects of glucagon-like peptide-1 receptor agonists on glycemic control and anthropometric profiles among diabetic patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Eur J Pharmacol. 2021;893: 173823.
90.
Courtney H, Nayar R, Rajeswaran C, Jandhyala R. Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists. Diabetes Metab Syndr Obes Targets Ther. 2017;10:79.
91.
Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng C-P, et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017;26(3):547–57.PubMedCentral
92.
Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 2017;26(3):539–46.PubMedCentral
93.
Yamamoto S, Kuramoto K, Wang N, Situ X, Priyadarshini M, Zhang W, et al. Autophagy differentially regulates insulin production and insulin sensitivity. Cell Rep. 2018;23(11):3286–99.PubMedCentral
94.
Kim O-K, Jun W, Lee J. Mechanism of ER stress and inflammation for hepatic insulin resistance in obesity. Ann Nutr Metab. 2015;67(4):218–27.
95.
Khambu B, Yan S, Huda N, Liu G, Yin X-M, editors. Homeostatic role of autophagy in hepatocytes. Seminars in liver disease; 2018: Thieme Medical Publishers.
96.
Forbes JM. The physiological deadlock between AMPK and gluconeogenesis: SOGA, a novel protein, may provide the key. Am J Pathol. 2010;177(4):1600–2.PubMedCentral
97.
Codogno P, Meijer AJ. Autophagy in the liver. J Hepatol. 2013;59(2):389–91.
98.
99.
Karsli-Uzunbas G, Guo JY, Price S, Teng X, Laddha SV, Khor S, et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 2014;4(8):914–27.PubMedCentral
100.
Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11(6):467–78.PubMedCentral
101.
Liu H-Y, Han J, Cao SY, Hong T, Zhuo D, Shi J, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284(45):31484–92.PubMedCentral
102.
Ezaki J, Matsumoto N, Takeda-Ezaki M, Komatsu M, Takahashi K, Hiraoka Y, et al. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy. 2011;7(7):727–36.PubMedCentral
103.
den Hartigh LJ, Goodspeed L, Wang SA, Kenerson HL, Omer M, O’Brien KD, et al. Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat. Exp Physiol. 2018;103(11):1469–80.
104.
Cruces-Sande M, Arcones AC, Vila-Bedmar R, Val-Blasco A, Sharabi K, Díaz-Rodríguez D, et al. Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting. FASEB J. 2020;34(1):399–409.
105.
Jiang S, Young JL, Wang K, Qian Y, Cai L. Diabetic-induced alterations in hepatic glucose and lipid metabolism: the role of type 1 and type 2 diabetes mellitus. Mol Med Rep. 2020;22(2):603–11.PubMedCentral
106.
Ke P-Y. Diverse functions of autophagy in liver physiology and liver diseases. Int J Mol Sci. 2019;20(2):300.PubMedCentral
107.
Kanasaki K, Kawakita E, Koya D. Relevance of autophagy induction by gastrointestinal hormones: focus on the incretin-based drug target and glucagon. Front Pharmacol. 2019;10:476.PubMedCentral
108.
Galsgaard KD, Lee J, Hubbard B, Zhang X-M, Cline G, Nasiri A, et al., editors. Glucagon promotes hepatic autophagy by AMPK-mediated mTORC1 inhibition. Diabetologia; 2020: Springer One New York Plaza, Suite 4600, New York, NY, United States.
109.
de Toro-Martín J, Fernández-Marcelo T, González-Rodríguez Á, Escrivá F, Valverde ÁM, Álvarez C, et al. Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats. Sci Rep. 2020;10(1):1–14.
110.
Han A, Zhang YN, Boehringer AS, Montes V, Andre MP, Erdman JW Jr, et al. Assessment of hepatic steatosis in nonalcoholic fatty liver disease by using quantitative US. Radiology. 2020;295(1):106–13.
111.
Yu J, Marsh S, Hu J, Feng W, Wu C. The pathogenesis of nonalcoholic fatty liver disease: interplay between diet, gut microbiota, and genetic background. Gastroenterol Res Pract. 2016;2016.
112.
Nassir F, Rector RS, Hammoud GM, Ibdah JA. Pathogenesis and prevention of hepatic steatosis. Gastroenterol Hepatol. 2015;11(3):167.
113.
Utzschneider KM, Kahn SE. The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2006;91(12):4753–61.
114.
Allaire M, Rautou P-E, Codogno P, Lotersztajn S. Autophagy in liver diseases: time for translation? J Hepatol. 2019;70(5):985–98.
115.
Wang K. Molecular mechanism of hepatic steatosis: pathophysiological role of autophagy. Expert Rev Mol Med. 2016;18.
116.
Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol. 2021;13(1):6.PubMedCentral
117.
Grefhorst A, van de Peppel IP, Larsen LE, Jonker JW, Holleboom AG. The role of lipophagy in the development and treatment of non-alcoholic fatty liver disease. Front Endocrinol. 2021:1099.
118.
Zheng W, Zhou J, Song S, Kong W, Xia W, Chen L, et al. Dipeptidyl-peptidase 4 inhibitor sitagliptin ameliorates hepatic insulin resistance by modulating inflammation and autophagy in ob/ob mice. Int J Endocrinol. 2018;2018.
119.
El-Zayadi A-R. Hepatic steatosis: a benign disease or a silent killer. World J Gastroenterol: WJG. 2008;14(26):4120.PubMedCentral
120.
Czaja MJ. Function of autophagy in nonalcoholic fatty liver disease. Dig Dis Sci. 2016;61(5):1304–13.PubMedCentral
121.
