Mechanisms of COVID-19 pathogenesis in diabetes.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a global pandemic impacting 254 million people in 190 countries. Comorbidities, particularly cardiovascular disease, diabetes, and hypertension, increase the risk of infection and poor outcomes. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme-2 receptor, generating inflammation and cytokine storm, often resulting in multiorgan failure. The mechanisms and effects of COVID-19 on patients with high-risk diabetes are not yet completely understood. In this review, we discuss the variety of coronaviruses, structure of SARS-CoV-2, mutations in SARS-CoV-2 spike proteins, receptors associated with viral host entry, and disease progression. Furthermore, we focus on possible mechanisms of SARS-CoV-2 in diabetes, leading to inflammation and heart failure. Finally, we discuss existing therapeutic approaches, unanswered questions, and future directions.

INTRODUCTION

In 2019, a new worldwide public health crisis emerged with the spread of novel coronavirus disease 2019 (COVID-19), of Wuhan, China origin. This outbreak, the first to receive such designation since the H1N1 influenza pandemic of 2009, was officially denoted a pandemic in March 2020 by the World Health Organization (WHO). As of November 2021, over 253 million cases of confirmed COVID-19 led to more than 5.1 million deaths worldwide (1).

Although COVID-19 transmission dynamics are not completely understood, respiratory droplets generated from symptomatic coughing and sneezing are thought to drive viral spread (2). Studies have reported asymptomatic individuals may also transmit the disease, and asymptomatic cases may not equate with lower viral burden compared with symptomatic cases (2). These respiratory droplets may remain viable on surfaces for several days, depending on environmental conditions (3). Infection can occur either through inhalation of infectious droplets or through manual transmission of infectious droplets from contaminated surfaces to the nose, mouth, or eyes (4). In addition to being aerosolized, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present in contaminated sewage, providing the opportunity for fecal-to-oral transmission through contaminated drinking water (5). According to the Centers for Disease Control and Prevention (CDC), COVID-19 can affect all ages, but the elderly with underlying health conditions, such as diabetes, cardiovascular disease, hypertension, and cancer, may be severely affected (6). Symptoms of the virus may range from mild cold symptoms to severe, often fatal, pneumonia, known as severe acute respiratory syndrome (SARS) (7). Several articles have been published by scientists on COVID-19 infection and its interactions with angiotensin-converting enzyme 2 (ACE2) with various diseases in past 2 years that lead to cardiovascular complications (8–11). This article provides current views on the understanding of the nature of SARS-CoV-2 and COVID-19 in diabetes. In this review, we briefly explore the history of coronaviruses and the structure of SARS-CoV-2, the virus causing COVID-19, with a focus on the comorbidity of diabetes.

CORONAVIRUSES

Coronaviruses (CoVs) belong to the order Nidovirales, family Coronaviridae, and subfamily Orthocoronavirinae. These viruses, originally considered solely zoonotic agents, contain an envelope and single-stranded ribonucleic acid (RNA) ranging from 26 to 32 kb (12). These viruses are considered the largest among RNA viruses and are classified into four genera: α-coronavirus (α-CoV), β-coronavirus (β-CoV), γ-coronavirus (γ-CoV), and δ-coronavirus (δ-CoV), based upon genetic and antigen criteria (Table 1) (13, 14). The literature suggests α- and β-coronaviruses infect only mammals, whereas γ- and δ-coronaviruses infect birds, and in some instances, mammals (14). On the whole, humans, camels, cattle, cats, rodents, and bats are among the common CoV target hosts (12). Evidence suggests many α-CoVs enter the host through the aminopeptidase N (APN) receptor, whereas SARS-CoVs use the host ACE2 receptor (Table 1) (14–16). Coronaviruses have been implicated in recent important outbreaks, including SARS-CoV, Middle East Respiratory Syndrome (MERS-CoV), and SARS-CoV-2 (17).

Table 1.

Classification of CoVs and target receptors

Type	Name of Virus	Infects	Receptors	Hosts
α-CoVs	Transmissible gastroenteritis coronavirus (TGEV)	Pigs	APN
	Canine coronavirus (CCoV)	Dogs	APN
	Porcine respiratory coronavirus (PRCoV)	Porcine
	Feline coronavirus (FeCoV)	Cats	APN
	Porcine epidemic diarrhea coronavirus (PEDV)	Pigs	APN
	Human coronavirus 229E (HCoV-229E)	Human	APN	Bats
	Human coronavirus NL63 (HCoV-NL63)	Human	ACE2	Palm, civets, and bats
β-CoVs	Bat coronavirus (BCoV)	Bats	N-acetyl-9 O-acetylneuraminic acid
	Porcine hemagglutinating encephalomyelitis virus (HEV)	Pigs
	Murine hepatitis virus (MHV)	Rodents	mCEACAM
	Human coronavirus 4408 (HECoV-4408)	Human
	Human coronavirus OC43 (HCoV-OC43)	Human		Cattle
	Human coronavirus HKU1 (HCoV-HKU1)	Human		Mice
	Severe acute respiratory syndrome coronavirus (SARS-CoV)	Human	ACE2	Palm, civets, and bats
	Middle Eastern respiratory syndrome coronavirus (MERS-CoV)	Human	DPP4 or CD26	Bats and camels
	Severe acute respiratory syndrome coronavirus (SARS-CoV-2)	Human	ACE2	Bats
γ-CoVs	Avian infectious bronchitis virus (IBV)	Birds
	Turkey coronavirus (TCoV)	Birds
δ-CoVs	Bulbul corona virus (HKU11)	Rodents
	Porcine coronavirus (HKU15)	Pigs

ACE2, angiotensin-converting enzyme 2; APN, aminopeptidase N; DPP4, dipeptidyl peptidase 4; mCEACAM, murine carcinoembryonic antigen related adhesion molecule 1.

SARS-CoV-2

SARS-CoV-2, closely related to SARS-CoV (18), is a β-CoV. Although COVID-19 primarily affects the respiratory system, the disease can also affect other organs, including digestive, immune, nervous, excretory, reproductive, and hormonal systems (Fig. 1).

Figure 1.

A: coronavirus disease 2019 (COVID-19) affects multiple organ systems. B: structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). E, envelope protein; M, membrane protein; N, nucleocapsid protein; PL, papain like protease; S, spike protein; 3CL, chymotrypsin-like protease; nsp, nonstructural proteins.

