Coronavirus Disease 2019,Diabetes,and Inflammation: A Systemic Review

Abstract

People with cardiometabolic diseases [namely type 2 diabetes (T2D), obesity, or metabolic syndrome] are more susceptible to coronavirus disease 2019 (COVID-19) infection and endure more severe illness and poorer outcomes. Hyperinflammation has been suggested as a common pathway for both diseases. To examine the role of inflammatory biomarkers shared between COVID-19 and cardiometabolic diseases, we reviewed and evaluated published data using PubMed, SCOPUS, and World Health Organization COVID-19 databases for English articles from December 2019 to February 2022. Of 248 identified articles, 50 were selected and included. We found that people with diabetes or obesity have (i) increased risk of COVID-19 infection; (ii) increased risk of hospitalization (those with diabetes have a higher risk of intensive care unit admissions) and death; and (iii) heightened inflammatory and stress responses (hyperinflammation) to COVID-19, which worsen their prognosis. In addition, COVID-19-infected patients have a higher risk of developing T2D, especially if they have other comorbidities. Treatments controlling blood glucose levels and or ameliorating the inflammatory response may be valuable for improving clinical outcomes in these patient populations. In conclusion, it is critical for health care providers to clinically evaluate hyperinflammatory states to drive clinical decisions for COVID-19 patients.

Introduction

Severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2; coronavirus disease 2019 (COVID-19)], the novel coronavirus, has impacted millions of people, claiming over 6 million lives worldwide as per Our World in Data (from the beginning of the pandemic till November 30, 2022).¹ The COVID-19 infection overwhelmed local health care systems with a sudden influx of critically ill patients seeking medical care.^2
–4 In recent history, coronavirus pandemics included the SARS-CoV-1 in 2003, which affected 26 countries; Middle East respiratory syndrome-CoV in 2012, which affected 27 countries; and COVID-19 in 2019, which is still lurking globally.⁵

With highly variable symptom presentation, from asymptomatic cases to severe infection with multiorgan damage, the COVID-19 pandemic revealed our underpreparedness in diagnosing and managing emerging infectious diseases. Research into developing evidence-based guidelines for early identification of at-risk individuals will enhance our preparedness against emerging infectious diseases.

The incidence of obesity and type 2 diabetes (T2D) was rising to a pandemic proportion globally before COVID-19 emerged as a raging pandemic worldwide. The triad of obesity, T2D, and COVID-19 is a menacing tale of two pandemics causing disproportionate mortality rates. COVID-19 symptoms tend to be highly unpredictable, with sudden worsening of symptoms among adults with cardiometabolic illnesses, especially T2D. People with diabetes are not only more susceptible to COVID-19 infection but also endure more severe illness and poorer outcomes, that is, mortality.⁶

Novel data suggest that visceral obesity and hyperglycemia in the nondiabetic and diabetic ranges could also be important independent risk factors for severe COVID-19. In addition, as obesity and T2D have been found to impair the development of immunological memory, it cannot be excluded that obesity and hyperglycemia might also negatively affect the efficacy of a COVID-19 vaccine.⁷ However, the accurate pathophysiological link between the increased COVID-19 disease vulnerability and T2D still requires a precise scientific explanation.

The pathophysiological mechanisms leading to severe COVID-19 illnesses among vulnerable populations are an immediate research priority to develop interventions to curb COVID-19-related mortality rates. A hyperinflammatory response has been suggested for T2D and obesity, with increased accumulation of resident immune cells in multiple tissues, which in turn enables a heightened state of basal inflammation through enhanced cytokine and chemokine production, leading to the impairment of beta-cell function and exacerbation of insulin resistance.^8,9

Collectively, these acquired abnormalities impair immune function, likely leading to greater susceptibility to infection in individuals with T2D.^9,10 Additionally, the interplay between nonalcoholic fatty liver disease and diabetes has also been projected to play a role in the impairment of glucose and lipid metabolic pathways, leading to a hyperinflammatory response and in turn susceptibility to COVID-19 infection.¹¹

As the primary product of lipogenesis is the saturated fatty acid palmitate, which induces hepatic inflammation and endoplasmic reticulum stress, it is well established that increased hepatic lipogenesis strongly associates with insulin resistance and increased cardiometabolic risk profile.^11
–13

Methods

This review evaluated published data regarding the effects of COVID-19 infection in people with diabetes and metabolic syndrome using the PubMed, SCOPUS, and World Health Organization (WHO) COVID-19 databases for English articles from December 2019 to February 2022. The strategy was to combine and distill all currently available studies and reviews to provide an overview of the relationship between metabolic syndrome, diabetes, inflammation, and COVID-19. The search was performed by combining terms: [diabetes AND inflammatory cytokines AND COVID-19 AND mortality].

