Activation of mechanistic target of rapamycin complex 1: the common link between rheumatoid arthritis and diabetes mellitus

Activation of mechanistic target of rapamycin complex 1: the common link between rheumatoid... An increased prevalence of diabetes mellitus (DM) in patients with RA has emerged in recent years. The article by Albrecht et al. [1] in this issue of Rheumatology is a welcome addition to this debate. Evidence suggests that dysregulation in the mechanistic target of rapamycin complex 1 (mTORC1) signalling is key to explaining the association between RA and DM. mTOR is the core constituent of the phosphatidylinositol 3-kinase-related kinase protein family and works in two distinct multiprotein complexes known as mTORC1 and mTORC2 [2]. mTORC1 is the major regulator of survival, growth, proliferation and motility in response to mitogens, energy and nutrient levels. Due to its central role in cellular functions, mTORC1 dysregulation is involved in a large number of diseases [2]. Upregulation of mTORC1 has also been observed in several immune disorders, including RA [3]. In some of these disorders, mTORC1 expression has shown to be positively correlated with the insulin resistance index as determined by homoeostasis model assessment (HOMA) [4]. This comes as no surprise since mTORC1 also plays a key role in DM pathogenesis [2]. In particular, several studies have clearly identified mTORC1 hyperactivation as a major determinant of hypertrophic obesity and related inflammation and insulin resistance. First, mTORC1 activates S6 kinase (S6K), which in turn causes phosphorylation and degradation of insulin receptor substrate 1/2 (IRS1/2), which impairs insulin signalling. Second, mTORC1 causes insulin resistance by affecting growth factor receptor-bound protein 10 (Grb10). Thus, hyperactivation of mTORC1 causes insulin resistance by at least two mechanisms [2] (Fig. 1). Glucose activates mTORC1 and causes expansion and hypertrophy of β cells as well as increasing insulin secretion. β cell hyperfunction compensates for insulin resistance, preventing hyperglycaemia. Lastly, hyperfunction causes β cell failure and manifest diabetes. In fact, prolonged overactivation of mTORC1 might result in a predominant S6K negative-feedback loop with decrease in IRS1/2 levels and reduction of IRS2/pancreatic and duodenal homeobox 1 (PDX1) pathway, fostering β-cell death. Remarkably, dietary restriction reduces mTORC1 activity and improves insulin sensitivity [2]. Fig. 1 View largeDownload slide The role of the mTORC1 pathway in RA and DM pathogenesis Activation of mTORC1 causes insulin resistance through a negative-feedback loop by mediating IRS1 serine phosphorylation via S6K and by blocking the association between IR and IRS1/2 via Grb10. TNF-α also contributes to insulin resistance by activating IKK-β, which inactivates TSC1, a key negative regulator of mTORC1. In addition, mTORC1 promotes Th17 differentiation and NLRP3 inflammasome activation. TNF-α, IL-17, IL-1β, IL-18 and IL-33 drive the inflammatory process in RA as well as in DM. Fig. 1 View largeDownload slide The role of the mTORC1 pathway in RA and DM pathogenesis Activation of mTORC1 causes insulin resistance through a negative-feedback loop by mediating IRS1 serine phosphorylation via S6K and by blocking the association between IR and IRS1/2 via Grb10. TNF-α also contributes to insulin resistance by activating IKK-β, which inactivates TSC1, a key negative regulator of mTORC1. In addition, mTORC1 promotes Th17 differentiation and NLRP3 inflammasome activation. TNF-α, IL-17, IL-1β, IL-18 and IL-33 drive the inflammatory process in RA as well as in DM. In addition, the mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells, as clearly verified by the immune-suppressive function of mTORC1 inhibitors such as rapamycin [2]. Notably, the differentiation of Th17 cells is controlled by mTORC1, which promotes Th17 differentiation [5] (Fig. 1). Significantly increased IL-17 levels have been found in the blood and SF of RA patients [6]. Using samples of bone obtained from surgery, the addition of IL-17 together with TNF-α and IL-1 induced in vitro bone-destructive cytokine production and bone resorption. Conversely, inhibition of IL-17 resulted in an anti-inflammatory effect and lower bone destruction. Intriguingly, evidence shows that IL-17 also plays a key role in insulin resistance and DM [7]. Obesity is one of the main known causes of the development of DM. In obese patients, increased plasma concentrations of insulin, IGF-1 and IL-17 are observed. Serum IL-17 is