STRUCTURE

Virions are spherical and pleomorphic in nature ranging from 100 to 160 nm in diameter. The core RNA particle of 27–32 kb is surrounded by a capsid with several glycoprotein projections, resembling a crown, hence the name “corona” (See online Graphical Abstract). The 3′-terminus of coronaviral genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein, all of which are required to produce a structurally complete viral particle (19). Each protein has a specific function: N protein binds to RNA genome to make the nucleocapsid; S protein is a homotrimer with two subunits (S1 and S2), which are essential for binding to host cell receptors; and E protein interacts with M to form the viral envelope, whereas M protein plays a major role in CoV assembly and shape of viral envelope regulation. These proteins carry major antigenic epitopes and are responsible for attachment to host cells and subsequent pathogenesis (19, 20). Up to 75% of the 5′-terminus of the genome encodes the proteins involved in genome transcription and replication. This includes a polyprotein, pp1ab, which is further proteolytically cleaved by mediation of two cysteine proteases, chymotrypsin-like protease (3CLpro) and papain-like enzyme (PLpro), into 16 nonstructural proteins (nsp; Fig. 1).

The functions of these nsps are represented in Table 2 (21, 22). 3CLpro is also known as MPro, as it plays a crucial role in the replication of virus particles and is considered a potential target for screening of the virus and therapeutic approaches (23). In addition to the genes encoding structural and replication proteins, nine accessory proteins and their specific functions are provided in Table 2 (21, 24).

Table 2.

Functional role of SARS-CoV-2 nsp and accessory proteins

Proteins	Functions
nsp1	Plays a role in degradation of host endogenous. mRNAs further inhibit host protein synthesis; reduces antiviral response in host
nsp2	Important for viral RNA synthesis and growth
nsp3	Papain-like protease 2 (PL2 pro). Plays major role proteolytic processing membrane rearrangement and synthesis of subgenomic RNA segment
nsp4	Viral membrane rearrangement, replication complex function
nsp5	3Chymotrypsin-like protease (3CL pro); plays major role proteolytic processing and formation of key functional enzymes such as replicase and helicase
nsp6	Restricts autophagosome expansion; replication complex function
nsp7	Potential sites of protein-protein interactions
nsp9	Interacts with nsp8 and binds to viral RNA, assumed that plays a role in viral RNA synthesis
nsp10	Takes part in viral gene transcription and replication; essential for nsp16 methyltransferase activity
nsp11	Short peptide with unknown function
nsp12	RNA-dependent RNA polymerase; plays a role in replication and transcription
nsp13	Helicase/triphosphatase
nsp14	Exoribonuclease; plays a role in the replication of RNA
nsp15	Uridine specific endoribonuclease; plays a role in virion replication cycle
nsp16	2-O′-methyltransferase
Orf3b	Modulator of IFN signaling network
Orf6	Type-I IFN agonist
Orf7a	Virus induced apoptosis
Orf7b	Involves in leucine zipper formation
Orf8	Inhibits heme metabolism
Orf9b	Type I IFN agonist
Orf9c	Overlaps with Orf9b
Orf10	Ubiquitin ligases

INF, interferon; Nsp, nonstructural proteins; orf, open reading frame.

SARS-CoV-2 SPIKE PROTEIN MUTATIONS

Given the capacity of SARS-CoV-2 to infect humans, understanding viral interactions with host receptors, such as ACE2, is critical for prevention and control of the disease. The spike protein is a clove-shaped transmembrane protein with three segments, consisting of an ectodomain region (EDR), a transmembrane region (TMR), and an intracellular domain with a tail (25). The receptor-binding domain (RBD, also known as S1) contains an NH2-terminal domain (NTD) and the COOH-terminal domain (CTD), together representing a major viral surface antigen (25). The S2 subunit consists of two heptads with repeated regions HR1 and HR2, as well as a hydrophobic fusion peptide (26). The 14 residues of the spike protein RBD are crucial in the interaction with ACE2, in which 18 amino acids take part in binding K341 to ACE2, specifically with the R453 residue of RBD, encompassing the most important role of viral entry (26). Any variation in the RBD at D454 or R441 disrupts binding activity with ACE2 (26).

Mutations in RBD and glycation of polybasic cleavage sites create obstacles in identifying effective therapeutics. The spike protein RBD is the most variable region of the SARS-CoV-2 genome (27). Six amino acids, including L455, F486, Q493, S494, N501, and Y505, have been identified as critical for binding with the host ACE2 receptor (28) (Fig. 2).

Figure 2.

A: mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. F, phenylalanine; L, leucine; N, asparagine; P, proline; Q, glutamine; R, arginine RBD, receptor-binding domain; S, serine; T, threonine; Y, tyrosine. B: angiotensin-converting enzyme 2 (ACE2) in Ang-(1–7) formation and beneficial effects in diabetes. D, aspartic acid; F, phenylalanine; H, histidine; I, isoleucine; L, leucine; NEP, neutralendopeptidase; P, proline; PEP, prolylendopeptidase; R, arginine; ROS, reactive oxygen species; S, serine; V, valine; Y, tyrosine.

SARS-CoV-2 contains a polybasic cleavage site (RRAR) at the junction of the two subunits of the spike protein, S1 and S2, allowing effective cleavage by furin and other proteases (28, 29). In addition, the amino acid proline may associate with RRAR to form PRRAR, making turns that lead to O-linked glycans. S673, T678, and S686 are unique polybasic sequences at the cleavage site of SARS-CoV-2 (29). The functional consequence of these polybasic cleavage sites is complex and incompletely understood but is thought to contribute to the difficulty in determining pathogenesis and transmissibility. Moreover, the functional significance of O-linked glycans is unknown but assumed to shield key spike protein amino acids through a mucin-like domain. Evidence suggests several viruses use these mucin domains as shields to invade host immune systems (30). However, future studies are required to determine the involvement, if any, of these sites to SARS-CoV-2 infections.

The spike protein plays a crucial role in host entry (15). In SARS-CoV infections, the initial interaction of S1 and ACE2 is thought to further S2-mediated fusion. Therefore, S1 and S2 have become important pharmacological targets for therapeutic intervention. Recent studies demonstrated anti-ACE2 antibodies blocked viral entry in Vero E6 cells (31). In addition, the spike protein can initiate immune response in host cells (32). Another mechanism of viral binding to host cells is via dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) receptors or liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) (33, 34). The O-glycosylation sites of asparagine-associated S protein are important sites for viral entry into the host (35), but the potential of similar binding interactions in SARS-CoV-2 infections is yet to be deciphered.

The WHO and CDC classified COVID-19 variants into three classes: 1) variants of concern (VOCs), including variants that spread widely and cause severe disease; 2) variants of interest (VOIs), including those containing similar mutations as VOCs but spreading less extensively; and 3) variants of high consequence (VOHs), indicating significant reductions in vaccine effectiveness, high severity of disease, and increased hospitalizations. Among variants of concern, α- (B.1.1.7), β- (B.1.351), γ- (P.1), δ- (B.1.617.2), and ο-variants are important.

α-variant (B.1.1.7) is known as the UK variant, containing 23 mutations with 17 amino acid changes. This variant has increased transmissibility and reduced response to vaccines. Now considered a common variant, α was initially the cause of increased risk of mortality.

