key: cord-0857337-n2bb2jm8 authors: Tsilingiris, Dimitrios; Dalamaga, Maria; Liu, Junli title: SARS-CoV-2 adipose tissue infection and hyperglycemia: A further step towards the understanding of severe COVID-19 date: 2022-01-13 journal: Metabol Open DOI: 10.1016/j.metop.2022.100163 sha: 94bb37330cd862ec527364a9ac8b24da3ee033a4 doc_id: 857337 cord_uid: n2bb2jm8 Numerous studies have highlighted the prognostic significance of hyperglycemia in the outcomes of SARS-CoV-2 infection. A number of mechanisms have been proposed as potential drivers of this association, which were, however, up until recently based rather on speculation than on investigational evidence. It has been recently come to light that the development of insulin resistance in the frame of COVID-19 is likely the driving force behind the development of overt hyperglycemia. This results through the infectious insult of the adipose tissue, and is observed in conjunction with aberrant adipokine secretion by host adipocytes, such as decreased adiponectin, as well as a switch towards an antiviral immune secretory profile. These data could have a considerable relevance not only for the management of hyperglycemia in the course of the infection but also for the overall understanding of the pathogenesis of severe COVID-19. The novel coronavirus disease 2019 caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) constitutes an unprecedented public health challenge with important implications in morbidity and mortality globally [1] [2] . Worldwide, as of January 7, 2022, there have been 298, 915,721 confirmed cases of COVID-19, including 5,469,303 confirmed deaths reported to WHO, and these numbers continue to rise every day [3] . While SARS-CoV-2 infection is related with substantial pulmonary disease, including pneumonia and acute respiratory distress syndrome (ARDS), COVID-19 may present with a plethora of extrapulmonary manifestations [4] . Meta-analyses of population-based studies have reported that obesity and diabetes mellitus are significant and independent risk factors for COVID-19 severity, hospitalization, ICU admission, and death in subjects with COVID-19 [5] [6] . However, independently from pre-existing DM, hyperglycemia is a biomarker of unfavorable prognosis, being associated with nosocomial adverse outcomes, risk of developing acute respiratory distress syndrome (ARDS) and a 7-fold increased mortality in comparison to well-controlled glycemia [7] [8] [9] [10] . Altered glucose homeostasis, considered a tailored response for an effective immune response in infection, is attributed to the following physiological mechanisms: 1) the hypersecretion of inflammatory cytokines, particularly interleukin (IL)-6, IL-1b, and tumor necrosis factor (TNF)-α; 2) the enhanced hypothalamo-pituitary axis resulting in cortisol production; 3) the increase in the release of catecholamines, glucagon and growth hormone; 4) decreased blood flow in muscles resulting in lower glucose uptake J o u r n a l P r e -p r o o f by muscles; 5) liver gluconeogenesis fueling the increased metabolic state [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] . The The presented findings are affirmative of previous reports on elevated levels of circulating free FAs in COVID-19 infection, consistent with a failure of insulin to suppress lipolysis and impaired insulin action at the adipocyte level [24] . The insulin resistant metabolic profile manifesting profoundly as hyperglycemia was associated with an increased risk of adverse outcomes in the initial cohort of 3,854 patients studied by Reiterer et al [22] . Nonetheless, hyperglycemia among those hospitalized with COVID-19-related ARDS did not confer an additional mortality risk, which came in stark contrast to the increased corresponding risks observed in the two control groups. This finding gives rise to the notion that it may not be the detrimental effects of hyperglycemia per se and/or insulin resistance that mediate the worse prognosis Another implication concerns the potential tropism of SARS-CoV-2 for lipid-laden cells and tissues, which was highlighted in the study by Zickler et al [23] . Based on their findings, this may be at least partly due to the upregulated ACE2 membrane J o u r n a l P r e -p r o o f expression. Ectopic lipid deposition is a feature of metabolic burden in obesity, and is associated with systemic insulin resistance and overt hyperglycemia [15, [26] [27] [28] [29] [30] . It can be speculated that this may render tissues which are not principal targets of SARS-CoV-2 (apart from adipose tissue also liver among obese patients as demonstrated in the study) prone to infection, predisposing to a more diffuse organ involvement and higher rates of replication and virion production. In turn, this could partly account for the considerably worse outcome among patients with obesity and diabetes mellitus, and could advocate for a preventive role of antidiabetic medications with known ameliorating effects of fat distribution (e.g. thiazolidinediones). In any case, these recent findings have revealed a rather unexpected mechanism behind COVID-19-related hyperglycemia contributing to the understanding of the pathogenetic mechanisms of SARS-CoV-2 infection. Whether this new evidence will suffice to drastically change the common practice of hyperglycemia management in the frame of SARS-CoV-2 remains to be elucidated. Vaccine induced thrombotic thrombocytopenia: The shady chapter of a success story Anti-viral treatment for SARS-CoV-2 infection: A race against time amidst the ongoing pandemic Extrapulmonary manifestations of COVID-19 Understanding the Co-Epidemic of Obesity and COVID-19: Current Evidence, Comparison with Previous Epidemics, Mechanisms, and Preventive and Therapeutic Perspectives Diabetes Mellitus and SARS-CoV-2 Infection: Pathophysiologic Mechanisms and Implications in Management Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes Circulating leptin, soluble leptin receptor and free leptin index in critically ill patients with sepsis: a prospective observational study The Role of Adipose Tissue and Adipokines in Sepsis: Inflammatory and Metabolic Considerations, and the Obesity Paradox Is There an Obesity Paradox in Critical Illness? Epidemiologic and Metabolic Considerations Cedecea lapagei bacteremia following cement-related chemical burn injury Platelet markers correlate with glycemic indices in diabetic, but not diabetic-myelodysplastic patients with normal platelet count Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies Classic and Novel Adipocytokines at the Intersection of Obesity and Cancer: Diagnostic and Therapeutic Strategies Dionyssiou-Asteriou A. Circulating oxidized LDL levels, current smoking and obesity in postmenopausal women Cutaneous manifestations in relation to immunologic parameters in a cohort of primary myelodysplastic syndrome patients Palmoplantar and scalp psoriasis occurring during anti-tumour necrosis factor-alpha therapy: a case series of four patients and guidelines for management Circulating adiponectin and leptin in relation to myelodysplastic syndrome: a case-control study Circulating resistin is a significant predictor of mortality independently from cardiovascular comorbidities in elderly, non-diabetic subjects with chronic kidney disease Circulating eNampt and resistin as a proinflammatory duet predicting independently mortality in critically ill patients with sepsis: A prospective observational study Kinetics of circulating fetuin-A may predict mortality independently from adiponectin, high molecular weight adiponectin and prognostic factors in critically ill patients with sepsis: A prospective study Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2 Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans. Cell metabolism COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status Management of diabetes and hyperglycaemia in the hospital Ectopic Fat Accumulation in Distinct Insulin Resistant Phenotypes; Targets for Personalized Nutritional Interventions Emerging roles for stress kinase p38 and stress hormone fibroblast growth factor 21 in NAFLD development Circulating Omentin-1 as a Biomarker at the Intersection of Postmenopausal Breast Cancer Occurrence and Cardiometabolic Risk: An Observational Cross-Sectional Study Prediabetes screening: Questionable benefits in the golden years The Role of Mitochondrial Adaptation and Metabolic Flexibility in the Pathophysiology of Obesity and Insulin Resistance: an Updated Overview