Diabetes, obesity, and insulin resistance in COVID-19: molecular interrelationship and therapeutic implications

Diabetology & Metabolic Syndrome - Tập 13 Số 1 - 2021
Andrey dos Santos1, Daniéla Oliveira Magro2, Rosana Evangelista Poderoso3, Mário José Abdalla Saad1
1Department of Internal Medicine-FCM, State University of Campinas-UNICAMP, Campinas, SP, Brazil
2Department of Surgery, Faculty of Medical Sciences, State University of Campinas-UNICAMP, Campinas, SP, Brazil
3Faculty of Medical Sciences, State University of Campinas-UNICAMP, Campinas, SP, Brazil

Tóm tắt

Abstract Background

Our understanding of the pathophysiology of the COVID-19 manifestations and evolution has improved over the past 10 months, but the reasons why evolution is more severe in obese and diabetic patients are not yet completely understood.

Main text

In the present review we discuss the different mechanisms that may contribute to explain the pathophysiology of COVID-19 including viral entrance, direct viral toxicity, endothelial dysfunction, thromboinflammation, dysregulation of the immune response, and the renin–angiotensin–aldosterone system.

Conclusions

We show that the viral infection activates an integrated stress response, including activations of serine kinases such as PKR and PERK, which induce IRS-1 serine phosphorylation and insulin resistance. In parallel, we correlate and show the synergy of the insulin resistance of COVID-19 with this hormonal resistance of obesity and diabetes, which increase the severity of the disease. Finally, we discuss the potential beneficial effects of drugs used to treat insulin resistance and diabetes in patients with COVID-19.

Từ khóa


Tài liệu tham khảo

Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017–32.

Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, Amadou C, Arnault G, Baudoux F, Bauduceau B, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63(8):1500–15.

Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, Su X, Cao B. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020;395(10235):1517–20.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e278.

Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590–2.

Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, Yi F, Yang HC, Fogo AB, Nie X, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219–27.

Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, Sepe PA, Resasco T, Camporotondo R, Bruno R, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020;22(5):911–5.

Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158(6):1831-3.e1833.

Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 2020;526(1):135–40.

Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181(5):1016-35.e1019.

Pan XW, Xu D, Zhang H, Zhou W, Wang LH, Cui XG. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med. 2020;46(6):1114–6.

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–8.

Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;20(7):389–91.

Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8.

Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13(1):34–45.

Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38–44.

Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019;133(9):906–18.

Koupenova M, Corkrey HA, Vitseva O, Manni G, Pang CJ, Clancy L, Yao C, Rade J, Levy D, Wang JP, et al. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019;10(1):1780.

Semple JW, Italiano JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–74.

Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355–62.

Yeaman MR. Platelets in defense against bacterial pathogens. Cell Mol Life Sci. 2010;67(4):525–44.

Bikdeli B, Madhavan MV, Gupta A, Jimenez D, Burton JR, Der Nigoghossian C, Chuich T, Nouri SN, Dreyfus I, Driggin E, et al. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost. 2020;120(7):1004–24.

Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res. 2019;181:77–83.

Kim KD, Zhao J, Auh S, Yang X, Du P, Tang H, Fu YX. Adaptive immune cells temper initial innate responses. Nat Med. 2007;13(10):1248–52.

Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39(5):529–39.

Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185–94.

Tomar B, Anders HJ, Desai J, Mulay SR. Neutrophils and neutrophil extracellular traps drive necroinflammation in COVID-19. Cells. 2020;9(6):1383.

Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Egeblad M, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999.

Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, Kahn CR, Wagner DD. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015;21(7):815–9.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–8.

Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, Tobin KA, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.

Cummings MJ, Baldwin MR, Abrams D, Jacobson SD, Meyer BJ, Balough EM, Aaron JG, Claassen J, Rabbani LE, Hastie J, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763–70.

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Du C, Zhang Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–43.

Zhou F. Clinical course and risk factors for mortality of adult inpatients with COVID-19in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46:846–8.

Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653–9.

Gilliam-Davis S, Gallagher PE, Payne VS, Kasper SO, Tommasi EN, Westwood BM, Robbins ME, Chappell MC, Diz DI. Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components. Physiol Genomics. 2011;43(13):829–35.

Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, Levitt KS, Oudit GY, Al-Omran M, Stewart DJ, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol. 2008;295(4):H1377–84.

Mizuiri S, Aoki T, Hemmi H, Arita M, Sakai K, Aikawa A. Urinary angiotensin-converting enzyme 2 in patients with CKD. Nephrology (Carlton). 2011;16(6):567–72.

Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, McCray PB, Chappell M, Hackam DJ, Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg. Am J Physiol Lung Cell Mol Physiol. 2018;314(1):L17–31.

Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015;47(4):693–705.

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8.

Sánchez-Aguilar M, Ibarra-Lara L, Del Valle-Mondragón L, Rubio-Ruiz ME, Aguilar-Navarro AG, Zamorano-Carrillo A, Ramírez-Ortega MDC, Pastelín-Hernández G, Sánchez-Mendoza A. Rosiglitazone, a ligand to PPAR γ, Improves blood pressure and vascular function through renin-angiotensin system regulation. PPAR Res. 2019;2019:1371758.

Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep. 2014;16(6):431.

Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans. 2006;34(Pt 1):7–11.

Donnelly N, Gorman AM, Gupta S, Samali A. The eIF2α kinases: their structures and functions. Cell Mol Life Sci. 2013;70(19):3493–511.

Leiria LOS, Arantes-Costa FM, Calixto MC, Alexandre EC, Moura RF, Folli F, Prado CM, Prado MA, Prado VF, Velloso LA, et al. Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons. Cell Rep. 2015;11(6):934–43.

Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol. 2004;167(1):27–33.

Nagahara N, Yoshii T, Abe Y, Matsumura T. Thioredoxin-dependent enzymatic activation of mercaptopyruvate sulfurtransferase. An intersubunit disulfide bond serves as a redox switch for activation. J Biol Chem. 2007;282(3):1561–9.

Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153(5):1011–22.

Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D. Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 2003;22(5):1180–7.

Hirata AE, Alvarez-Rojas F, Carvalheira JB, Carvalho CR, Dolnikoff MS, Abdalla Saad MJ. Modulation of IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of MSG-rats. Life Sci. 2003;73(11):1369–81.

Zanotto TM, Quaresma PG, Guadagnini D, Weissmann L, Santos AC, Vecina JF, Calisto K, Santos A, Prada PO, Saad MJ. Blocking iNOS and endoplasmic reticulum stress synergistically improves insulin resistance in mice. Mol Metab. 2017;6(2):206–18.

Saad MJ, Folli F, Araki E, Hashimoto N, Csermely P, Kahn CR. Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and dexamethasone. Mol Endocrinol. 1994;8(5):545–57.

Bezerra RM, Ueno M, Silva MS, Tavares DQ, Carvalho CR, Saad MJ, Gontijo JA. A high-fructose diet induces insulin resistance but not blood pressure changes in normotensive rats. Braz J Med Biol Res. 2001;34(9):1155–60.

Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC, Clement N, Moes S, Colombi M, Meier JA, et al. Insulin resistance causes inflammation in adipose tissue. J Clin Invest. 2018;128(4):1538–50.

Huang SC, Smith AM, Everts B, Colonna M, Pearce EL, Schilling JD, Pearce EJ. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity. 2016;45(4):817–30.

Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–7.

Ayres JS. Immunometabolism of infections. Nat Rev Immunol. 2020;20(2):79–80.

Wang D. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. J Am Med Assoc. 2020;323:1061-1069.

Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, Gao YD. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020;75(7):1730–41.

Deng SQ, Peng HJ. Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China. J Clin Med. 2020;9(2):575.

Iacobellis G, Penaherrera CA, Bermudez LE, Bernal Mizrachi E. Admission hyperglycemia and radiological findings of SARS-CoV2 in patients with and without diabetes. Diabetes Res Clin Pract. 2020;164:108185.

Zhang Y, Li H, Zhang J, Cao Y, Zhao X, Yu N, Gao Y, Ma J, Zhang H, Guo X, et al. The clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease 2019: a single-centre, retrospective, observational study in Wuhan. Diabetes Obes Metab. 2020;22(8):1443–54.

Wang F, Yang Y, Dong K, Yan Y, Zhang S, Ren H, Yu X, Shi X. Clinical characteristics of 28 patients with diabetes and Covid-19 in Wuhan, China. Endocr Pract. 2020;26(6):668–74.

Rayman G, Lumb A, Kennon B, Cottrell C, Nagi D, Page E, Voigt D, Courtney H, Atkins H, Platts J, et al. Guidance on the management of Diabetic Ketoacidosis in the exceptional circumstances of the COVID-19 pandemic. Diabet Med. 2020;37(7):1214–6.

Kim NY, Ha E, Moon JS, Lee YH, Choi EY. Acute hyperglycemic crises with coronavirus disease-19: case reports. Diabetes Metab J. 2020;44(2):349–53.

Tian S. Pulmonary pathology of early-phase novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol. 2020;15:700–4.

Chee YJ, Ng SJH, Yeoh E. Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. Diabetes Res Clin Pract. 2020;164:108166.

Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. The protein expression profile of ACE2 in human tissues. Mol Syst Biol. 2020;16(7):e9610.

Nam SY, Seo HH, Park HS, An S, Kim JY, Yang KH, Kim CS, Jeong M, Jin YW. Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation. J Biol Chem. 2010;285(41):31157–63.

Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47(3):193–9.

Fignani D, Licata G, Brusco N, Nigi L, Grieco GE, Marselli L, Overbergh L, Gysemans C, Colli ML, Marchetti P, et al. SARS-CoV-2 receptor angiotensin I-converting enzyme type 2 (ACE2) is expressed in human pancreatic. Front Endocrinol (Lausanne). 2020;11:596898.