β (B.1.351 or 501Y.V2)-variant was first identified as the South African variant with increased transmission and virulence. This variant has reduced antibody neutralization by convalescent plasma obtained from patients with COVID-19, as well as reduced vaccine efficacy.

γ (B.1.1.28.1 or P.1)-variant was first identified as the Brazil variant, having approximately 35 mutations with 17 amino acid changes. This variant has increased transmissibility and virulence, and reduced antibody neutralization, resulting in the potential for severe reinfections.

δ (B.1.617.2)-variant was first identified in India and was responsible for increased mortality, transmission, virulence, and reduced antibody neutralization. This variant is considered extremely contagious and can cause severe illness in unvaccinated individuals.

Omicron (ο) (B.1.1.529) is a new variant with multiple mutations, identified in South Africa. Omicron is highly transmissible and has increased health risk for younger adults, including risk of hospitalization. In addition, this variant is suspected to be significantly resistant to mRNA vaccines and convalescent therapy. Current data suggest Omicron infection might be less severe than prior variants.

Emerging variants have acquired mutations leading to an amino acid change from asparagine (N) to tyrosine (Y) at position 501 in the RBD of the spike protein, along with two additional mutations, K417N/T and E484K, increasing the binding affinity of the RBD to ACE2 (36). The major concerns for the emergence of new variants are the degree of transmissibility, disease severity, and reduced immunity (escape from both innate as well as adaptive immunity stimulated by vaccines).

ACE2 AND ASSOCIATED RECEPTORS FOR SARS-CoV-2 HOST ENTRY

Receptors play a major role in the mechanism of action in the progression of any viral disease. ACE2, the primary receptor for SARS-CoV-2 host entry, is an important peptidase in the renin-angiotensin-aldosterone system (RAAS pathway) of blood pressure regulation, wound healing, and inflammation (37, 38). The kidney hormone, renin, initiates proteolytic cleavage of angiotensinogen into a 10-amino acid peptide angiotensin I (ANG I). This ANG I peptide is then converted into an 8-amino acid peptide, angiotensin II (ANG II) by angiotensin-converting enzyme (ACE) (39), degrading bradykinin, and playing a role in cardiovascular complications resistance (40). ACE also metabolizes Ang-(1–7). ACE inhibitors increase circulating levels of Ang-(1–7) by preventing its metabolism and shunting ANG I through the endopeptidase neprilysin. ANG II is an important physiological effector in vasoconstriction and blood pressure, sodium uptake, and aldosterone release (41). In addition, ANG II has been implicated in atherosclerosis, endothelial dysfunction, inflammation, congestive heart failure (42), and the production of reactive oxygen species (ROS) in diabetes (43). ANG II is mediated by the angiotensin II type 1 (AT1) membrane receptor, present on the surface of blood vessels, as well as cells of the lung, heart, brain, and kidney (44). ANG II is further cleaved into Ang-(1–7) peptide by ACE2, which opposes the actions of ACE (39), promoting vasodilation and antihypertrophic and antifibrotic effects (45). Reduced levels of ACE2 lead to diabetic cardiomyopathy, whereas increased levels attenuate cardiac dysfunction induced by ANG II (46, 47). Ang-(1–7) can directly form from ANG I via either neutral endopeptidase (NEP) or prolylendopeptidase (PEP), or by the action of ACE2 to Ang-(1–9) and then Ang-(1–7) by ACE (Fig. 2) (38).

ACE2 is a membrane-associated carboxypeptidase and is expressed in vascular endothelia, heart, lungs, kidneys, testes, and intestine (48). SARS-CoV-2 binds to ACE2 through S proteins called spike proteins. Specifically, these S proteins have more affinity to the lysine 353, proximal residues of the NH2-terminus of β-sheet 5, and α-helix of extracellular portion of ACE2, consistent with the studies of Li et al. (49). ACE2 modulates the expression of neutral amino acid transporters on pancreatic β cells and improves microvascular function (50). ACE2 knockout mice show evidence of abnormal glucose tolerance and impairments in islet function (48), whereas the loss of ACE2 aggravates diabetic cardiomyopathy (51). Evidence suggests that increased expression of ACE2 leads to greater SARS infection and inflammation (52). ACE2 expression was increased with pathological states in association with the activation of RAAS system. It plays a pivotal role in downregulating the RAS system and acts as an anti-inflammatory agent. An increase in ACE2 receptors facilitates COVID-19 viral entry into cells, thereby increasing the susceptibility to viral infection. However, downregulation of ACE2, after viral infection, might also aggravate inflammation and cytokine storm (53). These findings and others potentiate the effects of ACE2 in diabetes and associated complications. Reduced ACE2 expression, possibly due to glycosylation, has been noted in patients with diabetes, potentially explaining the increased susceptibility and severity of acute respiratory distress syndrome (ARDS) with COVID-19 (19). ACE2/Ang-(1–7) functions as an anti-inflammatory and antioxidant (Fig. 2) in protecting the lungs against viral infections and ARDS (54).

Recent study suggests the transmembrane protease, serine 2 (TMPRSS2) is associated with ACE2 and plays a major role in SARS-CoV-2 entry, as it does in other coronaviruses (55). TMPRSS2 is a serine protease, significantly expressed in lung and gastrointestinal (GI) tissues (56). This protease has the ability to cleave the envelope glycoproteins of the influenza virus, as well as coronavirus spike proteins (57). Inactivation of TMPRSS2 results in attenuation of lung damage and inflammation in mice upon MERS and SARS-CoV infection (57). The TMPRSS2 inhibitor camostat successfully attenuated SARS-CoV-2 infection in ex vivo cultured human lung cells (55). Whether glucose plays a role in TMPRSS2 regulation in relation to diabetes is not yet known.

Dipeptidyl peptidase (DPP4) has been identified as a receptor for MERS-CoV and SARS-CoV (58). However, whether DPP4 plays a role as a SARS-CoV-2 receptor is still ambiguous. An in silico study proposed SARS-CoV-2 might bind to DPP4/CD26 (cluster of differentiation 26) (59), potentially through sites on immune cells and other tissues (60). Recent studies showed the involvement of DPP4 as a possible receptor for SARS-CoV-2 (61). Qi et al. (62) showed high expression of DPP4 with ACE2. Furthermore, Vankadari and Wilce (61) suggested the glycoprotein residues of SARS-CoV-2 binding ACE2 may also have the affinity to interact with DPP4. Other receptors, such as sialic acid, basigin or CD147, and cathepsin B and L, are reported to play a role in SARS-CoV-2 entry and pathogenesis.