We used the following MeSH terms: inflammation, inflammation mediators, cytokines, interleukin-1beta, interferon-gamma, and TNF-alpha; and keywords: “pro-inflammatory cytokine” OR “pro-inflammatory cytokines” OR “proinflammatory cytokine” OR “proinflammatory cytokines” OR “inflammatory cytokine” OR “inflammatory cytokines” OR “cytokine” OR “cytokines” OR “interleukin 1” OR “il1b” OR “il-1b” OR “il-1 beta” OR “1l1 beta” OR “il-1b” OR “interleukin 1 beta” OR “interleukin-1beta” OR “interleukin-1beta” OR “interleukin-1b” OR “interleukin 1 b” OR “immune interferon” OR “type ii interferon” OR “gamma interferon” OR “IFNg” OR “IFNgamma” OR “IFN gamma” OR “cachectin” OR “tnf-alpha” OR “tnf-alpha” OR “tnfalpha” OR “tumor necrosis factor alpha” OR “tumor necrosis factor” OR “T cells.”

The literature search was conducted by experienced medical librarians at the University of Texas Medical Branch. Clinical trials, case reports, case–control and cohort studies, review articles, and observational studies were specifically identified and their reference citation lists were searched for additional publications not identified in the original database searches. There were 201 PubMed results, 32 SCOPUS results, and 15 WHO results that were analyzed, yielding a total number of 248 articles with 15 duplicates in the initial search. The remaining 233 articles were then screened by abstract, title, and respective keywords (Fig. 1).

FIG. 1.

Selection process. Studies were excluded if (i) the article did not mention infection with COVID-19, (ii) the study did not include diabetes or metabolic syndrome, or (iii) the article did not relate to the goal of this review. COVID-19, coronavirus disease 2019.

Each article was reviewed by two lead research team members independently and discussed to reach a consensus. Articles were excluded if the study had only been published in an abstract form. The full text was retrieved if the article appeared potentially relevant or the relevance was unknown. The data from each article were extracted using standard data extraction forms and discussed among the authors to ensure consistency.

Following a rigorous selection process, 50 articles met the criteria and were included in this review and summarized in Table 1. Studies were excluded if (i) the article did not mention infection with COVID-19, (ii) the study did not include diabetes or metabolic syndrome, or (iii) the article did not relate to the goal of this review (Fig. 1). We have combined the available information from previous literature to provide a complete review of the complex interplay between metabolic conditions and infection with COVID-19.

Table 1.

Summary of Results (50 Included Records)