Scheen AJ. Metformin and COVID-19: from cellular mechanisms to reduced mortality. Diabetes Metab. 2020;46:423–6.

Sharma S, Ray A, Sadasivam B. Metformin in COVID-19: a possible role beyond diabetes. Diabetes Res Clin Pract. 2020;164:108183.

Hariyanto TI, Kurniawan A. Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection. Obes Med. 2020;19:100290.

Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, Locy ML, Ravi S, Deshane J, Mannon RB, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121–7.

Chen JY, Qiao K, Liu F, Wu B, Xu X, Jiao GQ, Lu RG, Li HX, Zhao J, Huang J, et al. Lung transplantation as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019-related pulmonary fibrosis. Chin Med J (Engl). 2020;133(12):1390–6.

Schopman JE, Simon AC, Hoefnagel SJ, Hoekstra JB, Scholten RJ, Holleman F. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014;30(1):11–22.

Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis. 2020;63(3):390–1.

Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr. 2020;14(3):247–50.

Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, Berland J, Gueret P, Wyart P, Deturck R, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab. 2010;95(11):4993–5002.

Cure E, Cumhur Cure M. Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis. Diabetes Metab Syndr. 2020;14(4):405–6.

Lorenzo-González C, Atienza-Sánchez E, Reyes-Umpierrez D, Vellanki P, Davis GM, Pasquel FJ, Cardona S, Fayfman M, Peng L, Umpierrez GE. Safety and efficacy of DDP4-inhibitors for management of hospitalized general medicine and surgery patients with type 2 diabetes. Endocr Pract. 2020. https://doi.org/10.4158/EP-2019-0481.

Li Y, Zhang Z, Yang L, Lian X, Xie Y, Li S, Xin S, Cao P, Lu J. The MERS-CoV receptor DPP4 as a candidate binding target of the SARS-CoV-2 spike. iScience. 2020;23(8):101400.

Chen Y, Yang D, Cheng B, Chen J, Peng A, Yang C, Liu C, Xiong M, Deng A, Zhang Y, et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020;43(7):1399–407.

Xu Z, Wang Z, Wang S, Ye Y, Luo D, Wan L, Yu A, Sun L, Tesfaye S, Meng Q, et al. The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID-19. J Diabetes. 2020. https://doi.org/10.1111/1753-0407.13084.

Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, Lei F, Wang H, Xie J, Wang W, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing Type 2 Diabetes. Cell Metab. 2020;31(6):1068-77.e1063.

Rhee SY, Lee J, Nam H, Kyoung D-S, Kim DJ. Effects of a DPP-4 inhibitor and RAS blockade on clinical outcomes of patients with diabetes and COVID-19. medRxiv. 2020:2020.2005.2020.20108555.

Fadini GP, Morieri ML, Longato E, Bonora BM, Pinelli S, Selmin E, Voltan G, Falaguasta D, Tresso S, Costantini G, et al. Exposure to dipeptidyl-peptidase-4inhibitors and COVID-19 among people with type 2 diabetes: a case-control study. Diabetes Obes Metab. 2020. https://doi.org/10.1111/dom.14097.

Solerte SB, D’Addio F, Trevisan R, Lovati E, Rossi A, Pastore I, Dell’Acqua M, Ippolito E, Scaranna C, Bellante R, et al. Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective observational study. Diabetes Care. 2020;43:2999–3006.

Kock G, Bringmann A, Held SA, Daecke S, Heine A, Brossart P. Regulation of dectin-1-mediated dendritic cell activation by peroxisome proliferator-activated receptor-gamma ligand troglitazone. Blood. 2011;117(13):3569–74.

Chen Y, Niu Z, Cui J, Shen P. The inhibitory effect of troglitazone on macrophage differentiation mediated by repressing NF-κB activation independently of PPARγ. 2014;10(3):261–8.

Zhang W, Xu YZ, Liu B, Wu R, Yang YY, Xiao XQ, Zhang X. Pioglitazone upregulates angiotensin converting enzyme 2 expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis. ScientificWorldJournal. 2014;2014:603409.

Mohapatra J, Sharma M, Singh S, Chatterjee A, Swain P, Balaraman R, Patel PR, Jain MR. Subtherapeutic dose of pioglitazone reduces expression of inflammatory adipokines in db/db mice. Pharmacology. 2009;84(4):203–10.

Zhang Y, Cui Y, Shen M, Zhang J, Liu B, Dai M, Chen L, Han D, Fan Y, Zeng Y, et al. Association of diabetes mellitus with disease severity and prognosis in COVID-19: a retrospective cohort study. Diabetes Res Clin Pract. 2020;165:108227.

Yan Y, Yang Y, Wang F, Ren H, Zhang S, Shi X, Yu X, Dong K. Clinical characteristics and outcomes of patients with severe covid-19 with diabetes. BMJ Open Diabetes Res Care. 2020;8(1):e001343.

Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, Knighton P, Holman N, Khunti K, Sattar N, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020;8(10):813–22.