Hazari Y, Bravo-San Pedro JM, Hetz C, Galluzzi L, Kroemer G. Autophagy in hepatic adaptation to stress. J Hepatol. 2020;72(1):183–96.
122.
Xiong X, Tao R, DePinho RA, Dong XC. The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J Biol Chem. 2012;287(46):39107–14.PubMedCentral
123.
Hammoutene A, Lasselin J, Vion A-C, Colnot N, Paradis V, Lotersztajn S, et al. Defective autophagy in liver sinusoidal endothelial cells promotes non alcoholic steatohepatitis and fibrosis development. J Hepatol. 2018;68:S29.
124.
Kwanten WJ, Martinet W, Francque SM. Autophagy in non-alcoholic fatty liver disease (NAFLD). Autophagy Curr Trends Cell Physiol Pathol. 2016:456–83.
125.
Xie X, Yan D, Li H, Zhu Q, Li J, Fang Y-p, et al. Enhancement of adiponectin ameliorates nonalcoholic fatty liver disease via inhibition of FOXO1 in type I diabetic rats. J Diabetes Res. 2018;2018.
126.
Cheng Z. The FoxO–autophagy Axis in health and disease. Trends Endocrinol Metab. 2019;30(9):658–71.
127.
Dong XC. FOXO transcription factors in non-alcoholic fatty liver disease. Liver Res. 2017;1(3):168–73.PubMedCentral
128.
Kwanten WJ, Martinet W, Michielsen PP, Francque SM. Role of autophagy in the pathophysiology of nonalcoholic fatty liver disease: a controversial issue. World J Gastroenterol: WJG. 2014;20(23):7325.PubMedCentral
129.
Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14(5):283–96.PubMedPubMedCentral
130.
Di Malta C, Cinque L, Settembre C. Transcriptional regulation of autophagy: mechanisms and diseases. Front Cell Dev Biol. 2019;7:114.PubMedCentral
131.
Zhang D, Ma Y, Liu J, Deng Y, Zhou B, Wen Y, et al. Metformin alleviates hepatic steatosis and insulin resistance in a mouse model of high-fat diet-induced nonalcoholic fatty liver disease by promoting transcription factor EB-dependent autophagy. Front Pharmacol. 2021:1907.
132.
Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253–70.
133.
Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15(6):647–58.PubMedCentral
134.
Li B, Wu X, Chen H, Zhuang C, Zhang Z, Yao S, et al. miR199a-5p inhibits hepatic insulin sensitivity via suppression of ATG14-mediated autophagy. Cell Death Dis. 2018;9(3):1–15.
135.
Ghareghani P, Shanaki M, Ahmadi S, Khoshdel AR, Rezvan N, Meshkani R, et al. Aerobic endurance training improves nonalcoholic fatty liver disease (NAFLD) features via miR-33 dependent autophagy induction in high fat diet fed mice. Obes Res Clin Pract. 2018;12(1):80–9.
136.
Naito T, Kuma A, Mizushima N. Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle. J Biol Chem. 2013;288(29):21074–81.PubMedCentral
137.
Zhou W, Ye S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int. 2018;42(10):1282–91.
138.
Ma D, Molusky MM, Song J, Hu C-R, Fang F, Rui C, et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol Endocrinol. 2013;27(10):1643–54.PubMedCentral
139.
Pereira S, Park E, Mori Y, Haber CA, Han P, Uchida T, et al. FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress. Am J Physiol-Endocrinol Metab. 2014;307(1):E34–46.PubMedCentral
140.
Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem. 2009;42(13–14):1331–46.
141.
Tan SH, Shui G, Zhou J, Li JJE, Bay B-H, Wenk MR, et al. Induction of autophagy by palmitic acid via protein kinase C-mediated signaling pathway independent of mTOR (mammalian target of rapamycin). J Biol Chem. 2012;287(18):14364–76.PubMedCentral
142.
Mei S, Ni H-M, Manley S, Bockus A, Kassel KM, Luyendyk JP, et al. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J Pharmacol Exp Ther. 2011;339(2):487–98.PubMedCentral
143.
Abel ED, O’Shea KM, Ramasamy R. Insulin resistance: metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol. 2012;32(9):2068–76.PubMedCentral
144.
Saito T, Kuma A, Sugiura Y, Ichimura Y, Obata M, Kitamura H, et al. Autophagy regulates lipid metabolism through selective turnover of NCoR1. Nat Commun. 2019;10(1):1–16.
145.
Wang Y, Ding Y, Li J, Chavan H, Matye D, Ni H-M, et al. Targeting the enterohepatic bile acid signaling induces hepatic autophagy via a CYP7A1–AKT–mTOR axis in mice. Cell Mol Gastroenterol Hepatol. 2017;3(2):245–60.
146.
Schulze RJ, Drižytė K, Casey CA, McNiven MA. Hepatic lipophagy: new insights into autophagic catabolism of lipid droplets in the liver. Hepatol Commun. 2017;1(5):359–69.PubMedCentral
147.
Byrnes K, Blessinger S, Bailey N, Scaife R, Liu G, Khambu B. Therapeutic regulation of autophagy in hepatic metabolism. Acta Pharmaceutica Sinica B. 2021;12:33.PubMedCentral
148.
Ohsaki Y, Cheng J, Fujita A, Tokumoto T, Fujimoto T. Cytoplasmic lipid droplets are sites of convergence of proteasomal and autophagic degradation of apolipoprotein B. Mol Biol Cell. 2006;17(6):2674–83.PubMedCentral
149.