Author	Study design	N	Results
Agrawal et al.¹⁶	Review	—	Uncontrolled diabetes ↑COVID-19 infection and mortality/morbidity. COVID-19 infection ↓ glycemic control  complications.
Ahirwar et al.²⁰	Review	—	Chronic hyperglycemia ↑interferon, TNF-α, IL-1β, and IL-6.
Ajaz et al.⁴⁸	Observational	23 pts w/COVID-19	↑FGF-21  ↑COVID-19 severity.
Alzaid et al.⁴⁶	Observational	30 PWD and 15 w/o T2D pts w/COVID-19	T2D  ↑IRF5 and ↑COVID-19 severity.
Amin et al.²³	Review	—	Obesity  ↑inflammatory gene expression and lymphoid tissue reorganization.
Baidya et al.³⁸	Review	—	COVID-19 ↑diabetes risk. Diabetes impacts TNF-α; impairs IL-1; and IL-6 secretion from mononuclear cells.
Baron et al., 2020⁷⁹	Observational	61,414,470 general practice pts	PWD ↑in-hospital mortality from COVID-19.
Belikina et al.²⁶	Case–control	32 PWD/32 pts w/COVID-19	T2D  ↓blood oxygen supply and ↑severity and extension of viral pneumonia, need for active therapy, and hospital stays.
Bonansea et al.¹⁷	Review	—	Diabetes ↑ACE-2 and ↑COVID-19 infection risk.
Bonyek-Silva et al.⁶⁰	Case–control	29 PWD/24 pts w/COVID-19	LTB4 and ALOX5 are linked to ↑inflammatory response and ICU care. Diabetes linked to ↓pulmonary function in COVID-19.
Bramante et al.⁵⁵	Retrospective cohort analysis	6256 PWD w/COVID-19	Metformin is protective against COVID-19 through sex-specific ↓TNF-α.
Chen et al., 2020⁸⁰	Retrospective study	99 pts w/COVID-19	IL-6, CRP, and waist-to-hip ratio and ↑mortality.
Cheng et al., 2021³⁷	Retrospective cohort	103 PWD/123 controls	PWD ↑inflammatory response and COVID-19 severity.
Chiappetta et al.¹⁴	Cross-sectional	33 pts w/MetS	Obesity ↑IL-6 and CRP and ↓EOSS score.
Das, 2020⁵²	Review	—	Obesity ↓BALs and ↑inflammation.
de Souza et al.²⁷	Observational; cross-sectional	244 PWD/694 controls	Patients ≥65 years, obese, and with pre-existing disease  ↑COVID-19-related hospitalizations. No difference between obese and nonobese patients with regard to hospitalization length, ICU admittance, or COVID-19 symptoms.
Fisk et al.⁵⁷	Perspective review	—	Endothelin-A antagonists + SGLT2i as potential TTT.
Guisado-Vascoet al.⁴⁷	Letter to Editor	—	NF-κB and JNK1 pathway linked to ↑COVID-19 severity in pts w/obesity.
Helmi et al.³¹	Review	—	Alterations to TNF, NF-κB, estrogen, and insulin signaling in COVID-19.
Ibrahim et al.³⁴	Review	—	Link between islet ACE-2 expression and islet phenotype associated with COVID-19.
Islam et al., 2022⁸¹	Review	—	↓TNF signaling pathway, cytokine–cytokine receptor interaction, IL-17 signaling, and NF-κB  ↓survival and ↑disease severity.
Iwamura et al.³⁹	Systematic review	—	T2D↑ ESR, CRP, IL-6, and TNF-α and ↓lymphocyte counts and procalcitonin.
Klonoff et al.²	Commentary	—	Hyperglycemia impairs immune response/pulmonary function.
Koufakis et al.⁵⁶	Commentary	—	SGLT2i ↓leptin, IL-6, and TNF-α.
Krause et al.¹⁵	Commentary	—	MetS  impaired heat shock response ↓ inflammation resolution and ↑COVID-19 complications and mortality.
Lin et al.¹⁸	Bibliometric analysis	—	ACE-2 receptor linked to cytokine storm.
Magalhães et al.²⁴	Review	—	Gut dysbiosis ↑IL-6, LPS, and TLR4.
Moin et al.⁴⁰	Prospective case–control	23 PWD and 23 controls	T2D ↑Ras and COVID-19 severity/infection. Neutrophil-activating peptide-2, thrombospondin-1, platelet factor-4, kininogen-1, coagulation factor IX, kininogen-1, and heparin cofactor-2 are altered in T2D vs. controls.
Melvin et al.⁵⁹	Commentary	—	COVID-19 ↑ IL-1β, TNF-α, and IL-6.
Méry et al.⁴⁴	Retrospective cohort	155 pts	Obesity ↓INF-1 and ↑IL-6, IP-10, and INF-3.
Miller et al.⁴⁹	Hypothesis	—	NAD⁺ deficiency may ↑COVID-19 mortality through SIRT1.
Montefusco et al.²⁹	Cohort	551 pts w/COVID	COVID ↑new-onset hyperglycemia  ↑COVID-19 mortality/severity.
Mrugacz et al.¹⁹	Review	—	COVID-19 uses ACE-2 for cellular entry.
Ponsford et al.⁵⁰	Meta-analysis	—	BMI and lifetime smoking score ↑COVID-19 severity.
Rais et al.²²	Review	—	Hyperglycemia  cytokine storm through ↑inflammatory macrophages.
Rathmann et al.³²	Retrospective cohort study	35,865 pts w/COVID-19	TNF-α ↑T2D.
Remuzzi and Remuzzi⁴	Review	—	Diabetes ↑ COVID ARDS.
Schlicht et al.⁵¹	Case–control	7 severe pts w/COVID-19/7 controls	DPP-4 ↓in pts w/COVID-19.
Simonnet et al.²⁵	Retrospective cohort	124 ICU pts w/COVID-19	Obesity/BMI ↑disease severity and death.
Tang et al.⁴³	Experiment	—	SARS-CoV-2 ↓insulin expression and ↑glucagon and trypsin 1.
Unnikrishnan et al.³⁰	Review	—	COVID-19 ↑hyperglycemia.
Vasbinder et al.⁴²	Observational study	2044 hospitalized pts w/COVID-19	COVID-19 ↑T2D through hyperinflammation.
Viurcos-Sanabria et al., 2021²¹	Review	—	Hyperglycemia ↑IL-1β, IL-6, TNF-α, LDH, and lactate.
Wautier and Wautier⁴¹	Review	—	RAGE and STING1 ↑inflammation.
Wu et al.⁵³	Review	—	COVID-19 targets β cells ↑diabetes risk.
Xiao et al., 2020⁸²	Retrospective cohort	602 pts w/COVID-19	↑APTT, PT, D-dimer, and CRP linked to ↑COVID mortality.
Xie et al.³³	Review	Review	Diabetes ↑Ang II ↑inflammation.
Xie et al., 2022⁸³	Cohort study	181,280 pts w/COVID-19	COVID-19 ↑diabetes risk.
Yin et al.⁵⁸	Review	—	Diabetes ↑angiotensin II. ACE-2 deficiency after COVID-19 infection is protective.
Zhou et al.³	Retrospective cohort	191 pts w/COVID-19	HTN, diabetes, CAD ↑ COVID mortality.