MECHANISM OF SARS-CoV-2 MORBIDITY IN DIABETES

Diabetes is the seventh leading cause of death in the world and is associated with vascular complications, severely impacting quality of life (63). The relationship between diabetes and susceptibility to infection has long been clinically recognized (64). Infections, specifically pneumonia and influenza, often cause serious problems in elderly subjects, particularly with an underlying condition of type 2 diabetes (65). Whether diabetes itself, or associated complications such as cardiomyopathy and nephropathy, account for the susceptibility to infections is not yet clear (66). Hyperglycemia is considered a significant predictor for increased severity and mortality in subjects infected with H1N1, SARS-CoV, and MERS-CoV, whereas studies conflict in the setting of SARS-CoV-2 (67–70). Additional studies on SARS-CoV-2 infection in patients with diabetes suggest significant different development in complications that lead to a greater mortality rate in men with diabetes as compared with women (71). Another study performed by Ciarambino et al. (72) on males versus females suggest female subjects with COVID-19 to male subjects and found male subjects have a higher hospital stay, a higher admission to intensive care unit (ICU), and a higher death rate.

SARS-CoV-2 infection can complicate diabetes through 1) increasing glucose levels, leading to oxidative stress and inflammation; 2) binding ACE2 on acinar cells and causing tissue damage; and 3) inhibiting lymphocyte proliferation because of hyperglycemia (Fig. 3). Infection of SARS-CoV-2 triggers higher stress and glucose levels in subjects with diabetes via the secretion of glucocorticoids and catecholamines (73). Increased glucocorticoids and catecholamines contribute to impaired immune function, potentially increasing risk of infection.

Figure 3.

A: coronavirus disease 2019 (COVID-19) mechanism of action in diabetes. ACE2, angiotensin-converting enzyme 2; AGE, advanced glycation end products; ANG 2, angiotensin 2; ARDS, acute respiratory distress syndrome; ROS, reactive oxygen species. B: potential inflammatory mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in subjects with type 2 diabetes (T2D). CCL2, C-C motif chemokine ligand 2/monocyte chemotactic protein-1; CXCL-10, C-X-C motif chemokine 10; IFNγ, interferon-γ; TMPRSS2, transmembrane serine protease 2; TNF-α, tumor necrosis factor-α.

Increased glucose levels also promote viral replication and increase viral load (66, 74). Kohio et al. (74) demonstrated pulmonary epithelial cells exposed to hyperglycemia are more susceptible to influenza infection and enhanced viral replication. In addition, hyperglycemia promotes the synthesis of advanced glycation end products (AGEs), ROS, and molecules associated with tissue damage, such as proinflammatory cytokines and adhesion molecules (66, 75). Diabetes is a chronic inflammatory condition involving metabolic and vascular dysfunction, almost certainly playing a role in the greater susceptibility to infection.

In subjects with diabetes, SARS-CoV-2 binding to the ACE2 on the outer surface of acinar cells (76) causes damage and leads to hypoglycemic conditions, resulting in increased platelet activity and proinflammatory monocyte movement, both involved in cardiovascular complications (27, 77). In healthy individuals, infection with SARS-CoV-2 can even cause temporary hyperglycemia (76), as happened in SARS-CoV (78). In addition, reports of elevated levels of amylase and lipase (76) in both plasma and urine potentially confirm pancreatic injury during SARS-CoV-2 infection, suggesting the possibility of acute pancreatitis.

Poorly controlled diabetes with increased glucose levels inhibits lymphocyte proliferation (79); impairs immune cell function, including that of monocyte/macrophage (66, 80), and natural killer (NK) cells (66, 80); and promotes complement activation (81). Impaired immunity, in turn, leads to delayed hypersensitivity (82), worsening the outcome with regard to vascular complications in patients with diabetes. Zwaka et al. (83) demonstrated C5b-9 complex activation in cardiomyocytes induces nuclear factor-κB (NF-κB) activation and further promotes proinflammatory tumor necrosis factor-alpha (TNF-α) secretion. Studies have shown increased C3 fragment deposition in lung biopsies and increased 5a levels in plasma of patients with COVID-19, thus supporting COVID-19-associated complement dysfunction and potentially drawing attention to suggested uses of complement inhibitors in the disease (84). The etiology of the diabetic inflammatory and immune response, influence of the virus on insulin secretion and glycemic control, and the relationship of glucose variability to SARS-CoV-2 virulence are questions yet to be answered.

Recent studies suggested the increased risk of diabetes in subjects with COVID-19 who are not having any history of preexisting diabetes (85). The RAS plays an important role in regulating vascular function and blood pressure and maintains fluid and electrolyte homeostasis. It contains an active counterregulatory system with ANG II, the product of ACE by activating the ACE-ANG-II/AT1R axis, and generates deleterious effects including vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress. Under pathological conditions, this pathway becomes predominant. As mentioned earlier, ACE2 is expressed in multiple organs and plays a major role in maintaining homeostasis both at physiological and pathophysiological states via RAAS and ACE2/angiotensin-(1–7)/MAS axis. Upon activation by angiotensin-(1–7), the angiotensin-(1–7)/Mas-receptor (MAS) axis generates beneficial effects of vasodilatory, vascular protective, anti-inflammatory, antiproliferative, and antifibrotic effects (86). It has been reported that SARS-CoV-2 infection downregulates ACE-2 in multiple organs, thereby producing an imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS axis, locally and leading to organ injuries (87). This might be due to decreased insulin secretion and increased insulin resistance which might induce hyperglycemia-induced RAS activation. In addition, SARS-CoV-2 infection might also increase A disintegrin and metalloprotease-17 (ADAM17), which plays a major role in increased risk of hyperglycemia, insulin resistance, and inflammation by activating a variety of proinflammatory cytokines including TNF-α and IL-6 (88). This increased inflammation in turn leads to β-cell damage (89, 90). Evidence suggests that patients with diabetes and severe COVID-19 have shown a cytokine storm syndrome, including high levels of IL-6 and TNF-α (53). According to Al-Aly et al. (85), 50% of subjects with COVID-19 developed diabetes with increased hbA1c (>10%) and TG (> 9%) along with increased hyperglycemia after 20 wk of SARS-CoV-2 infection. This might be due to the damage to pancreatic β cells that secrete insulin. Reduced insulin secretion led to increase in glucose levels and increased inflammation and disease progression. According to Fignani et al., (91) β cells have high expression of ACE2 and lead to local cellular inflammation. Recent studies (85) demonstrated the high-dimensional approach to identify the subsequent consequences after SARS-CoV-2 infection impacted various organ systems via vascular dysfunction, nitric oxide-mediated microvascular function (92), contribution of von Willebrand factor (93) in thrombosis and inflammation (94–98), leading to respiratory, cardiovascular, gastrointestinal, neurological, cognitive, metabolic, and nephrological disorders along with anemia and general body aches, as well as general illness. The study of Al-Aly et al. (85) also showed the use of various therapeutic agents including pain medications, antidepressants, antihypertensive, and oral hypoglycemic agents increasing the risk along with the evidence of laboratory abnormalities in several organ systems. Consequently, the postacute burden was increased regardless of patient’s hospitalization, but the risk gradient increases with the severity of the SARS-CoV-2 infection depending on the severe conditions the subjects confronted. Furthermore, their studies revealed a significant health loss in COVID-19 survivors of acute infection due to the affected respiratory as well as other end-organ systems. Therefore, these studies suggested the health care system develop treatment approaches that avoid chronic conditions in subjects with COVID-19.