Zamani M, Taher J, Adeli K. Complex role of autophagy in regulation of hepatic lipid and lipoprotein metabolism. J Biomed Res. 2017;31(5):377.PubMedCentral
150.
Fisher EA. The degradation of apolipoprotein B100: multiple opportunities to regulate VLDL triglyceride production by different proteolytic pathways. Biochimica et Biophysica Acta (BBA)-Mol Cell Biol Lipids. 2012;1821(5):778–81.
151.
Andreo U, Guo L, Chirieac DV, Tuyama AC, Montenont E, Brodsky JL, et al. Insulin-stimulated degradation of apolipoprotein B100: roles of class II phosphatidylinositol-3-kinase and autophagy. PLoS ONE. 2013;8(3): e57590.PubMedCentral
152.
Huang M, Yang X, Wang Z, Long J, Wang A, Zhang Y, et al. Lipophagy: a new perspective of natural products in type 2 diabetes mellitus treatment. Diabetes Metab Syndr Obes Targets Ther. 2021;14:2985.
153.
Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract. 2011;93:S52–9.
154.
Álvarez-Mercado AI, Rojano-Alfonso C, Micó-Carnero M, Caballeria-Casals A, Uroz CP, Casillas-Ramírez A. New insights into the role of autophagy in liver surgery in the setting of metabolic syndrome and related diseases. Front Cell Dev Biol. 2021;9:1250.
155.
Özcan U, Cao Q, Yilmaz E, Lee A-H, Iwakoshi NN, Özdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61.
156.
Villalobos-Labra R, Subiabre M, Toledo F, Pardo F, Sobrevia L. Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity. Mol Aspects Med. 2019;66:49–61.
157.
Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death. EMBO J. 2005;24(6):1243–55.PubMedCentral
158.
Akhter MS, Uddin MA, Kubra K-T, Barabutis N. Autophagy, unfolded protein response and lung disease. Curr Res Cell Biol. 2020:100003.
159.
Ding W-X, Ni H-M, Gao W, Yoshimori T, Stolz DB, Ron D, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007;171(2):513–24.PubMedCentral
160.
Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem. 2006;281(40):30299–304.
161.
Ogata M, Hino S-i, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic ReticulumStress. Mol Cell Biol. 2006;26(24):9220–31.PubMedCentral
162.
Ding W-X, Ni H-M, Gao W, Hou Y-F, Melan MA, Chen X, et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem. 2007;282(7):4702–10.
163.
Ding W-X. Role of autophagy in liver physiology and pathophysiology. World J Biol Chem. 2010;1(1):3.PubMedCentral
164.
Yan H, Gao Y, Zhang Y. Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model of nonalcoholic fatty liver disease. Mol Med Rep. 2017;15(1):180–6.
165.
Wang H, Sun R-Q, Zeng X-Y, Zhou X, Li S, Jo E, et al. Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice. Endocrinology. 2015;156(1):169–81.
166.
Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos M, Pardo V, Miquilena-Colina M, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014;5(4):e1179.PubMedCentral
167.
Ma X, McKeen T, Zhang J, Ding W-X. Role and mechanisms of mitophagy in liver diseases. Cells. 2020;9(4):837.PubMedCentral
168.
Doblado L, Lueck C, Rey C, Samhan-Arias AK, Prieto I, Stacchiotti A, et al. Mitophagy in human diseases. Int J Mol Sci. 2021;22(8):3903.PubMedCentral
169.
Rocha M, Apostolova N, Diaz-Rua R, Muntane J, Victor VM. Mitochondria and T2D: role of autophagy, ER stress, and inflammasome. Trends Endocrinol Metab. 2020;31:725.
170.
Tiganis T. Reactive oxygen species and insulin resistance: the good, the bad and the ugly. Trends Pharmacol Sci. 2011;32(2):82–9.
171.
Besse-Patin A, Estall JL. An intimate relationship between ROS and insulin signalling: implications for antioxidant treatment of fatty liver disease. Int J Cell Biol. 2014;2014.
172.
Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, et al. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem. 2009;284(22):14809–18.PubMedCentral
173.
Su Z, Nie Y, Huang X, Zhu Y, Feng B, Tang L, et al. Mitophagy in hepatic insulin resistance: therapeutic potential and concerns. Front Pharmacol. 2019;10:1193.PubMedCentral
174.
Feng J, Lu S, Ou B, Liu Q, Dai J, Ji C, et al. The role of JNk signaling pathway in obesity-driven insulin resistance. Diabetes Metab Syndr Obes Targets Ther. 2020;13:1399.
175.
Pietrocola F, Pedro B-S, Manuel J. Targeting autophagy to counteract obesity-associated oxidative stress. Antioxidants. 2021;10(1):102.PubMedCentral
176.
Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longevity. 2014;2014.
177.
Crişan TO, Plantinga TS, van de Veerdonk FL, Farcaş MF, Stoffels M, Kullberg B-J, et al. Inflammasome-independent modulation of cytokine response by autophagy in human cells. PLoS ONE. 2011;6(4): e18666.PubMedCentral
178.
Condello M, Pellegrini E, Caraglia M, Meschini S. Targeting autophagy to overcome human diseases. Int J Mol Sci. 2019;20(3):725.PubMedCentral
179.
Barbier L, Ferhat M, Salamé E, Robin A, Herbelin A, Gombert J-M, et al. Interleukin-1 family cytokines: keystones in liver inflammatory diseases. Front Immunol. 2019;10:2014.PubMedCentral
180.