ACE-2, angiotensin-converting enzyme 2; ALOX5, arachidonate 5-lipoxygenase; Ang II, angiotensin II; APTT, partial thromboplastin time (activated); ARDS, acute respiratory distress syndrome; BALs, bioactive lipids; BMI, body mass index; CAD, coronary artery disease; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; DPP-4, dipeptidyl peptidase-4; EOSS, Edmonton Obesity Staging System; ESR, erythrocyte sedimentation rate; FGF-21, fibroblast growth factor 21; HTN, hypertension; ICU, intensive care unit; IL, interleukin; INF, interferon; IP-10, interferon gamma-induced protein 10; IRF5, interferon regulatory factor 5; JNK1, c-Jun N-terminal kinase 1; LDH, lactate dehydrogenase; LPS, lipopolysaccharides; LTB4, leukotriene B4; MetS, metabolic syndrome; NAD⁺, nicotinamide adenine dinucleotide; NF-κB, nuclear factor-κB; PT, prothrombin time; pts, patients; PWD, people with diabetes; RAGE, advanced glycation end product receptor; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; SGLT2i, sodium/glucose cotransporter-2 inhibitor; SIRT1, silent information regulator 1; STING1, stimulator of interferon response CGAMP interactor 1; T2D, type 2 diabetes; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-alpha; w/, with; w/o, without.

By understanding how COVID-19 infection affects individuals with diabetes and metabolic syndrome, tailored treatments and clinical management steps may be enacted in the future to improve health outcomes for affected patients.

Results

Obesity/metabolic syndrome/T2D impact on COVID-19 risk of infection

Long-term inflammatory processes, such as obesity, are associated with development of T2D, atherosclerosis, and hypertension, which are known factors that adversely affect COVID-19 outcomes.^14
–16 One possible mechanism is the heat shock response, which is impaired in individuals with metabolic diseases and can account for the increased levels of inflammation and adverse outcomes in individuals suffering from COVID-19.¹⁵ Diabetes also increases angiotensin-converting enzyme 2 (ACE-2) receptor expression in human cells, making it easier for COVID to infect patients.^15,17
–19

Additionally, uncontrolled hyperglycemia in diabetes and correlating abdominal obesity induce abnormal secretion of adipokines and cytokines [i.e., tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), IL-6, and lactate dehydrogenase]. In addition, uncontrolled diabetes and obesity decrease T cell activity and reduce viral clearance, altogether making people with diabetes more susceptible to COVID-19 respiratory infection (Fig. 2).^20
–22 Obesity can also change the structure of lymphoid tissue and increase the expression of inflammatory genes within.²³

FIG. 2.

Obesity or T2D: COVID-19-related mechanisms. Individuals with diabetes, MetS, or obesity have an induced proinflammatory response leading to (i) increased risk of COVID-19 infection; (ii) increased risk of severity, morbidity, and mortality; (iii) increased recovery time; and (iv) increased insulin resistance. T2D, type 2 diabetes.