significantly higher in patients with DM than in controls. IL-17 deficiency increased glucose tolerance and sensitivity to insulin in young mice. IL-1β, IL-18 and IL-33 are further important pro-inflammatory cytokines belonging to the IL-1 family that are involved in the pathogenesis of both RA and DM [6]. The drugs which target these factors, such as anakinra and canakinumab, are widely used in the treatment of RA. The NLRP3 inflammasome is the best-characterized inflammasome to date and acts as an activation platform for cytokines [8]. Once activated, NLRP3 recruits the apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). ASC is a key adaptor molecule bridging NLRP3 with procaspase-1 within the inflammasome complex, with the consequent activation of procaspase-1. The active form, caspase-1, cleaves pro-inflammatory cytokines such as pro-IL-1β, pro-IL-18 and pro-IL-33 into their active forms, namely IL-1β, IL-18 and IL-33. Intriguingly, mTORC1-induced glycolysis provides a critical mechanism for NLRP3 inflammasome activation in macrophages [8] (Fig. 1). Downregulation of glycolysis by inhibition of mTORC1 suppresses caspase-1 activation in macrophages and subsequently pro-IL-1β maturation. Finally, TNF-α, a pro-inflammatory cytokine that plays a pivotal role in regulating the inflammatory response in RA [6], activates IκB kinase (IKK)-β, which inactivates hamartin (TSC1), a key negative regulator of mTORC1 [2] (Fig. 1). Thus TNF-α impairs insulin signalling and contributes to insulin resistance. As a result, anti-TNF agents—which inhibit joint destruction in RA patients, improving the clinical picture and quality of life—also decrease mTORC1 activity and improve insulin sensitivity [9]. Therefore it comes as no surprise that metformin, which is a drug inhibiting mTORC1 and reducing insulin resistance, attenuates RA, decreasing the serum levels of the pro-inflammatory cytokines TNF-α, IL-17 and IL-1 [10]. In light of the above and according to the results by Albrecht et al. [1], RA patients with higher risk of developing DM are the ones who are less frequently treated with targeted therapies by rheumatology specialists. Simply put, it is recommended to adequately treat the main disease to prevent the associated comorbidities. Once again, mTOR signalling appears to be the key to better understand the pathogenesis and explain the association of a large number of diseases. Currently mTOR signalling inhibitors do not act selectively on mTORC1 rather than on mTORC2. Further work is needed to develop mTORC1-specific inhibitors, unlocking the full therapeutic potential of this remarkable pathway. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. References 1 Albrecht K, Luque Ramos A, Hoffmann F, Redeker I, Zink A. High prevalence of diabetes in patients with rheumatoid arthritis: results from a questionnaire survey linked to claims data. Rheumatology  2017, doi: 10.1093/rheumatology/kex414. 2 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell  2012; 149: 274– 93. Google Scholar CrossRef Search ADS PubMed  3 Cejka D, Hayer S, Niederreiter B et al.   Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum  2010; 62: 2294– 302. Google Scholar CrossRef Search ADS PubMed  4 Monfrecola G, Balato A, Caiazzo G et al.   Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop. J Eur Acad Dermatol Venereol  2016; 30: 1631– 3. Google Scholar CrossRef Search ADS PubMed  5 Nagai S, Kurebayashi Y, Koyasu S. Role of PI3K/Akt and mTOR complexes in Th17 cell differentiation. Ann N Y Acad Sci  2013; 1280: 30– 4. Google Scholar CrossRef Search ADS PubMed  6 Xiaoyin Niu X, Chen G. Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis. J Immunol Res  2014; 2014: 698192. Google Scholar PubMed  7 De Vita V, Melnik BC. Activated mTORC1 signalling: the common driving force of type 2 diabetes and hidradenitis suppurativa. J Am Acad Dermatol  2017; doi: 10.1016/j.jaad.2017.11.061. 8 Moon JS, Hisata S, Park MA et al.   mTORC1 induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep  2015; 12: 102– 15. Google Scholar CrossRef Search ADS PubMed  9 Qu W, Han C, Li M, Zhang J, Jiang Z. Anti-TNF-α antibody alleviates insulin resistance in rats with sepsis-induced stress hyperglycemia. J Endocrinol Invest  2017, doi: 10.1007/s40618-017-0742-7. 10 Kang KY, Kim YK, Yi H et al.   Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol  2013; 16: 85– 92. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Activation of mechanistic target of rapamycin complex 1: the common link between rheumatoid arthritis and diabetes mellitus