Mao Y, Yu F, Wang J, Guo C, Fan X. Autophagy: a new target for nonalcoholic fatty liver disease therapy. Hepatic Med Evid Res. 2016;8:27.
181.
Zeng T-s, Liu F-m, Zhou J, Pan S-x, Xia W-f, Chen L-l. Depletion of Kupffer cells attenuates systemic insulin resistance, inflammation and improves liver autophagy in high-fat diet fed mice. Endocrine J. 2015:EJ15-0046.
182.
Neel BA, Lin Y, Pessin JE. Skeletal muscle autophagy: a new metabolic regulator. Trends Endocrinol Metab. 2013;24(12):635–43.
183.
Consitt LA, Dudley C, Saxena G. Impact of endurance and resistance training on skeletal muscle glucose metabolism in older adults. Nutrients. 2019;11(11):2636.PubMedCentral
184.
Qin B, Zhou Z, He J, Yan C, Ding S. IL-6 inhibits starvation-induced autophagy via the STAT3/Bcl-2 signaling pathway. Sci Rep. 2015;5(1):1–10.
185.
Song X, Shen Q, Fan L, Yu Q, Jia X, Sun Y, et al. Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome. Oncotarget. 2018;9(15):11905.PubMedCentral
186.
Yang L, Lin H, Lin W, Xu X. Exercise ameliorates insulin resistance of type 2 diabetes through motivating short-chain fatty acid-mediated skeletal muscle cell autophagy. Biology. 2020;9(8):203.PubMedCentral
187.
Shi L, Zhang T, Zhou Y, Zeng X, Ran L, Zhang Q, et al. Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway. Endocrine. 2015;50(2):378–89.
188.
Møller AB, Kampmann U, Hedegaard J, Thorsen K, Nordentoft I, Vendelbo MH, et al. Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes. Sci Rep. 2017;7(1):1–11.
189.
Kruse R, Vind BF, Petersson SJ, Kristensen JM, Højlund K. Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes. Diabetologia. 2015;58(9):2087–95.
190.
Sarparanta J, Garcia-Macia M, Singh R. Autophagy and mitochondria in obesity and type 2 diabetes. Curr Diabetes Rev. 2017;13(4):352–69.
191.
Lv P, Huang J, Yang J, Deng Y, Xu J, Zhang X, et al. Autophagy in muscle of glucose-infusion hyperglycemia rats and streptozotocin-induced hyperglycemia rats via selective activation of m-TOR or FoxO3. PLoS ONE. 2014;9(2): e87254.PubMedCentral
192.
Færch K, Vistisen D, Pacini G, Torekov SS, Johansen NB, Witte DR, et al. Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes. 2016;65(11):3473–81.
193.
Hegarty B, Furler S, Ye J, Cooney G, Kraegen E. The role of intramuscular lipid in insulin resistance. Acta Physiol Scand. 2003;178(4):373–83.
194.
Gilbert M. Role of skeletal muscle lipids in the pathogenesis of insulin resistance of obesity and type 2 diabetes. J Diabetes Invest. 2021;12(11):1934–41.
195.
Sadeghi A, Shabani M, Alizadeh S, Meshkani R. Interplay between oxidative stress and autophagy function and its role in inflammatory cytokine expression induced by palmitate in skeletal muscle cells. Cytokine. 2020;125: 154835.
196.
Lam T, Harmancey R, Vasquez H, Gilbert B, Patel N, Hariharan V, et al. Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway. Cell Death Discovery. 2016;2(1):1–12.
197.
da Silva Rosa SC, Martens MD, Field JT, Nguyen L, Kereliuk SM, Hai Y, et al. BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation. Autophagy. 2021;17(9):2257–72.
198.
Morales-Scholz MG, Swinton C, Murphy RM, Kowalski GM, Bruce CR, Howlett KF, et al. Autophagy is not involved in lipid accumulation and the development of insulin resistance in skeletal muscle. Biochem Biophys Res Commun. 2021;534:533–9.
199.
Paré M, Baechler B, Fajardo V, Earl E, Wong E, Campbell T, et al. Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function. Biochimica et Biophysica Acta (BBA) Mol Cell Res. 2017;1864(4):708–18.
200.
Campbell TL, Mitchell AS, McMillan EM, Bloemberg D, Pavlov D, Messa I, et al. High-fat feeding does not induce an autophagic or apoptotic phenotype in female rat skeletal muscle. Exp Biol Med. 2015;240(5):657–68.
201.
Jani S, Da Eira D, Hadday I, Bikopoulos G, Mohasses A, de Pinho RA, et al. Distinct mechanisms involving diacylglycerol, ceramides, and inflammation underlie insulin resistance in oxidative and glycolytic muscles from high fat-fed rats. Sci Rep. 2021;11(1):1–12.
202.
Cerella C, Dicato M, Diederich M. Modulatory roles of glycolytic enzymes in cell death. Biochem Pharmacol. 2014;92(1):22–30.
203.
Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell. 2014;53(4):521–33.PubMedCentral
204.
Nakai N, Kitai S, Iida N, Inoue S, Nakata K, Murakami T, et al. Induction of autophagy and changes in cellular metabolism in glucose starved C2C12 myotubes. J Nutr Sci Vitaminol. 2020;66(1):41–7.
205.
Altajar S, Baffy G. Skeletal muscle dysfunction in the development and progression of nonalcoholic fatty liver disease. J Clin Transl Hepatol. 2020;8(4):414.PubMedCentral
206.