In people with diabetes or obesity, gut dysbiosis was also postulated to play a role in increasing COVID-19 infection, with an increase in the proportion of bacteria with a proinflammatory profile.²⁴ Due to this dysbiosis, elderly, diabetic, and hypertensive people present a higher propensity to mount an inflammatory environment in the gut with poor immune editing, culminating in weakness of the intestinal permeability barrier and high bacterial product translocation to the bloodstream, crucial for development of the cytokine storm in the severe form of the disease (Fig. 2).²⁴

Hospitalization (+/−intensive care unit)

Individuals with diabetes account for 30% of hospitalized cases,⁶ represent 20% of intensive care unit (ICU) admissions,³ and have an increased risk of more severe illness and in-hospital death.^6,25 In addition, people with diabetes were also found to have a significantly lengthened hospital stay due to COVID-19 when compared with controls.²⁶

A cross-sectional study of Brazilian COVID-19 survivors found a higher prevalence of COVID-19-related hospitalizations in patients older than 65 years (7 times compared with adults aged 18–39 years; P = 0.0001), with overweight and obesity (83% and 166% higher, respectively, compared with normal weight individuals), and with pre-existing diseases (P = 0.003).²⁷ However, this same study found no significant difference between obese and nonobese populations with regard to the length of hospitalization, ICU admittance, or increased COVID-19 symptoms.²⁷

In a European, noninterventional, multicenter cohort study, obesity and impaired metabolic health increased the risk of COVID-19-related mortality in young and middle-aged adults to the level observed in older adults.²⁸

Post-COVID

In patients surviving COVID-19, persistent insulin resistance and β cell dysfunction, manifested as impaired glycemic control, predispose to long-term hyperglycemia and concomitant health risks.^29,30 A study investigating the impacts of COVID-19 on human genes and metabolic pathways found alterations to insulin signaling.³¹ TNF, cytokine, nuclear factor-κB (NF-κB), Toll-like receptor, T-cell receptor, B-cell receptor, Foxo, and transforming growth factor signaling pathways are among them, and pathways such as apoptosis, estrogen signaling, oxidative phosphorylation, protein processing in the endoplasmic reticulum, prolactin signaling, adipocytokine, neurotrophin signaling, and longevity-regulating pathways act a major source of the linkage between COVID-19 and T2D (Fig. 2).³¹

Just as T2D has been shown to increase the risk of severe COVID-19 infection, conversely it has been demonstrated that individuals affected with COVID-19 have a higher incidence of T2D in both the acute postrecovery period and beyond.^32,33 In one retrospective cohort study, rates of T2D were 20.5 per 1000 individuals in the COVID-19 group compared with only 13.6 per 1000 individuals in the control group.³² Similarly, 30-day survivors of COVID-19 demonstrated a higher risk of diabetes and antihyperglycemic use, an effect that correlated with the severity of COVID-19 infection.

Such increased risk is higher in people with comorbidities such as hypertension, cardiovascular disease, hyperlipidemia, obesity, and prediabetes.³³ Genetic factors around islet ACE-2 expression may also play a role in COVID-19-induced β cell injury.³⁴ In addition, a post-COVID autoimmune trigger was observed, increasing the incidence of new-onset type 1 diabetes. The autoantigen ATP4A was identified in children with hyperinflammatory multisystem inflammatory syndrome post-COVID, predisposing them to type 1 diabetes.^35,36

Inflammatory indices associated with worse COVID-19 outcomes

General

People with diabetes are more likely to develop severe COVID-19 than patients without T2D. They were found to have more severe lymphopenia and inflammatory responses and were more likely to have moderate to severe COVID-19 than non-T2D patients.³⁷ COVID-19 patients with T2D had a higher state of inflammation measured by the erythrocyte sedimentation rate and levels of C-reactive protein (CRP), IL-6, TNF-α, and procalcitonin, with lower lymphocyte counts and T lymphocyte subsets.^38,39

A prospective study identified elevated/altered proteins among patients with T2D and COVID-19, including neutrophil-activating peptide-2, thrombospondin-1, platelet factor-4, kininogen-1, coagulation factor IX, kininogen-1, and heparin cofactor-2, suggesting a possible association between T2D and worse COVID-19 outcomes.⁴⁰

The advanced glycation end product receptor, a receptor closely associated with the development of obesity, was linked to endothelial cells and monocyte recruitment in inflammatory processes in COVID-19.⁴¹ This presents a troubling state of increased inflammation with a decreased lymphocyte count to overcome the viral infection. The continued inflammatory state with a weakened immune system increases susceptibility to the COVID-19-induced cytokine storm, leading to septic shock and multiple organ failure.¹⁵

Hyperglycemia itself was found to increase inflammatory markers (i.e., IL-β, IL-6, and TNF-α) and macrophages, contributing to the cytokine storm.²² Additionally, the increased glucose circulating in people with diabetes presents an opportunity for SARS-CoV-2 to thrive. In patients with COVID-19, but without T2D, increased mitochondrial utilization of glucose was reported, suggesting a higher utilization in those with diabetes.³⁷