Evidence suggests increased incidence of pediatric type 1 diabetes during the COVID-19 pandemic (99). A recent cohort study suggested the increased risk of diabetes among persons aged <18 yr following COVID-19 (>30 days) (100). Furthermore, these studies suggested health care providers screen for diabetes in this age group with a history of SARS-CoV-2 infection. The study also listed some of the symptoms including frequent urination, increased thirst, increased hunger, weight loss, tiredness or fatigue, stomach pain, and nausea or vomiting that emphasize the importance of prevention strategies for COVID-19, including vaccination and chronic disease prevention and treatment in this age group. However, the underlying pathological mechanism is not yet known.

Evidence suggests that respiratory infections are associated with subsequent increased risk of type 1 diabetes. The study of Lonnrot et al. (101) suggested an islet autoimmunity-triggering effect by respiratory infections. Furthermore, Ruiz et al. (102) found a twofold increase in the incidence of diabetes during the pandemic of influenza A (H1N1). Similarly, various studies reported that SARS-CoV-2 damages pancreatic cells, which play a major role in insulin synthesis (103–105). Recent reports suggest that SARS-CoV-2 infection leads to type 1 diabetes compared with individuals who are not infected with virus (106–108). The study of Trieu et al. (109) found an increased rate of new-onset T1DM, T2DM, and DKA in children and adolescents during the COVID-19 pandemic as compared with a similar time frame of previous 2-yr records. Overall, it is difficult to determine whether type I diabetes is due to COVID-19 or whether it is just an infection which brought out the preexisting one. If so, whether β-cell damage due to COVID-19 is reversible and what kind of long-term pathological mechanism it will develop remains unknown.

Endothelial dysfunction is another major concern in diabetes-associated COVID-19 manifestations. Endothelium plays a key role in physiology and pathophysiology as it is the first organ to encounter any damage and injury (110). The association between viral infections, inflammatory processes, and endothelial cells is very complex. It has been noticed the presence of viral components in the endothelial cells and endothelial-associated inflammation in various organs such as lung, heart, kidney, skin, and liver biopsies of patients with COVID-19 (111). According to Evans et al. (112), endothelial dysfunction is a common clinical feature observed in patients with COVID-19. Endothelial dysfunction is a systemic condition found in various diseases including diabetes in which the endothelium loses its physiological properties of vasodilation, fibrinolysis, and antiaggregation (113). The pathophysiology of respiratory disease in patients with diabetes is multifactorial including endothelial dysfunction, microangiopathy, oxidative stress, and variations in the connective tissue which are majorly associated (114). Recent studies reported NADPH oxidase (NOX) activation by elevated levels of ANG II, as well as cytokine storm decreases the bioavailability of nitric oxide leading to redox imbalance, inflammation, and endothelial dysfunction during SARS-CoV-2 infection (115, 116). Furthermore, prolonged endothelial dysfunction leads to microvascular obstruction via the activation of clotting cascade which in turn leads to multiorgan failure (117, 118). This might be due to extracellular vesicles containing microRNAs or exosomes released by endothelial cells contributing to the COVID-19 pathogenesis. Evidence supports the view that the endothelial dysfunction is a key target for prevention of COVID-19 (119).

Epigenetics of ACE2 binding with SARS-CoV-2 is considered to be a player in disease development following SARS-CoV-2 infection. Recent studies report that epigenetic variability of ACE2 including DNA methylation, histone modification, and alterations in long noncoding RNA and miRNA regulation of ACE2 during COVID-19 in subjects with diabetes will provide a better understanding to elucidate the underlying pathological mechanisms (120). Sawalah et al. (121) reported oxidative stress induced by SARS-CoV-2 infection leads to ACE2 hypomethylation and enhanced viremia in subjects with systemic lupus. Furthermore, Pinto et al. (122) suggested increased ACE2 expression in the lungs of patients with COVID-19 is due to histone modifications. Among various histone modifications, lysine demethylase 5B (also known as KDM5B) is one such type of histone modification that can influence removal of chromatin marks and transcription regulation and also plays a role in the repair of DNA. Inhibition of this modification developed resistance to infection (123), which suggests that targeting this type of histone modification may potentially prevent COVID-19. Demirci and Adan (124) identified several miRNAs that regulate SARS-CoV-2 infection during host and viral interaction. Various microRNAs, including miR-1246, miR-200c-3p, miR-421, and let-7b, could serve as potential clinical targets in pulmonary disorders and potentially in SARS-CoV-2 infection. In addition, various miRNAs have been reported in recent studies that are involved in SARS-CoV-2-induced nephropathy (125). Furthermore, Arghiani et al. (126) revealed various types of miRNAs that have potential for pathological as well as therapeutic ability during SARS-CoV-2 infection. All these studies caution that, in addition to spike protein mutations, ACE2 variability should also be considered during therapeutic development.

SARS-CoV-2 INCREASED INFLAMMATION IN DIABETES

Diabetes is a chronic inflammatory condition in which immune cell dysfunction plays a major role, including inhibition of phagocytosis, and neutrophil chemotaxis, which prevents counteraction against invading infectious organisms (80, 127). Recent phenome-wide Mendelian randomization analysis reported the increased lung ACE2 expression in subjects with diabetes (128), suggesting and supporting the possible hypothesis of binding of SARS-CoV-2 to lung cells. In addition, evidence suggests elevated furin levels in subjects with diabetes play a crucial role in viral entry by slicing spike protein S1 and S2 domains (129). Impairment of Th1 cell-mediated immunity and delayed hypersensitivity are often observed in subjects with diabetes (127). Kulcsar et al. (130) study demonstrated that MERS-CoV infection in high-fat diet-fed diabetic mice prolonged the disease by uncontrolled pulmonary inflammation, elevated levels of cytokines such as IL-17, and deficits in CD4 cell number, specifically in males with delayed recovery. Recent studies from patients infected with SARS-CoV-2 are consistent with these reports, showing altered CD4 and CD8 cell count, suggesting that SARS-CoV-2 infection may cause apoptosis in these cells and lead to lymphocytopenia, with elevated proinflammatory cytokine levels such as IL-6, serum ferritin, and C-reactive protein (CRP) (19, 78, 131). IL-6 has been considered a good predictor for disease severity and progression because of its longer half-life compared with TNF-α, which exacerbates further COVID-19 progression with ARDS (82, 132). Furthermore, these higher levels of cytokines in a cytokine storm, including IL-6, TNF-α, and other chemokines CCL2 and CXCL10, play a critical role in the progression of SARS-CoV-2 infection, leading to hyperinflammation and end-organ dysfunction (5, 41, 84). A significant increase in ferritin confirms the monocyte/macrophage activation and indicates the potential increase in inflammation (5, 133). In addition, elevated D-dimer and fibrinogen levels indicate that patients with diabetes are more vulnerable to increased hypercoagulation and intravascular coagulation (5, 133). Furthermore, microangiopathic changes can also occur and affect the respiratory tract in these patients, causing the obstruction of gaseous exchange in lungs.

