A Review of Progress of the Relation Between Stress Response and Diabetes Mellitus

YUAN Ke-fei, SHI Jia-yan, PENG Li-yuan, LI Chang-long, ZHANG Yuan-yuan


Stress response is an adaptive process of the organism to confront environmental perturbation. Moderate stress response induces the organism to establish effective adaptive strategies for survival, while excessive stress response results in stress injury, which is a major cause of a variety of physical or psychological diseases, including diabetes mellitus. Diabetes mellitus is a typical stress-related disease, with numerous evidence indicating that the development and progression of diabetes mellitus are closely related to stress response, such as metabolic stress, oxidative stress and endoplasmic reticulum stress. However, the detailed mechanisms of stress response mediated regulation of diabetes mellitus and how to prevent or treat diabetes mellitus via modification of stress response remain to be further investigated. Here, we will introduce the definition and regulatory mechanisms of stress response, as well as discuss the biological functions and mechanisms of various stress responses during the pathogenesis of diabetes mellitus. This review highlights recent advances of stress medicine associated with diabetes mellitus, in order to provide theoretical basis and reference for prevention and treatment of diabetes mellitus. Future studies should focus on elucidating the clinical application potential of the key factors of stress response that mediate the pathogenesis of diabetes mellitus, as well as boosting the related translational medicine studies.


Keywords: Stress, Stress response, Stress regulatory mechanism, Stress medicine, Diabetes mellitus


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RUSSELL G, LIGHTMAN S. The human stress response. Nat Rev Endocrinol,2019,15(9): 525–534.

FAN W. Epidemiology in diabetes mellitus and cardiovascular disease. Cardiovasc Endocrinol,2017,6(1): 8–16.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care,2014,37(Suppl 1): S81–S90.

SZABLEWSKI L. Glucose transporters in healthy heart and in cardiac disease. Int J Cardiol,2017,230: 70–75.

ZHANG Y, SOWERS J R, REN J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol,2018,14(6): 356–376.

WELLEN K E, THOMPSON C B. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell,2010,40(2): 323–332.

WANG Y, HU H, YIN J, et al. TLR4 participates in sympathetic hyperactivity post-MI in the PVN by regulating NF-κB pathway and ROS production. Redox Biol, 2019, 24: 101186[2020-12-28]. https://doi.org/ 10.1016/j.redox.2019.101186.

LIN L, CAO L, LIU Y, et al. B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3. Leukemia,2019,33(6): 1475–1486.

ZHANG Y, QU Y, LIN Y, et al. Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients. Nat Commun, 2017, 8(1): 464[2020-12-28]. https://www.nature.com/articles/s41467-017-00489-5. doi: 10.1038/s41467-017-00489-5.

WANG T, CAO Y, ZHENG Q, et al. SENP1-SIRT3 signaling controls mitochondrial protein acetylation and metabolism. Mol Cell,2019,75(4): 823–834.

CHIO I I C, TUVESON D A. ROS in cancer: the burning question. Trends Mol Med,2017,23(5): 411–429.

HAYES J D, DINKOVA-KOSTOVA A T, TEW K D. Oxidative stress in cancer. Cancer Cell,2020,38(2): 167–197.

SCHMIDLIN C J, DODSON M B, MADHAVAN L, et al. Redox regulation by NRF2 in aging and disease. Free Radic Biol Med,2019,134: 702–707.

KLOTZ L O, STEINBRENNER H. Cellular adaptation to xenobiotics: interplay between xenosensors, reactive oxygen species and FOXO transcription factors. Redox Biol,2017,13: 646–654.

SONG M, CUBILLOS-RUIZ J R. Endoplasmic reticulum stress responses in intratumoral immune cells: implications for cancer immunotherapy. Trends Immunol,2019,40(2): 128–141.

FRAKES A E, DILLIN A. The UPRER: sensor and coordinator of organismal homeostasis. Mol Cell,2017,66(6): 761–771.

CAKIR I, NILLNI E A. Endoplasmic reticulum stress, the hypothalamus, and energy balance. Trends Endocrinol Metab,2019,30(3): 163–176.

WANG M, KAUFMAN R J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature,2016,529(7586): 326–335.

RUEGSEGGER G N, CREO A L, CORTES T M, et al. Altered mitochondrial function in insulin-deficient and insulin-resistant states. J Clin Invest,2018,128(9): 3671–3681.

HOTAMISLIGIL G S. Inflammation, metaflammation and immunometabolic disorders. Nature,2017,542(7640): 177–185.

CHOUCHANI E T, KAZAK L, JEDRYCHOWSKI M P, et al. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature,2016,532(7597): 112–116.

FAKHRUDDIN S, ALANAZI W, JACKSON K E. Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J Diabetes Res, 2017, 2017: 8379327[2020-12-28]. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC5253173/. doi: 10.1155/2017/8379327.

NOLAN C J, RUDERMAN N B, KAHN S E, et al. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes,2015,64(3): 673–686.

USSHER J R, CAMPBELL J E, MULVIHILL E E, et al. Inactivation of the glucose-dependent insulinotropic polypeptide receptor improves outcomes following experimental myocardial infarction. Cell Metab, 2018,27(2): 450–460.

JAIS A, SOLAS M, BACKES H, et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell,2016,165(4): 882–895.

KENNY H C, ABEL E D. Heart failure in type 2 diabetes mellitus. Circ Res,2019,124(1): 121–141.

LEVASSEUR E M, YAMADA K, PIÑEROS A R, et al. Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis. Sci Signal, 2019, 12(610): eaax0715[2020-12-28]. https://stke.sciencemag.org/content/12/610/eaax0715.long. doi: 10.1126/scisignal.aax0715.

WEIR G C. Glucolipotoxicity, β-cells, and diabetes: the emperor has no clothes. Diabetes,2020,69(3): 273–278.

GERBER P A, RUTTER G A. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal,2017,26(10): 501–518.

LEE Y S, WOLLAM J, OLEFSKY J M. An integrated view of immunometabolism. Cell,2018,172(1/2): 22–40.

KLEINER S, GOMEZ D, MEGRA B, et al. Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity. Proc Natl Acad Sci U S A,2018,115(32): E7642–E7649.

POCIOT F, LERNMARK Å. Genetic risk factors for type 1 diabetes. Lancet,2016,387(10035): 2331–2339.

CATRYSSE L, VAN LOO G. Inflammation and the metabolic syndrome: the tissue-specific functions of NF-κB. Trends Cell Biol,2017,27(6): 417–429.

KITADA M, OGURA Y, MONNO I, et al. Sirtuins and type 2 diabetes: role in inflammation, oxidative stress, and mitochondrial function. Front Endocrinol, 2019, 10: 187[2020-12-28]. https://doi.org/10.3389/fendo.2019.00187.

STUART C A, HOWELL M E, CARTWRIGHT B M, et al. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation. Physiol Rev, 2014, 2(12): e12236[2020-12-28]. https://doi.org/10.14814/phy2.12236.

PETERSEN M C, SHULMAN G I. Mechanisms of insulin action and insulin resistance. Physiol Rev,2018,98(4): 2133–2223.

YANG J D, HAINAUT P, GORES G J, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol,2019,16(10): 589–604.

KAHN C R, WANG G, LEE K Y. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest,2019, 129(10): 3990–4000.

REILLY S M, SALTIEL A R. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol,2017,13(11): 633–643.

ZHANG Y, KIM M S, JIA B, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature,2017,548(7665): 52–57.


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