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1462-0324
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10.1093/rheumatology/key038
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Abstract

An increased prevalence of diabetes mellitus (DM) in patients with RA has emerged in recent years. The article by Albrecht et al. [1] in this issue of Rheumatology is a welcome addition to this debate. Evidence suggests that dysregulation in the mechanistic target of rapamycin complex 1 (mTORC1) signalling is key to explaining the association between RA and DM. mTOR is the core constituent of the phosphatidylinositol 3-kinase-related kinase protein family and works in two distinct multiprotein complexes known as mTORC1 and mTORC2 [2]. mTORC1 is the major regulator of survival, growth, proliferation and motility in response to mitogens, energy and nutrient levels. Due to its central role in cellular functions, mTORC1 dysregulation is involved in a large number of diseases [2]. Upregulation of mTORC1 has also been observed in several immune disorders, including RA [3]. In some of these disorders, mTORC1 expression has shown to be positively correlated with the insulin resistance index as determined by homoeostasis model assessment (HOMA) [4]. This comes as no surprise since mTORC1 also plays a key role in DM pathogenesis [2]. In particular, several studies have clearly identified mTORC1 hyperactivation as a major determinant of hypertrophic obesity and related inflammation and insulin resistance. First, mTORC1 activates S6 kinase (S6K), which in turn causes phosphorylation and degradation of insulin receptor substrate 1/2 (IRS1/2), which impairs insulin signalling. Second, mTORC1 causes insulin resistance by affecting growth factor receptor-bound protein 10 (Grb10). Thus, hyperactivation of mTORC1 causes insulin resistance by at least two mechanisms [2] (Fig. 1). Glucose activates mTORC1 and causes expansion and hypertrophy of β cells as well as increasing insulin secretion. β cell hyperfunction compensates for insulin resistance, preventing hyperglycaemia. Lastly, hyperfunction causes β cell failure and manifest diabetes. In fact, prolonged overactivation of mTORC1 might result in a predominant S6K negative-feedback loop with decrease in IRS1/2 levels and reduction of IRS2/pancreatic and duodenal homeobox 1 (PDX1) pathway, fostering β-cell death. Remarkably, dietary restriction reduces mTORC1 activity and improves insulin sensitivity [2]. Fig. 1 View largeDownload slide The role of the mTORC1 pathway in RA and DM pathogenesis Activation of mTORC1 causes insulin resistance through a negative-feedback loop by mediating IRS1 serine phosphorylation via S6K and by blocking the association between IR and IRS1/2 via Grb10. TNF-α also contributes to insulin resistance by activating IKK-β, which inactivates TSC1, a key negative regulator of mTORC1. In addition, mTORC1 promotes Th17 differentiation and NLRP3 inflammasome activation. TNF-α, IL-17, IL-1β, IL-18 and IL-33 drive the inflammatory process in RA as well as in DM. Fig. 1 View largeDownload slide The role of the mTORC1 pathway in RA and DM pathogenesis Activation of mTORC1 causes insulin resistance through a negative-feedback loop by mediating IRS1 serine phosphorylation via S6K and by blocking the association between IR and IRS1/2 via Grb10. TNF-α also contributes to insulin resistance by activating IKK-β, which inactivates TSC1, a key negative regulator of mTORC1. In addition, mTORC1 promotes Th17 differentiation and NLRP3 inflammasome activation. TNF-α, IL-17, IL-1β, IL-18 and IL-33 drive the inflammatory process in RA as well as in DM. In addition, the mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells, as clearly verified by the immune-suppressive function of mTORC1 inhibitors such as rapamycin [2]. Notably, the differentiation of Th17 cells is controlled by mTORC1, which promotes Th17 differentiation [5] (Fig. 1). Significantly increased IL-17 levels have been found in the blood and SF of RA patients [6]. Using samples of bone obtained from surgery, the addition of IL-17 together with TNF-α and IL-1 induced in vitro bone-destructive cytokine production and bone resorption. Conversely, inhibition of IL-17 resulted in an anti-inflammatory effect and lower bone destruction. Intriguingly, evidence shows that IL-17 also plays a key role in insulin resistance and DM [7]. Obesity is one of the main known causes of the development of DM. In obese patients, increased plasma concentrations of insulin, IGF-1 and IL-17 are observed. Serum IL-17 is significantly higher in patients