It is well known that elevated glucose levels suppress antiviral immune response, which has been confirmed in influenza studies where hyperglycemia affected pulmonary dysfunction and resulted in fatal outcomes for some subjects with diabetes (80). This might be an explanation as to why people with diabetes have reduced antiviral interferon (IFN). Therefore, one can expect possible delay in clearance of SARS-CoV-2 may occur, which in turn can lead to severity and progression of COVID-19.

Overall, these studies suggest enhanced SARS-CoV-2 infection severity in diabetics attributed to increased inflammation, including 1) elevated levels of ACE2 have higher affinity for viral binding, 2) elevated levels of furin for efficient viral entry, 3) reduced T cell function or lymphocytopenia, 4) hyperinflammation or cytokine storm, 5) impaired monocyte/macrophage function, 6) increased coagulation, and 7) reduced and delayed viral clearance following SARS-CoV-2 infection in subjects with diabetes (Fig. 3).

With respect to diabetes and inflammation, DPP4 is critically relevant, playing a crucial role in immune regulation by T cell activation, CD86 upregulation, and promotion of inflammation via catalytic and noncatalytic mechanisms in type 2 diabetes (134). DPP4/CD26 is a transmembrane glycoprotein, expressed in many tissues, including immune cells, with a significant role in insulin and glucose metabolism (135). This serine protease regulates postprandial glucose by degradation of incretin peptides, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) (136). Furthermore, inhibition of DPP4 has gained attention as a therapeutic target in subjects with diabetes. Indeed, inhibition of DPP4-mediated degradation of gut hormones enhances acinar cell secretion and improves postprandial hyperglycemia in subjects with diabetes (136, 137). In addition, DPP4 cleaves and inactivates several protein markers such as cytokines, chemokines, and growth factors impacting inflammation and immune function (138). Treatment of mice with TNF-α and/or insulin was shown to induce a significant increase in DPP4 (135), suggesting its association with inflammation and immune cells.

DPP4 has also been identified as a receptor for MERS-CoV, SARS-CoV, and potentially for SARS-CoV-2 (58, 61). Antibodies raised against DPP4 have protective effects against human-CoV infection in bronchial epithelial cells (139). DPP4 knockout mice do not develop obesity or insulin resistance, suggesting that DPP4 may be an essential target for diabetes and applicable in COVID-19 (140). Moreover, DPP4 inhibitors (DPP4i) are widely used for the treatment of hyperglycemia in subjects with diabetes because of their significant inhibition on DPP4 catalytic activity. The preventive role in incretin hormone degradation leads to postprandial secretion of insulin, as well as lowered glucagon secretion and hepatic glucose levels (134, 141). These inhibitors are also useful for hypoglycemia and no side effects have been reported. Patients with diabetes even lowered triglycerides and increased high-density lipoprotein (HDL) with these inhibitors (142). Administration of 100 mg daily of sitagliptin or 50 mg, depending on glomerular filtration rate levels, in hospitalized patients improved mortality in diabetics with COVID-19 (143). However, the pharmacodynamics of DPP4i from the perspective of SARS-CoV-2 infection have not been explored.

Diabetes with COVID-19 is associated with an increased mortality rate, presumably because of impaired insulin secretion as well as increased peripheral insulin resistance. Critical illness, as well as viral infections, can cause peripheral insulin resistance (144). Evidence suggests several types of viruses, including Cytomegalovirus, Epstein-Barr virus, Rotavirus, Rubella virus, and enteroviruses, contribute to β-cell dysfunction and type 1 diabetes (145). Similar results were observed in SARS-CoV-2 infection resulting in β-cell dysfunction, insulin resistance, and increased C-peptide levels (146). With respect to diabetes and insulin resistance, C-peptide has been identified as a marker of insulin resistance.

C-peptide is a 31 amino acid peptide released from pancreatic β cells and shares a common precursor (proinsulin, PI 33–63) to insulin. The C-peptide level accurately reflects the function of pancreatic β cells, as it is not influenced by exogenous insulin administration nor degraded easily by the liver (147). Depending on the severity of the disease and β-cell functionality, the amount of insulin administration varies. Hence, it was suggested to use the ratio of C2h/C0 [which reflects the C-peptide level, 2 h after postprandial (C2h) versus fasting C-peptide levels (C0)], to better predict pancreatic β-cell function and required dosage of insulin administration (148). Increased C-peptide levels have been observed in β-cell tumor, insulinoma, obesity, kidney dysfunction, sulfonylurea therapy, type 2 diabetes, and atherogenic progression (149).

According to Ghosh et al. (150), no significant difference has been observed in C-peptide levels between individuals diagnosed with diabetes during COVID-19 and those with preexisting diabetes. Furthermore, no significant β-cell damage was observed during SARS-CoV-2 infection based on C-peptide levels. Farag et al. (151) demonstrated no significant difference between new onset of type 2 diabetes [3.6 ± 0.08 ng/mL] and preexisting diabetes with respect to C-peptide levels [3.5 ± 1 ng/mL]; however, increased mortality was observed in new onset type 2 diabetes occurring during SARS-CoV-2 infection. Similarly, dexamethasone use did not correlate with differences in C-peptide levels during COVID-19 or at 3-mo follow-up (146). C-peptide is a multifaceted bioactive peptide with different effects in type 1 and type 2 diabetes, all cell- and tissue-specific. This specificity of C-peptide makes it more difficult to define its role in disease pathogenesis, thus requiring further research to understand its role.

COVID-19 AND DIABETIC COMPLICATIONS

SARS-CoV-2 infection may lead to fatal ARDS. Several postmortem studies revealed pulmonary edema and individuals with diabetes have suffered from cardiac hypertrophy, diastolic dysfunction, and heart failure (131, 152). Metabolic dysfunction, such as hyperlipidemia, hyperglycemia, and hyperinsulinemia synergistically influence the cellular and structural alterations of the cardiac system and functionality in patients with diabetes (153). Increased glucose levels are considered a key factor in the development of diabetic cardiomyopathy via increased oxidative stress and protein kinase C alteration, affecting lipid metabolism and impacting calcium homeostasis (153). In addition, increased ACE2 expression in cardiac pericytes indicates cardiac susceptibility to SARS-CoV-2 infection, resulting in an elevated creatinine kinase and microvascular dysfunction and suggesting severity in progression of the disease (154). Meta-analyses have suggested patients with diabetes and cardiovascular complications have increased (approximately two- to threefold higher) mortality associated with COVID-19 (155, 156). An earlier report of 25 patients recovered from SARS-CoV showed 60% of subjects have hyperlipidemia and hyperglycemia with cardiovascular complications (157). In addition, a metabolic study revealed dysregulated lipid metabolism and increased free fatty acids and phospholipids in patients infected with SARS-CoV (157). As SARS-CoV-2 resembles SARS-CoV in structure, SARS-CoV-2 might cause similar or more severe chronic damage to the cardiovascular system in patients with diabetes. In addition, SARS-CoV-2 infection can lead to other serious complications of diabetes, such as ketoacidosis, pneumonia, dehydration, and hyperglycemia.

