Immunometabolic bases of type 2 diabetes in the severity of COVID-19

Table 1 Immunometabolic mechanisms of the main etiological factors associated with type 2 diabetes and their implications in the development of severe severe acute respiratory syndrome coronavirus-2 infection

Etiological component of T2D	Effect on immune responses	Implications in COVID-19	Ref.
Hyperglycemia	Stimulation of monocytes and macrophages to release IL-1β, IL-6, and TNF-α	Promotion of the cytokine storm and exacerbated inflammatory responses	Nielsen et al[23], Blair et al[24]
	Mitochondrial oxidative stress and production of reactive oxygen species	Activation of the proinflammatory cytokine storm	Robertson et al[39]
	Stimulation of lactate dehydrogenase activity	Upregulation of lactate pathway during severe COVID-19	Zhang et al[40]
	Increased NK cells with low levels of NKG2D and NKp46	Decreased degranulation and inefficient antiviral activity	Berrou et al[47]
	Low number of dendritic cells	Inefficient antigen presentation and decreased T cell activation	Zhong et al[52]
	Inhibition of T cell activation and proliferation	Increased viral load and COVID-19 progression	Macia et al[51]
	Decreased neutrophil migration and phagocytosis	Impaired viral clearance	Alba-Loureiro et al[53]
	Low number of IFN-γ-producing cells	Impaired antiviral response	Kalantar et al[54]
	Reduction of antibody titers	Inability to kill infected cells and increased viral load	Mathews et al[55]
Pancreatic β-cell exhaustion and hyperinsulinemia	β-cell apoptosis	Enhanced pancreatic damage through SARS-CoV-2 direct binding to ACE2 in β-cells	Weir[57]
	β-cell dysfunction through endoplasmic reticulum stress	Increased pancreatic inflammation	Butler et al[56]
	M1-like macrophage infiltration	Islet fibrosis and β-cell mass loss	Inoue et al[58], Westwell-Roper et al[59]
	Impaired insulin production	Increased hyperglycemia and promotion of proinflammatory cell activation	Zheng et al[64]
	Deterioration of exocrine pancreas	Increased pancreatic inflammation	Hayden et al[66]
Insulin resistance	Stimulation of proinflammatory cytokine release into circulation	Exacerbated systemic inflammation	Tabák et al[75], Akbari et al[80]
	Inactivation of the insulin signaling pathway via NF-κB	Suppression of IP-10 production and reduced insulin sensitivity	Antuna-Puente et al[81]
	Increased ACE2 receptor levels	Increased viral load and COVID-19 progression	Kuba et al[85]
	Decreased Th2 cell differentiation	Reduction of lymphocytes with anti-inflammatory functions	Viardot et al[92]
	Impaired ability of macrophages to respond to pathogens	Monocytopenia, COVID-19 progression, increased mortality risk	Rizo-Téllez et al[96]
	High blood neutrophil count	Neutrophilia, COVID-19 progression, increased mortality risk	DeFronzo et al[16]
Advanced glycation end products	Activation of the RAGE and sustained inflammatory responses	Increased pulmonary inflammation and mortality risk	Oczypok et al[101]
	Increased Th17 lymphocytes	Perpetuation of the cytokine storm and pulmonary inflammation	Wang et al[30]
	Activation of the classical complement pathway	Complement-mediated damage and membrane attack complex formation in lung tissue	Lupu et al[150]
	Non-enzymatic attachment of glucose to hemoglobin	Alteration of the hemoglobin 1-β chain, less oxygen bioavailability in peripheral tissues and breathing difficulty	Means[110]
	Non-enzymatic attachment of glucose to ACE2	Increased SARS-CoV-2 affinity and infection in pancreatic and lung tissue	Zhao et al[112], Bao et al[114]
	Glycation of CD147 in type II pneumocytes	Promotion of SARS-CoV-2 cell entry and increased viral load in pneumocytes	De Francesco et al[115]
	Neutrophil trafficking impairment	Hyper-reactive neutrophils that injure the vascular endothelium	Kraakman et al[154]
Endothelial dysfunction and prothrombotic state	Increased prothrombotic state	Enhanced blood clotting and severe coagulopathy	McFadyen et al[134]
	Hyper-activation of neutrophils in blood vessels	Vascular damage, blood vessel leaking, and sepsis	Joshi et al[126]
	Impaired vasodilatation with release of IL-6 and TNF-α	Microcirculatory malfunction and increased fibrinogen levels	Chi et al[29], Mangalmurti et al[27]
	Recruitment of immune cells	Blood vessel leaking and thrombosis	Ranucci et al[146]
	IL-6 production	Increased thrombopoietin production	Kraakman et al[154]
	Increased P2Y12 platelet receptor	Enhanced platelet adhesion and thrombosis	Dorsam et al[155]

Summary of the main immunometabolic mechanisms by which immune cells and cytokines act in synergy with preexisting hyperglycemia, β-cell dysfunction, hyperinsulinemia, insulin resistance, advanced glycation end products, endothelial dysfunction, and prothrombotic state to increase the severity, progression, and mortality of coronavirus disease 2019 in patients with type 2 diabetes. COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; T2D: Type 2 diabetes; NK: Natural killer; ACE2: Angiotensin-converting enzyme 2; IP-10: IFN-γ inducible protein-10; RAGE: Receptor for advanced glycation end products.