McMillan EM, Paré M-F, Baechler BL, Graham DA, Rush JW, Quadrilatero J. Autophagic signaling and proteolytic enzyme activity in cardiac and skeletal muscle of spontaneously hypertensive rats following chronic aerobic exercise. PLoS ONE. 2015;10(3): e0119382.PubMedCentral
207.
Ryu JY, Choi HM, Yang H-I, Kim KS. Dysregulated autophagy mediates sarcopenic obesity and its complications via AMPK and PGC1α signaling pathways: potential involvement of gut dysbiosis as a pathological link. Int J Mol Sci. 2020;21(18):6887.PubMedCentral
208.
Chen W, Wang L, You W, Shan T. Myokines mediate the cross talk between skeletal muscle and other organs. J Cell Physiol. 2021;236(4):2393–412.
209.
Amor M, Itariu BK, Moreno-Viedma V, Keindl M, Jürets A, Prager G, et al. Serum myostatin is upregulated in obesity and correlates with insulin resistance in humans. Exp Clin Endocrinol Diabetes. 2019;127(08):550–6.
210.
Liu XH, Bauman WA, Cardozo CP. Myostatin inhibits glucose uptake via suppression of insulin-dependent and-independent signaling pathways in myoblasts. Physiol Rep. 2018;6(17): e13837.PubMedCentral
211.
Pesce M, Ballerini P, Paolucci T, Puca I, Farzaei MH, Patruno A. Irisin and autophagy: first update. Int J Mol Sci. 2020;21(20):7587.PubMedCentral
212.
Zhang C, McFarlane C, Lokireddy S, Bonala S, Ge X, Masuda S, et al. Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia. 2011;54(6):1491–501.
213.
Eilers W, Cleasby M, Foster K. Development of antisense-mediated myostatin knockdown for the treatment of insulin resistance. Sci Rep. 2021;11(1):1–10.
214.
Camporez J-PG, Petersen MC, Abudukadier A, Moreira GV, Jurczak MJ, Friedman G, et al. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci. 2016;113(8):2212–7.PubMedCentral
215.
Ferraro E, Giammarioli AM, Chiandotto S, Spoletini I, Rosano G. Exercise-induced skeletal muscle remodeling and metabolic adaptation: redox signaling and role of autophagy. Antioxid Redox Signal. 2014;21(1):154–76.PubMedCentral
216.
Ye X, Shen Y, Ni C, Ye J, Xin Y, Zhang W, et al. Irisin reverses insulin resistance in C2C12 cells via the p38-MAPK-PGC-1α pathway. Peptides. 2019;119: 170120.
217.
Mi Q, Li Y, Wang M, Yang G, Zhao X, Liu H, et al. Circulating C1q/TNF-related protein isoform 15 is a marker for the presence of metabolic syndrome. Diabetes Metab Res Rev. 2019;35(1): e3085.
218.
Shokoohi Nahrkhalaji A, Ahmadi R, Fadaei R, Panahi G, Razzaghi M, Fallah S. Higher serum level of CTRP15 in patients with coronary artery disease is associated with disease severity, body mass index and insulin resistance. Arch Physiol Biochem. 2022;128(1):276–80.
219.
Mohassel Azadi S, Shateri H, Mohammadi M, Fadaei R, Sajedi F, Ziamajidi N. Increased circulating level of CTRP15 in patients with type 2 diabetes mellitus and its relation with inflammation and insulin resistance. J Diabetes Metab Disord. 2021;20(2):1499–504.PubMedCentral
220.
Vatannejad A, Fadaei R, Salimi F, Fouani FZ, Habibi B, Shapourizadeh S, et al. Plasma Complement C1q/tumor necrosis factor-related protein 15 concentration is associated with polycystic ovary syndrome. PLoS ONE. 2022;17(6): e0263658.PubMedCentral
221.
Pourranjbar M, Arabnejad N, Naderipour K, Rafie F. Effects of aerobic exercises on serum levels of myonectin and insulin resistance in obese and overweight women. J Med Life. 2018;11(4):381.PubMedCentral
222.
Seldin MM, Lei X, Tan SY, Stanson KP, Wei Z, Wong GW. Skeletal muscle-derived myonectin activates the mammalian target of rapamycin (mTOR) pathway to suppress autophagy in liver. J Biol Chem. 2013;288(50):36073–82.PubMedCentral
223.
Siewko K, Maciulewski R, Zielinska-Maciulewska A, Poplawska-Kita A, Szumowski P, Wawrusiewicz-Kurylonek N, et al. Interleukin-6 and interleukin-15 as possible biomarkers of the risk of autoimmune diabetes development. BioMed Res Int. 2019;2019:1.
224.
Krolopp JE, Thornton SM, Abbott MJ. IL-15 activates the Jak3/STAT3 signaling pathway to mediate glucose uptake in skeletal muscle cells. Front Physiol. 2016;7:626.PubMedCentral
225.
藤本拓. Overexpression of interleukin-15 exhibits improved glucose tolerance and promotes GLUT4 translocation via AMP-activated protein kinase pathway in skeletal muscle: 大阪大学; 2019.
226.
Orsatti CL, Orsatti FL, Bezerra TG, Quevedo A, Nahas EAP. Interleukin-15 are associated with insulin resistance in postmenopausal women with metabolic syndrome. Gynecol Endocrinol. 2022;38(9):765–70.
227.
Zhu L, Xie X, Zhang L, Wang H, Jie Z, Zhou X, et al. TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival. Nat Commun. 2018;9(1):1–14.
228.
