COVID-19 as a Trigger for Type 1 Diabetes Free

Abstract

Type 1 diabetes (T1D) is usually caused by immune-mediated destruction of islet β cells, and genetic and environmental factors are thought to trigger autoimmunity. Convincing evidence indicates that viruses are associated with T1D development and progression. During the COVID-19 pandemic, cases of hyperglycemia, diabetic ketoacidosis, and new diabetes increased, suggesting that SARS-CoV-2 may be a trigger for or unmask T1D. Possible mechanisms of β-cell damage include virus-triggered cell death, immune-mediated loss of pancreatic β cells, and damage to β cells because of infection of surrounding cells. This article examines the potential pathways by which SARS-CoV-2 affects islet β cells in these 3 aspects. Specifically, we emphasize that T1D can be triggered by SARS-CoV-2 through several autoimmune mechanisms, including epitope spread, molecular mimicry, and bystander activation. Given that the development of T1D is often a chronic, long-term process, it is difficult to currently draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area needs to be focused on in terms of the long-term outcomes. More in-depth and comprehensive studies with larger cohorts of patients and long-term clinical follow-ups are required.

Type 1 diabetes (T1D) is typically caused by immune-mediated destruction of pancreatic islet β cells. The exact etiology of T1D is not yet fully understood. Genetic and environmental factors have been proposed as potential triggers for autoimmune attack (1). Viral infection is one of the environmental factors that may cause diabetes, and frequent associations have been observed between T1D and viral infections (2-5). Viruses in the enterovirus family have particularly been identified as a possible cause of the disease (6). Enteroviruses can either produce cytotoxicity in pancreatic islet β cells directly or cause cell damage by triggering β-cell autoimmunity (7). Respiratory viruses are also thought to be a possible cause of T1D. An increased risk of β-cell autoimmunity in patients with respiratory infection was found in a prospective cohort study of environmental determinants of T1D. One or more T1D autoantibodies were present during serum transformation 9 months after respiratory infection. Autoantibodies have been detected in both patients with severe and mild respiratory disease (8). Another study on the relationship between T1D and influenza in 2018 showed that there was no clear association between T1D and seasonal influenza infection, but T1D events tripled among 76 173 individuals with H1N1 diagnosed in laboratories or professional medical institutions (9).

Currently, the focus of the world is the novel infectious disease COVID-19, caused by SARS-CoV-2, which was first discovered in China in December 2019. Early studies have focused on lung injury (10), but other organ dysfunctions have also been observed, especially in the intestine, kidney, olfactory epithelia, and pancreas (11-13). The collected evidence shows that SARS-CoV-2 can activate the immune system, leading to the synthesis of a plurality of autoantibodies, probably in the trigger effect of existing autoimmune diseases. Diabetes mellitus is a more common complication of COVID-19, and patients with diabetes who are infected with SARS-CoV-2 have higher rates of hospitalization and mortality (14). Recently, there has been a considerable increase in new cases of hyperglycemia, diabetic ketoacidosis (DKA), and diabetes among COVID-19 patients. Emerging diabetes has also been observed after SARS-CoV-2 infection (15, 16). Moreover, SARS-CoV-2 may be the underlying cause of new-onset T1D (17, 18). Although a causal relationship has not been confirmed, an increased prevalence of T1D association with COVID-19 may indicate SARS-CoV-2 orientation toward pancreatic islet β cells or unmasking of disease. However, the exact pathophysiology and impact of SARS-CoV-2 on the natural history of T1D remains unclear; therefore, this is an issue that deserves additional research. In fact, the scale of the problem is so great that an international registry has been set up to investigate the complex interaction between new-onset diabetes and COVID-19, called the CoviDIAB Project, and its findings will be reported in the future (15). In this article, we conduct a literature review of published studies focusing on COVID-19 and T1D and consider the possible pathways through which SARS-CoV-2 may affect β cells.

Association of T1D and SARS-CoV-2: Clinical Epidemiology

Hyperglycemia was considered an independent predictor of mortality in patients during the SARS-CoV pandemic in 2003. Patients with mild respiratory symptoms can also experience high blood sugar levels, even in the absence of glucocorticoid therapy; therefore, strengthening the hypothesis that the viral replication cycle in the endocrine pancreas leads to acute damage of β cells. It is worth noting that hyperglycemia persisted for 3 years after SARS-CoV recovery was found during follow-up, which may indicate that SARS-CoV may cause long-term injury to β cells (19).