Similar to other infections, the inflammation associated with COVID-19 results in fluctuations of glycemic control, predisposing these patients to further complications.¹⁶ On admission to the hospital with COVID-19 infection, people with diabetes have shown higher levels of soluble urokinase plasminogen activator receptor (suPAR), CRP, procalcitonin, and D-dimer than patients without T2D, with people with diabetes having 20.7% higher suPAR levels than those without T2D (adjusted odds ratio 1.23; 95% confidence interval 0.78–1.37).⁴²

Specifically, individuals with suPAR levels ≥14.8 ng/mL had a higher incidence of in-hospital death, need for mechanical ventilation, and renal replacement therapy.⁴² Altogether, uncontrolled T2D presents a chronic state of inflammation with hyperglycemia, which allows the SARS-CoV-2 virus to rapidly infect due to increased fuel and decreased host cellular defenses. Furthermore, COVID-19 infection was found to directly impact pancreatic β cells, increasing markers of cellular stress and inflammation and causing a decrease in insulin expression (Fig. 2).⁴³

Prognosis

Immunological features resulting from adipocyte dysfunction and neutrophil activation, evident in people with obesity, may be contributing factors to acute respiratory distress syndrome as well as capillary damage and thrombosis seen in those with COVID-19.⁴⁴ Patients with higher leukocyte and neutrophil counts, higher CRP, D-dimer, prothrombin time, partial thromboplastin time, and elevated international normalized ratio (INR) were all associated with a worse prognosis with COVID-19 (Fig. 2).^26,45

Severity

COVID-induced cytokine storms are often related to the severity of the disease. Various immunophenotypic variations and increased expression of certain inflammatory markers, including interferon regulatory factor 5, have also been shown to be associated with COVID-19 severity in T2D.⁴⁶ In people with diabetes, the NF-κB and c-Jun N-terminal kinase 1 pathways are overexpressed secondary to elevated free fatty acids, which promote B cell dysfunction and thus a proinflammatory state (Fig. 2).⁴⁷

Levels of fibroblast growth factor 21 (FGF-21), a mitokine and a biomarker of mitochondrial dysfunction, were associated with increased COVID-19 disease severity.⁴⁸ Both FGF-21 and IL-6 were found to correlate with higher COVID-19 severity and mortality (Fig. 2).³⁷

Another study has suggested that oxidative stress-induced nicotinamide adenine dinucleotide (NAD⁺) pool depletion may play a large role in the severity of SARS-CoV-2 due to its effects on production of silent information regulator 1 (SIRT1). Elderly patients and people with diabetes more commonly have niacin deficiency and an impaired SIRT1 function, predisposing to the cytokine storm.⁴⁹

The body mass index (BMI) in patients with COVID-19 was associated with an increased risk of other inflammatory complications such as sepsis.⁵⁰ A study examining dipeptidyl peptidase-4 (DPP-4) concentrations in those with severe SARS-CoV-2 infection compared with healthy patients found that levels of DPP-4 were significantly reduced in COVID-19 patients. However, this did not differ in those who were suffering from sepsis from a non-COVID infection.⁵¹

Bioactive lipids (BALs) are capable of inactivating viruses such as COVID-19 as well as restoring homeostasis after an inflammatory state in the body. Those with obesity are at higher risk of BAL deficiency, which results in less secretion of anti-inflammatory products such as lipoxin A4, resolvins, protectins, and maresins, which potentially puts these patients at higher risk of cytokine storm and mortality.⁵²

T2D impact on COVID-19 mortality/morbidity

People with diabetes have an increased mortality risk when they acquire COVID-19⁵³ and an increased risk of in-hospital death.⁶ Data from Italy show that more than two-thirds of those who died of COVID-19 had diabetes.⁴ Similarly, one study found that the incidence of in-hospital death, need for mechanical ventilation, and renal replacement therapy increased significantly in those with diabetes compared with those without diabetes.³³

A case–control study from Russia demonstrated that people with diabetes infected with COVID-19 were more likely to have severe pneumonia [evidenced by a 2.2-fold higher number of people with extensive (>50%) lung damage (P = 0.05) and persistent hypoxemia (P = 0.0004)] and a greater need for pharmacological interventions.²⁶

Another group from Russia performed a retrospective cohort analysis to assess risk factors for adult patients deceased from COVID-19 and concluded that comorbidities, such as hypertension (observed in 81% of deceased patients and more commonly in males—P < 0.001), obesity (observed in 655 deceased patients, with higher burden among females—P < 0.001), diabetes (observed in 37% of deceased patients and more commonly in females), and cancer (observed in 12% of deceased patients with no significant gender-based difference), were the major contributors to COVID-19-induced death.⁵⁴