Ara A, Wu Z, Xu A, Ahmed KA, Leary SC, Islam MF, et al. The critical role of AMPKα1 in regulating autophagy and mitochondrial respiration in IL-15-stimulated mTORC1Weak signal-induced T cell memory: an interplay between Yin (AMPKα1) and Yang (mTORC1) energy sensors in T cell differentiation. Int J Mol Sci. 2022;23(17):9534.PubMedCentral
229.
Yan J, Feng Z, Liu J, Shen W, Wang Y, Wertz K, et al. Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (−)-epigallocatechin-3-gallate. J Nutr Biochem. 2012;23(7):716–24.
230.
Ehrlicher SE, Stierwalt HD, Newsom SA, Robinson MM. Short-term high-fat feeding does not alter mitochondrial lipid respiratory capacity but triggers mitophagy response in skeletal muscle of mice. Front Endocrinol. 2021;12: 651211.
231.
Haines MS, Dichtel LE, Santoso K, Torriani M, Miller KK, Bredella MA. Association between muscle mass and insulin sensitivity independent of detrimental adipose depots in young adults with overweight/obesity. Int J Obes. 2020;44(9):1851–8.
232.
Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Bonconpagni S, et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 2008;8(5):425–36.
233.
Suzuki N, Motohashi N, Uezumi A, Fukada S-I, Yoshimura T, Itoyama Y, et al. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. J Clin Invest. 2007;117(9):2468–76.PubMedCentral
234.
McClung JM, Judge AR, Powers SK, Yan Z. p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol. 2010;298(3):C542–9.
235.
Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I. Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord. 2008;18(7):521–9.
236.
Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is required to maintain muscle mass. Cell Metab. 2009;10(6):507–15.
237.
Raben N, Hill V, Shea L, Takikita S, Baum R, Mizushima N, et al. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet. 2008;17(24):3897–908.PubMedCentral
238.
Qi Z, Chen L. Endoplasmic reticulum stress and autophagy. Autophagy Biol Dis. 2019:167–77.
239.
Madaro L, Marrocco V, Carnio S, Sandri M, Bouché M. Intracellular signaling in ER stress-induced autophagy in skeletal muscle cells. FASEB J. 2013;27(5):1990–2000.
240.
Ijuin T, Hosooka T, Takenawa T. Phosphatidylinositol 3, 4, 5-trisphosphate phosphatase SKIP links endoplasmic reticulum stress in skeletal muscle to insulin resistance. Mol Cell Biol. 2016;36(1):108–18.
241.
Ahlstrom P, Rai E, Chakma S, Cho HH, Rengasamy P, Sweeney G. Adiponectin improves insulin sensitivity via activation of autophagic flux. J Mol Endocrinol. 2017;59(4):339–50.
242.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig. 2003;112(12):1821–30.PubMedCentral
243.
Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25(1):4–7.
244.
Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Investig. 2006;116(7):1793–801.PubMedCentral
245.
Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Molecular metabolism. 2017;6(2):174–84.
246.
Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14(3):222–31.PubMedCentral
247.
Moon S, Jung HS. Endoplasmic reticulum stress and dysregulated autophagy in human pancreatic beta cells. Diabetes Metab J. 2022;46(4):533–42.PubMedCentral
248.
Bartolome A, Guillen C, Benito M. Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death. Autophagy. 2012;8(12):1757–68.PubMedCentral
249.
Ji J, Petropavlovskaia M, Khatchadourian A, Patapas J, Makhlin J, Rosenberg L, et al. Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β-cells. J Cell Mol Med. 2019;23(4):2890–900.PubMedCentral
250.
Mir SU, George NM, Zahoor L, Harms R, Guinn Z, Sarvetnick NE. Inhibition of autophagic turnover in β-cells by fatty acids and glucose leads to apoptotic cell death. J Biol Chem. 2015;290(10):6071–85.
251.
Elumalai S, Karunakaran U, Moon JS, Won KC. High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: prevention by Teneligliptin. Free Radical Biol Med. 2020;160:618–29.
252.
Yun HR, Jo YH, Kim J, Shin Y, Kim SS, Choi TG. Roles of autophagy in oxidative stress. Int J Mol Sci. 2020;21(9):3289.PubMedCentral
253.
Xia G, Zhu T, Li X, Jin Y, Zhou J, Xiao J. ROS-mediated autophagy through the AMPK signaling pathway protects INS-1 cells from human islet amyloid polypeptide-induced cytotoxicity. Mol Med Rep. 2018;18(3):2744–52.PubMedCentral
254.
Shigihara N, Fukunaka A, Hara A, Komiya K, Honda A, Uchida T, et al. Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagy. J Clin Investig. 2014;124(8):3634–44.PubMedCentral
255.
Kim J, Park K, Kim MJ, Lim H, Kim KH, Kim S-W, et al. An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer. Nat Commun. 2021;12(1):183.PubMedCentral
256.
Park MJ, Choi KM. Interplay of skeletal muscle and adipose tissue: sarcopenic obesity. Metabolism. 2023;144:155577.
257.
Kosacka J, Kern M, Klöting N, Paeschke S, Rudich A, Haim Y, et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol. 2015;409:21–32.
258.
Iula L, Keitelman IA, Sabbione F, Fuentes F, Guzman M, Galletti JG, et al. Autophagy mediates interleukin-1β secretion in human neutrophils. Front Immunol. 2018;9:269.PubMedCentral
259.
Saitoh T, Fujita N, Jang MH, Uematsu S, Yang B-G, Satoh T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 2008;456(7219):264–8.
260.