Diabetic ketoacidosis: During stress or illness, increased blood sugar levels lead to diabetic ketoacidosis (DKA), a medical emergency. DKA indicates lower or dysfunctional insulin levels, causing the body to use fats as another source of energy, resulting in ketones with increased acidity in blood.

Pneumonia: Pneumonia is a complication of infection in which air sacs of the lungs are inflamed. Diabetic subjects with COVID-19 have a higher risk of developing pneumonia, and thus a severe form of SARS-CoV-2 infection. Evidence suggests the administration of pneumococcal and influenza vaccination can help to minimize this form of severity in patients with diabetes.

Dehydration: This is a condition in which patients with diabetes and COVID-19 will lose excess fluids because of fever, requiring administration of intravenous fluids and potential intensive care unit (ICU) admission.

High blood sugar: SARS-CoV-2 infection can cause a stress response in the body, producing increased blood sugar levels and potentially spurring further disease progression.

All these complications are due to the alterations in cellular metabolism affected by viral infection. SARS-CoV-2 infection in mammalian cells can affect cellular metabolism by shifting oxidative phosphorylation to glycolysis, resulting in reduced adenosine triphosphate (ATP) generation. There is an upregulation of pyruvate kinase M2 and hexokinase 2, key rate-limiting enzymes in glycolysis, during SARS-CoV-2 infection. As a result, increased lactate levels (158) and decreased pyruvate dehydrogenase complex induce intracellular acidosis and energy depletion (159). In addition, during infection, persistent hypoxia leads to reduced glutathione synthesis from pentose phosphate pathway, which could result in reduced antioxidant defenses and increased oxidative damage (160). SARS-CoV-2 infection also elevates the hexosamine pathway during replication, resulting in the secretion of N-acetyl glucosamine transferase and subsequent interferon regulating factor-5 production, playing a major role in proinflammatory pathways leading to hyperinflammation, cytokine storm, and end-organ failure (161). Furthermore, the observed increase in vascular complications in patients with diabetes is primarily due to this underlying alteration in cellular metabolism (162).

THERAPEUTIC APPROACHES

Several therapeutic approaches have been proposed and evaluated in combatting the global COVID-19 pandemic. Among others, these include vitamin C and remdesivir. Many agents from Chinese traditional medicine have also been evaluated through clinical trials in China, without much success. Health care officials have suggested relying on social distancing, hand hygiene, and barrier precautions to prevent the spread of COVID-19. Antiviral, anti-inflammatory, and anti-immunomodulatory therapies have gained considerable attention. Therapeutic options have primarily consisted of antiviral agents, inhibiting viral entry, drugs repurposed as COVID-19 antiviral drugs inhibiting viral replication and assembly, immunomodulators, such as cytokines and their receptors, and adjunctive treatments and vaccines (Table 3) (163, 164). These therapeutics are widely available and have successfully reduced the risk of adverse events. In addition, RNA polymerase inhibitors, including galidesivir, ribavirin, penciclovir, and ponatinib, are in clinical trials, along with medications targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Docking studies reported reduced efficiency of hepatitis C virus protease inhibitors such as simeprevir, because of the high SARS-CoV-2 mutation rate (165).

Table 3.

Medications currently in use for COVID-19

Drug Classes	Molecules	Mode of Action
Antiviral drugs (inhibitors of cellular entry)	Remdesivir; lopinavir/ritonavir; favipiravir; umifenovir	Inhibits viral RNA synthesis; inhibits the RNA-dependent RNA polymerase (RdRP) of RNA viruses; induces lethal mutations in RNA leading to a nonviable virus phenotype; prevents viral host cell entry via inhibition of clathrin-mediated endocytosis and further preventing virus infection
Repurposed as antiviral drugs (inhibitors of replication, fusion and assembly)	Camostat mesylate; nafamostat mesylate	Acts as TMPRSS2 inhibitor
Immunomodulatory drugs (inhibits cytokine storm)	Sarilumab; siltuximab; tocilizumab; steroids  interferon-1; bevacizumab  fingolimod; eculizumab  ulinastatin; itolizumab	Blocks the interaction of cytokine and its receptor,  inhibits inflammation
Monoclonal antibodies (inhibits viral entry)	80R, F26G19, m396, CR3014, CR3022, F26G18, m396, 201, S230	Binds the S1 fragment of SARS-CoV-2 and blocks the interaction of the S1 subunit protein with ACE2 receptor
Adjuvant therapies	Anticoagulant (LMWH/UFH)  high-dose IV vitamin C  convalescent plasma  CytoSorb	Reduces oxidative stress, inflammation further inflammatory  response in SARS-CoV-2 infection
Vaccines	BNT162 (Pfizer-BioNTtech); mRNA-1273 (Moderna); AZD1222 (Astra-Zeneca); Janssen Johnson & Johnson; covaxin; CoronaVac	Controls further spread by generating antibodies against either active/inactive viral mRNA and protein with or without viral vectors

ACE2, angiotensin-converting enzyme 2; LMWH, low-molecular-weight heparin; TMPRSS2, transmembrane serine protease 2; UFH, unfractionated heparin.

VACCINES

Vaccines for SARS-CoV-2 were developed in only 8–10 mo, years faster than any other widely distributed vaccine. Despite their high efficacy and widespread distribution, vaccine breakthrough infections occur. In the United States, three major vaccines have been used in protecting over 75% of the population from severe disease.

The Pfizer-BioNTtech (BNT162): Pfizer-BioNTech vaccine, known as Comirnaty globally, is an mRNA vaccine delivered intramuscularly. This vaccine was originally approved by the Food and Drug Administration (FDA) for individuals over 16 yr and has now been extended for those 5–15 yr old. Clinical trials indicated the vaccine was 95% effective in preventing severe COVID-19 infection. The original series consisted of two doses 3 wk apart, but the CDC now recommends a booster for high-risk individuals, 6 mo following the second dose. Storage temperature for this vaccine is −70°C and it remains stable for 5 days at 2°C–8°C (166).

Moderna (mRNA-1273): Moderna released an FDA-authorized and CDC-recommended mRNA vaccine for individuals 18 yr of age and older. The original series consisted of two intramuscular shots administered 28 days apart, but a booster is now recommended for immunocompromised individuals. Moderna is 94% effective in preventing severe disease. The storage requirement for this vaccine is −20°C and it remains stable for 30 days at 2°C–8°C (166).