Chronic low-grade inflammation stages in obesity may predict mortality. The Edmonton Obesity Staging System (EOSS) has been shown to be a better predictor of all-cause mortality than BMI. Indeed, EOSS stages indicate hyperinflammation risk in patients infected with COVID-19. In patients at EOSS2 and EOSS3, IL-6 was shown to be increased and correlated positively with CRP and the waist-to-hip ratio.¹⁴ IL-6, CRP, and increased waist-to-hip ratio correlated with increased mortality (Fig. 2).¹⁴ Activation of the TNF-α, IL-17, and NF-κB signaling pathways increased COVID-19-induced mortality risk. Early identification and treatment of inflammation can improve mortality rates.¹⁴

Treatments to attenuate the COVID-19 prognosis

Glycemic control during COVID-19 infections is of utmost importance due to the adverse effects of hyperglycemia on pulmonary function and immune response.² Metformin was significantly associated with decreased mortality from COVID-19 in women with obesity or T2D in observational analyses. The suggested pathway was consistent with the sex-specific reduction in TNF-α in females over males by metformin.⁵⁵

With COVID-19, the risk of diabetic ketoacidosis is heightened and cessation of sodium/glucose cotransporter-2 inhibitor (SGLT2i) therapy is suggested. A counterargument is explored by identifying the potential of SGLT2 to ameliorate systemic and tissue-specific inflammation, hypoxia, and oxidative stress by downregulating adipokines and cytokines.⁵⁶ The addition of endothelin-A antagonists to SGLT2i therapy demonstrated possible benefits for patients with COVID-19.⁵⁷

Arachidonic acid supplementation has been shown in multiple studies to have anti-inflammatory effects by decreasing a variety of immune cell markers and regulating ACE-2 receptors, which suggest that arachidonic acid supplementation could be of benefit in preventing severe COVID-19 infection.⁵² Lower levels of ACE-2 can potentially result in decreased COVID-19 severity.⁵⁸

Other dietary supplementation treatments such as NAD⁺ precursors or SIRT1 activators have been proposed to minimize COVID-19 severity based on the mechanisms described above.⁴⁹ In addition, the IFN-β pathway was studied in diabetic macrophages. One in vitro study showed that IFN-β upregulated the COVID-19-induced loss of the SET domain bifurcated histone lysine methyltransferase 2 (SETDB2)-facilitated inflammatory response.⁵⁹ This suggests the potential benefit of IFN-β treatment in attenuating the macrophage-driven cytokine storm.

Another potential target for attenuating the cytokine storm is the leukotriene B4 (LTB4) signaling pathway, a lipid-based pathway associated with respiratory disease and lung injury, which was found to be associated with a more pronounced systemic inflammatory response in a Brazilian case–control study of people with diabetes infected with COVID-19.⁶⁰ High levels of arachidonate 5-lipoxygenase, the main molecule in the LTB4 signaling pathway, were found to be associated with increased intensive care unit admissions in people with diabetes infected with COVID-19.⁶⁰

Metabolic disorders and COVID-19 vaccine breakthrough infections

Although great advances with vaccine development combat the severity of COVID-19-induced infections, novel data indicate that risk factors might also promote vaccine breakthrough COVID-19 infections in fully vaccinated people.⁶¹ Scientific evidence reveals a role for obesity (BMI >23 kg/m²) and T2D in the development of severe COVID-19, particularly in younger adults.⁷

Novel data indicate not only that hyperglycemia and insulin resistance drive immunosenescence but also that hyperinsulinemia promotes increased risk of COVID-19 infections and complications.⁶² Together, these studies indicate that obesity and impaired metabolic health increase the risk of vaccine breakthrough COVID-19 infections in fully vaccinated individuals.^61,63
–65

Limitations

The current review is limited to articles published in English in peer-reviewed journals and indexed in PubMed, SCOPUS, and WHO COVID-19 databases. It included a variety of study designs that might impact the precision of collective conclusions. We did not implement a comprehensive bias assessment for the included records with the assumption that they have been subject to meticulous peer and editorial review during their publication process in journals indexed in reliable databases.

Discussion

The primary results of this review detail the effects that metabolic disorders have on the immune system in COVID-19 infection and disease progression. We found that people with diabetes or obesity have (i) increased risk of COVID-19 infection; (ii) increased risk of hospitalization (those with diabetes have a higher risk of ICU admissions) and death; and (iii) heightened inflammatory and stress responses (hyperinflammation) to COVID-19, which worsen their prognosis.