Kume S, Yamahara K, Yasuda M, Maegawa H, Koya D. Autophagy: emerging therapeutic target for diabetic nephropathy. Semin Nephrol. 2014;34(1):9–16.
261.
Huang S-S, Ding D-F, Chen S, Dong C-L, Ye X-L, Yuan Y-G, et al. Resveratrol protects podocytes against apoptosis via stimulation of autophagy in a mouse model of diabetic nephropathy. Sci Rep. 2017;7(1):45692.PubMedCentral
262.
Liu N, Xu L, Shi Y, Zhuang S. Podocyte autophagy: a potential therapeutic target to prevent the progression of diabetic nephropathy. J Diabetes Res. 2017;2017.
263.
Lin JS, Susztak K. Podocytes: the Weakest Link in Diabetic Kidney Disease? Curr Diab Rep. 2016;16(5):45.PubMedCentral
264.
Deshpande S, Abdollahi M, Wang M, Lanting L, Kato M, Natarajan R. Reduced autophagy by a microRNA-mediated signaling cascade in diabetes-induced renal glomerular hypertrophy. Sci Rep. 2018;8(1):1–13.
265.
Yang D, Livingston MJ, Liu Z, Dong G, Zhang M, Chen J-K, et al. Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol Life Sci. 2018;75(4):669–88.PubMed
266.
Yamahara K, Yasuda M, Kume S, Koya D, Maegawa H, Uzu T. The role of autophagy in the pathogenesis of diabetic nephropathy. J Diabetes Res. 2013;2013:1.
267.
Kitada M, Ogura Y, Monno I, Koya D. Regulating autophagy as a therapeutic target for diabetic nephropathy. Curr Diab Rep. 2017;17(7):53.
268.
Tang C, Livingston MJ, Liu Z, Dong Z. Autophagy in kidney homeostasis and disease. Nat Rev Nephrol. 2020;16(9):489–508.PubMedCentral
269.
Gong Q, Wang H, Yu P, Qian T, Xu X. Protective or harmful: the dual roles of autophagy in diabetic retinopathy. Front Med. 2021;8.
270.
Becker K, Klein H, Simon E, Viollet C, Haslinger C, Leparc G, et al. In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy. Sci Rep. 2021;11(1):10494.PubMedCentral
271.
de Faria JML, Dátilo MN. Deficient autophagy contributes to the development of diabetic retinopathy. The Eye and Foot in Diabetes: IntechOpen; 2019.
272.
Intartaglia D, Giamundo G, Conte I. Autophagy in the retinal pigment epithelium: a new vision and future challenges. FEBS J. 2021;289:7199.PubMedCentral
273.
Taki K, Horie T, Kida T, Mimura M, Ikeda T, Oku H. Impairment of autophagy causes superoxide formation and caspase activation in 661 W cells, a cell line for cone photoreceptors, under hyperglycemic conditions. Int J Mol Sci. 2020;21(12):4240.PubMedCentral
274.
Huang C, Lu H, Xu J, Yu H, Wang X, Zhang X. Protective roles of autophagy in retinal pigment epithelium under high glucose condition via regulating PINK1/Parkin pathway and BNIP3L. Biol Res. 2018;51(1):1–9.
275.
Zhang X, Li T, Cheng H-J, Wang H, Ferrario CM, Groban L, et al. Chronic GPR30 agonist therapy causes restoration of normal cardiac functional performance in a male mouse model of progressive heart failure: insights into cellular mechanisms. Life Sci. 2021;285: 119955.PubMedCentral
276.
Wang F, He Q, Gao Z, Redington AN. Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning. Basic Res Cardiol. 2021;116(1):1–16.
277.
Kanamori H, Takemura G, Goto K, Tsujimoto A, Mikami A, Ogino A, et al. Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes. Autophagy. 2015;11(7):1146–60.PubMedCentral
278.
Che Y, Wang ZP, Yuan Y, Zhang N, Jin YG, Wan CX, et al. Role of autophagy in a model of obesity: a long-term high fat diet induces cardiac dysfunction. Mol Med Rep. 2018;18(3):3251–61.PubMedCentral
279.
Kobayashi S, Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy. Biochimica et Biophysica Acta (BBA) Mol Basis Dis. 2015;1852(2):252–61.
280.
Clément M, Chappell J, Raffort J, Lareyre F, Vandestienne M, Taylor AL, et al. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arterioscler Thromb Vasc Biol. 2019;39(6):1149–59.PubMedCentral
281.
Madrigal-Matute J, de Bruijn J, van Kuijk K, Riascos-Bernal DF, Diaz A, Tasset I, et al. Protective role of chaperone-mediated autophagy against atherosclerosis. Proc Natl Acad Sci. 2022;119(14): e2121133119.PubMedCentral
282.
Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective. Autophagy. 2021;17(10):2706–33.PubMedCentral
283.
Yamamoto A, Mizushima N, Tsukamoto S. Fertilization-induced autophagy in mouse embryos is independent of mTORC1. Biol Reprod. 2014;91(1):7.
284.
Sumarac-Dumanovic M, Apostolovic M, Janjetovic K, Jeremic D, Popadic D, Ljubic A, et al. Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome. Mol Cell Endocrinol. 2017;440:116–24.
285.
Zhang C, Hu J, Wang W, Sun Y, Sun K. HMGB1-induced aberrant autophagy contributes to insulin resistance in granulosa cells in PCOS. FASEB J. 2020;34(7):9563–74.
286.