RNA vaccines are cutting-edge technology in which the mRNA is encapsulated in a lipid nanoparticle (LPN) (167). Once the vaccine is administered to the muscle, the LPN particle attaches to the host cell and mRNA enters the cytoplasm where protein synthesis machinery ribosomes translate the harmless spike protein found on the SARS-CoV-2 surface (167). These translated proteins are processed and presented by antigen-presenting cells to T-helper (Th) cells via T cell receptor. The activated Th cell produces cytokines interleukin (IL)-2, -4, and -5, activating B-cells for antibody production against the spike protein (168).

The Johnson & Johnson Janssen (JNJ-78436735) COVID-19 vaccine is a viral vector vaccine containing modified, and harmless, virus protein which cannot reproduce. This modified virus can generate an immune response. The FDA authorized a single intramuscular shot in individuals of 18 yr and over. An additional booster dose is recommended 2 mo following the first dose. This vaccine was 85% effective in preventing severe COVID-19. Storage temperature for this vaccine is 2°C–8°C and it is stable for 3 mo (166).

All components used in preparation of COVID-19 vaccine are safe, and most are used in commercial food products. The approved COVID-19 vaccines are highly effective in preventing serious illness and death. Even among varying ethnicities and individuals with underlying comorbidities, all three vaccines are highly effective in preventing severe COVID-19. The mild side effects of sore arm, pain and redness at the injection site, fatigue, headache, muscle pain, and fever, especially following the second dose, are rewarded by highly successful reduction in number and severity of infections and reductions in hospitalization and deaths.

Patients with diabetes with SARS-CoV-2 infection are at higher risk and increased mortality compared with nondiabetic individuals, and therefore are considered high risk and urgent priority for vaccination (169). Individuals with comorbidities have not been associated with increased severe allergies or life-threatening reactions to COVID-19 vaccinations (169). To maintain normal glucose levels before COVID-19 vaccination, antidiabetic medications such as insulin, metformin, sulfonylureas, glucagon-like peptide-1, thiazolidinediones, DPP4 inhibitors, sodium glucose transporter-2 inhibitors, and others have been recommended to maximize effectiveness of the preventative (170, 171).

FUTURE PERSPECTIVES AND UNANSWERED QUESTIONS

Diabetes increases the risk for COVID-19, posing the following questions:

Is maintaining euglycemia enough to prevent COVID-19 progression? Is administration of insulin useful during COVID-19? Can supplementing with human recombinant ACE2 (hrACE2) levels serve as a decoy for viral binding to host ACE2 receptors, thereby reducing disease progression? Monteil et al. (172) study reported that clinical-grade human recombinant soluble ACE2 (hrsACE2) has the ability to reduce viral growth in vitro (Vero E6 cells). Furthermore, this study also demonstrated how hrsACE2 can significantly block early stages of SARS-CoV-2 infections in engineered human blood vessel organoids and kidney organoids which can be readily infected. However, this study did not explain how hrsACE2 will act in later stages of disease and whether it has the same efficacy as in early stages, the authors did not test the lung organoid, which is a major target for COVID-19, which are the limitations and remain unknown.

Can DPP4 modulation serve as a potential target for preventing risk and progression of ARDS in patients with diabetes? If so, what would be the success rate?

Is COVID-19 mortality associated with diabetes a consequence of viral binding to host ACE2? Could mortality be improved with renin-angiotensin system (RAS) blocking? Would combinatorial therapeutic approaches be more beneficial compared with individual therapy?

How beneficial are ACE2-modulating medications, such as ACE inhibitors or ang II receptor blockers (ARBs)? Recent clinical study (173) suggested that oral administration of 50-mg losartan, an ARB, for 10 days did not improve arterial partial pressure of oxygen to fraction of inspired oxygen (: ) ratio in the hospitalized patients with COVID-19 and acute lung injury. Further studies are needed with large cohort studies under acute as well as chronic conditions to understand further details. This study also suggests the caution in ARB usage. If these medications enhance SARS-CoV-2 binding, replication, and increase the severity of COVID-19, then what could be the alternatives for subjects with underlying medical conditions? This suggests that clinicians should take extra care while treating these subjects.

Can RAS blockers, ACE inhibitors, ARBs, and DPP4 inhibitors be useful in healthy individuals infected with COVID-19?

How efficient is maintaining social distance and wearing masks in preventing infection? How long we are going to be wearing masks and are masks causing inadvertent consequences? What about air and water transmission of COVID-19? How efficient can our technology control aerosols?

Although vaccines have been successful, some significant, though rare, side effects have been noted. How can we avoid these side effects, and for how long will these vaccines remain effective?

The major hurdle to elucidate the exact underlying pathological mechanisms of COVID-19 with comorbidities such as diabetes is due to the limited preclinical model studies available in the literature. Recently, Ma et al. (174) reported the aggravated blood glucose control and bone metabolism in diabetes (Ob/Ob) mice with SARS-CoV-2 infection. Furthermore, this study showed impairment of immune response during infection in these mice. Recent literature suggested the hACE2 model to evaluate diabetes and COVID-19 (175) by using various chemical/diet-induced disease methods which help to elucidate the association between comorbidity and COVID-19 pathogenesis. Shou et al. (176) suggested Chinese hamsters are highly susceptible to diabetes, which may be used to establish COVID-19 model with preexisting diabetes. The existing gap in diabetic-COVID-19 research in pathological mechanisms and new specific diabetic-focused medications are needed by developing novel models.

CONCLUSIONS

Early management and containment of COVID-19 variants, as well as rapid diagnosis, is crucial in control of the disease prevention of disease progression. Diabetes-associated complications are important predictors of morbidity and mortality in subjects suffering with COVID-19. Urgency in understanding the potential predisposition of genetic and population differences in SARS-CoV-2 will provide underlying pathophysiological mechanisms. Although vaccines are available, specific therapeutics capable of controlling glycemia and reducing inflammation in patients with diabetes are needed, particularly medications to maintain insulin levels and control hyperglycemia during COVID-19 infection. Preclinical and clinical studies are needed in determining mechanisms of disease progression in patients with COVID-19 with underlying hyperglycemia. Narrowing gaps in existing knowledge will potentiate powerful interventions to counteract SARS-CoV-2 in patients with diabetes.

GRANTS

This study was supported, in part, by National Institute of Cancer Grant R01-CA-221813 (to C. A. Narasimhulu), National Institutes of Diabetes and Digestive and Kidney Diseases Grant 1R01DK120866-01 (to D. K. Singla), and by the Endowed Chair Advent Health (to D. K. Singla).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.A.N. prepared figures; C.A.N. drafted manuscript; D.K.S. and C.A.N. edited and revised manuscript; D.K.S. approved final version of manuscript.