In addition, COVID-19-infected patients have a higher risk of developing T2D, especially if they have other comorbidities. Treatments controlling blood glucose levels and/or ameliorating the inflammatory response may be valuable for improving clinical outcomes in these patient populations.

People with diabetes have an increased risk of COVID-19 infection, hyperinflammation, hospitalization, ICU admission, and death. It is known that hyperglycemia in diabetes disrupts the phagocytic killing and containment of pathogens⁶⁶ and that patients with poorly controlled diabetes have lower levels of neutrophil chemotaxis and natural killer cells, making them more susceptible to infection.^67,68

Additionally, the SARS-CoV-2 virus can act through inflammasomes to release IL-1β and IL-18.⁶⁹ With inflammation and overactivation of T cell function, as depicted by suppression of regulatory T (Treg) cells and increase in T helper 17 cells and CD8⁺ T cells, corresponding inflammatory mediators (such as IL-17A, IL-4, IL-10, IL-13, IFN-γ, and TNF-α) are released.^70
–72

The subsequent cytokine storm leads to mesenchymal activation in tubular epithelial cells, endothelial cells, and macrophages.⁷³ Changes to endothelial cells can compound pre-existing cardiovascular comorbidities and lead to further hypertension and impaired organ perfusion.⁷⁴ Diabetes and the SARS-CoV-2 virus can have a synergistic effect and can lead to provocation and cyclic cascade effects on cytokine release, which lead to further damage and inflammation.⁷⁵

The involvement of humoral immunity, however, is controversial in T2D; in some studies, plasma immunoglobulin levels have reportedly been normal, whereas other studies reported decreased levels of IgM and IgG.⁷⁶ This combination of impaired phagocytic entrapment, elevated inflammatory cytokines, overactivated T cells, and suppressed Treg cells may contribute to altered immune function in people with diabetes. Thus, patients with metabolic disorders infected with COVID-19 carry a greater risk of increased infection severity as well as a predisposition for complications.

Notably, this review points toward the potential risks of incidental T2D following COVID-19 infection. The clinical manifestations of COVID-19, including microcoagulation, cytokine storm, and systemic inflammation, are directly related to endothelial dysfunction.⁷⁷ The SARS-CoV-2 virus gains entry into host cells through ACE-2 receptors present in vital organs and the vascular endothelium.¹⁸

Through the damage-associated molecular pattern signaling cascade, inflammation is induced and results in insulin resistance and the adiponectin paradox, which further links acute metabolic dysfunction to possible progression into chronic disease.⁷⁸ Entry alone results in damage of islet cells and decreased insulin release.³⁸

Additionally, the viral particles unleash a plethora of endocrine–immune–vascular interactions that determine the clinical course of the COVID-19 illness. By this mechanism alone, the virus disrupts hormonal balance and blood glucose control, resulting in dysregulation and altered osmotic balance.

While preventative and vaccination efforts have helped reduce infection rates and disease transmission, targeting hyperglycemia and hyperinflammation in comorbid conditions, such as T2D, obesity, and metabolic disorders, is crucial for reducing COVID-related morbidity and mortality. Screening for hyperinflammation may serve as a marker for disease severity, and drug therapies can be tailored to target the synergistic inflammatory effects induced by T2D and COVID-19.

Conclusions

Controlled inflammation serves a functional purpose of heightened immune response and arms our body with the necessary tools to defeat pathogens such as COVID-19. However, in a chronic state of inflammation such as in long-term T2D, the body becomes susceptible to infection and requires more time and resources to recover.

During the height of the COVID-19 pandemic and with subsequent waves of infection, time and resources are critical in providing optimal and efficient treatment. Thus, it is critical for health care providers to clinically evaluate hyperinflammatory states with a thorough physical examination with levels of inflammatory markers to drive clinical decisions for COVID-19 patients since early identification and treatment of hyperinflammation can improve mortality rates.

The lessons learned from COVID-19 should pave the way for better disaster preparedness to protect vulnerable patients with comorbid conditions in the future.

Footnotes

Acknowledgments

The authors would like to acknowledge Julie Trumble and Alison R. DeVries for performing the search and providing guidance on the manuscript format and editing.

Authors' Contributions

M.F., H.Sa., and H.Se. were involved in the conceptualization. SLIM, B.M., M.J., A.P., and M.F. were involved in reviewing all articles, applying eligibility criteria, and identifying review articles. All authors contributed extensively to manuscript writing, figure and table design, and revision.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this article.

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