Mu Y, Yan W-J, Yin T-L, Zhang Y, Li J, Yang J. Diet-induced obesity impairs spermatogenesis: a potential role for autophagy. Sci Rep. 2017;7(1):1–13.
287.
Cunard R. Endoplasmic reticulum stress in the diabetic kidney, the good, the bad and the ugly. J Clin Med. 2015;4(4):715–40.PubMedCentral
288.
Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011;60(6):1770–8.PubMedCentral
289.
Zhou H, Chen Y, Huang S-w, Hu P-f, Tang L-j. Regulation of autophagy by tea polyphenols in diabetic cardiomyopathy. J Zhejiang Univ-Sci B. 2018;19(5):333–41.PubMedCentral
290.
Akbari H, Hosseini-Bensenjan M, Salahi S, Moazzen F, Aria H, Manafi A, et al. Apelin and its ratio to lipid factors are associated with cardiovascular diseases: a systematic review and meta-analysis. PLoS ONE. 2022;17(8): e0271899.PubMedCentral
291.
Morissette G, Lodge R, Bouthillier J, Marceau F. Receptor-independent, vacuolar ATPase-mediated cellular uptake of histamine receptor-1 ligands: possible origin of pharmacological distortions and side effects. Toxicol Appl Pharmacol. 2008;229(3):320–31.
292.
Fallah H, Akbari H, Abolhassani M, Mohammadi A, Gholamhosseinian A. Berberis integerrima ameliorates insulin resistance in high-fructose-fed insulin-resistant rats. Iran J Basic Med Sci. 2017;20(10):1093.PubMedCentral
293.
Abdelaziz DH, Thapa S, Abdulrahman B, Vankuppeveld L, Schatzl HM. Metformin reduces prion infection in neuronal cells by enhancing autophagy. Biochem Biophys Res Commun. 2020;523(2):423–8.
294.
Mardones P, Rubinsztein DC, Hetz C. Mystery solved: trehalose kickstarts autophagy by blocking glucose transport. Sci Signal. 2016;9(416):fs2.
295.
Wang Q, Ren J. mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: role of p38 MAPK and Foxo1. Pharmacol Res. 2016;111:357–73.PubMedCentral
296.
Paech F, Bouitbir J, Krähenbühl S. Hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front Pharmacol. 2017;8:367.PubMedCentral
297.
Sheng Z, Ma L, Sun JE, Zhu LJ, Green MR. BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood J Am Soc Hematol. 2011;118(10):2840–8.
298.
Choi S-S, Kim E-S, Jung J-E, Marciano DP, Jo A, Koo JY, et al. PPARγ antagonist Gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes. 2016;65(4):829–39.PubMedCentral
299.
Kwak HJ, Choi H-E, Jang J, Park SK, Bae Y-A, Cheon HG. Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism. Cell Signal. 2016;28(8):788–97.
300.
Ashrafizadeh M, Yaribeygi H, Atkin SL, Sahebkar A. Effects of newly introduced antidiabetic drugs on autophagy. Diabetes Metab Syndr. 2019;13(4):2445–9.
301.
Zhou Y, Guo Z, Yan W, Wang W. Cardiovascular effects of sitagliptin–an anti-diabetes medicine. Clin Exp Pharmacol Physiol. 2018;45(7):628–35.
302.
Arab HH, Gad AM, Reda E, Yahia R, Eid AH. Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: targeting AMPK/mTOR and Nrf2/HO-1 pathways. Life Sci. 2021;269: 119031.
303.
Lin Z, Wang Z, Zhou X, Zhang M, Gao D, Zhang L, et al. Discovery of new fluorescent thiazole–pyrazoline derivatives as autophagy inducers by inhibiting mTOR activity in A549 human lung cancer cells. Cell Death Dis. 2020;11(7):1–12.
304.
Yin J, Gu L, Wang Y, Fan N, Ma Y, Peng Y. Rapamycin improves palmitate-induced ER stress/NF κ B pathways associated with stimulating autophagy in adipocytes. Mediat Inflam. 2015;2015.
305.
Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging (Albany NY). 2009;1(6):515.
306.
Zhu X, Liu Q, Wang M, Liang M, Yang X, Xu X, et al. Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in fibroblasts. PLoS ONE. 2011;6(11): e27081.PubMedCentral
307.
Kim SH, Kim G, Han DH, Lee M, Kim I, Kim B, et al. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy. 2017;13(10):1767–81.PubMedCentral
Metadata
Title
Crosstalk between autophagy and insulin resistance: evidence from different tissues
Authors
Asie Sadeghi
Maryam Niknam
Mohammad Amin Momeni-Moghaddam
Maryam Shabani
Hamid Aria
Alireza Bastin
Maryam Teimouri
Reza Meshkani
Hamed Akbari
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01424-9

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue

Review

Review of surgical treatment of iatrogenic iliofemoral artery injury in the pediatric population after catheterization

Research

Comprehensive analysis of research related to rehabilitation and COVID-19, hotspots, mapping, thematic evolution, trending topics, and future directions

Research

Association between clonal hematopoiesis-related gene mutations and unfavorable functional outcome in patients with large-artery atherosclerotic stroke

Research

Synergistic anticancer activity of cisplatin combined with tannic acid enhances apoptosis in lung cancer through the PERK-ATF4 pathway

Research

Correlation analysis of clinical, pathological, imaging and genetic features of ground-glass nodule featured lung adenocarcinomas between high-risk and non-high-risk individuals

Research

Common clinical blood and urine biomarkers for ischemic stroke: an Estonian Electronic Health Records database study