with DM than in controls. IL-17 deficiency increased glucose tolerance and sensitivity to insulin in young mice. IL-1β, IL-18 and IL-33 are further important pro-inflammatory cytokines belonging to the IL-1 family that are involved in the pathogenesis of both RA and DM [6]. The drugs which target these factors, such as anakinra and canakinumab, are widely used in the treatment of RA. The NLRP3 inflammasome is the best-characterized inflammasome to date and acts as an activation platform for cytokines [8]. Once activated, NLRP3 recruits the apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). ASC is a key adaptor molecule bridging NLRP3 with procaspase-1 within the inflammasome complex, with the consequent activation of procaspase-1. The active form, caspase-1, cleaves pro-inflammatory cytokines such as pro-IL-1β, pro-IL-18 and pro-IL-33 into their active forms, namely IL-1β, IL-18 and IL-33. Intriguingly, mTORC1-induced glycolysis provides a critical mechanism for NLRP3 inflammasome activation in macrophages [8] (Fig. 1). Downregulation of glycolysis by inhibition of mTORC1 suppresses caspase-1 activation in macrophages and subsequently pro-IL-1β maturation. Finally, TNF-α, a pro-inflammatory cytokine that plays a pivotal role in regulating the inflammatory response in RA [6], activates IκB kinase (IKK)-β, which inactivates hamartin (TSC1), a key negative regulator of mTORC1 [2] (Fig. 1). Thus TNF-α impairs insulin signalling and contributes to insulin resistance. As a result, anti-TNF agents—which inhibit joint destruction in RA patients, improving the clinical picture and quality of life—also decrease mTORC1 activity and improve insulin sensitivity [9]. Therefore it comes as no surprise that metformin, which is a drug inhibiting mTORC1 and reducing insulin resistance, attenuates RA, decreasing the serum levels of the pro-inflammatory cytokines TNF-α, IL-17 and IL-1 [10]. In light of the above and according to the results by Albrecht et al. [1], RA patients with higher risk of developing DM are the ones who are less frequently treated with targeted therapies by rheumatology specialists. Simply put, it is recommended to adequately treat the main disease to prevent the associated comorbidities. Once again, mTOR signalling appears to be the key to better understand the pathogenesis and explain the association of a large number of diseases. Currently mTOR signalling inhibitors do not act selectively on mTORC1 rather than on mTORC2. Further work is needed to develop mTORC1-specific inhibitors, unlocking the full therapeutic potential of this remarkable pathway. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest. References 1 Albrecht K, Luque Ramos A, Hoffmann F, Redeker I, Zink A. High prevalence of diabetes in patients with rheumatoid arthritis: results from a questionnaire survey linked to claims data. Rheumatology  2017, doi: 10.1093/rheumatology/kex414. 2 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell  2012; 149: 274– 93. Google Scholar CrossRef Search ADS PubMed  3 Cejka D, Hayer S, Niederreiter B et al.   Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum  2010; 62: 2294– 302. Google Scholar CrossRef Search ADS PubMed  4 Monfrecola G, Balato A, Caiazzo G et al.   Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop. J Eur Acad Dermatol Venereol  2016; 30: 1631– 3. Google Scholar CrossRef Search ADS PubMed  5 Nagai S, Kurebayashi Y, Koyasu S. Role of PI3K/Akt and mTOR complexes in Th17 cell differentiation. Ann N Y Acad Sci  2013; 1280: 30– 4. Google Scholar CrossRef Search ADS PubMed  6 Xiaoyin Niu X, Chen G. Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis. J Immunol Res  2014; 2014: 698192. Google Scholar PubMed  7 De Vita V, Melnik BC. Activated mTORC1 signalling: the common driving force of type 2 diabetes and hidradenitis suppurativa. J Am Acad Dermatol  2017; doi: 10.1016/j.jaad.2017.11.061. 8 Moon JS, Hisata S, Park MA et al.   mTORC1 induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep  2015; 12: 102– 15. Google Scholar CrossRef Search ADS PubMed  9 Qu W, Han C, Li M, Zhang J, Jiang Z. Anti-TNF-α antibody alleviates insulin resistance in rats with sepsis-induced stress hyperglycemia. J Endocrinol Invest  2017, doi: 10.1007/s40618-017-0742-7. 10 Kang KY, Kim YK, Yi H et al.   Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol  2013; 16: 85– 92. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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RheumatologyOxford University Press

Published: Mar 7, 2018

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