It is not known whether SARS-CoV-2 infection causes new-onset diabetes or worsens the condition of patients with existing diabetes, but epidemiological data support these potentials. The incidence rate of T1D has been reported to increase by 80% compared with previous years during the pandemic in London (17). In a large retrospective study of COVID-19 patients hospitalized in New York, 6.6% of patients developed DKA and 5.7% had not been diagnosed with diabetes previously (20). A study conducted at 216 pediatric diabetes centers in Germany reported 532 newly diagnosed T1D in children and adolescents and found a significant increase in DKA at the time of diagnosis (21). In addition, an increase in new- onset T1D cases in children was recognized after the initial COVID-19 outbreak in of Romania (22). COVID-19 can lead to pancreatic tissue injury and disrupt glucose regulation, DKA, and pancreatitis in some patients (16, 23-26). A study in London, showed that 5.7% of the 35 COVID-19 cases were diagnosed with diabetes. Compared with previously reported non–COVID-19 DKAs, patients with COVID-19 had worsening DKA and higher insulin needs (27).

Clinical studies have revealed a potential link between SARS-COV-2 infection and diabetes onset (28, 29). A patient was diagnosed with T1D after a 1-month recovery from COVID-19, and glutamic acid decarboxylase-65 autoantibody was positive (30). In contrast, Hollstein et al. (31) reported a patient with T1D after SARS-CoV-2 infection with no islet-associated autoantibodies. Adnan et al. (32) reported that 2 children with DKA complicated by SARS-CoV-2 infection had no known history of T1D. Bernhard et al. described the clinical presentation of 3 South Asian migrant workers who presented with DKA (33). One large cohort (181 280 participants) study of the US Department of Veterans Affairs showed that people with COVID-19 had an increased risk of diabetes compared with the control group (odds ratio [OR], 1.40; 95% CI, 1.36-1.44) after a follow-up of 352 days (34). To evaluate the risk of new diabetes diagnosis >30 days after acute infection with SARS-CoV-2, the Centers for Disease Control and Prevention estimated the incidence of diabetes among patients aged <18 years diagnosed with COVID-19 from retrospective cohorts constructed using IQVIA health care claims data from March 1, 2020, through February 26, 2021, and showed that new diabetes diagnoses were 166% (IQVIA) and 31% (HealthVerity) more likely to occur among patients with COVID-19 than among those without COVID-19 during the pandemic. Individuals aged <18 years with COVID-19 were more likely to receive a new diabetes diagnosis >30 days after infection than those without COVID-19 and those with prepandemic acute respiratory infections (35). Results from the DPV registry of Germany showed a significant increase in the incidence of T1D in children during the COVID-19 pandemic, with the peak incidence of T1D occurring 3 months after the peak COVID-19 incidence (36).A meta-analysis showed that after COVID-19, patients of all ages and sexes had an elevated incidence and relative risk for a new diagnosis of diabetes. The relative risk of T1D was 1.48 (1.26-1.75) (37).

Although these studies can provide information on the risk of T1D following SARS-CoV-2 infection, it remains to be seen whether COVID-19 can actually cause new diabetes. Moreover, specific T1D autoantibodies may not be detected until months or years after their effective production in affected individuals; T1D onset can be further delayed, leading to difficult recognition of the trigger factor (38).Additional data are needed to understand the underlying pathogenic mechanisms (either immune-mediated β-cell ablation or direct perturbation of β-cell function), whether COVID-19 triggers diabetes in people who are predisposed or causes new diabetes entirely, or whether a COVID-19-associated diabetes diagnosis is transient or leads to a chronic condition.

Evidence of SARS-CoV-2 Infection in Pancreatic Cells

Pancreatic cells were found to allow SARS-CoV-2 to enter and build infections in vitro. A platform based on human pluripotent stem cells showed that human pancreatic β cells are highly permissive to SARS-CoV-2 infection (39). Similarly, another study used the human induced pluripotent stem cell (iPSC) technique to survey the potentially harmful effects of SARS-CoV-2 infection in iPSC-derived pancreatic cells. iPSC-derived pancreatic cells allow SARS-CoV-2 to enter and establish infection (40). Alexander et al. (41) showed that both exocrine and endocrine pancreatic cells in humans can be infected with SARS-CoV-2, both in vivo and in vitro. The infection can reduce the number of insulin-secreting granules and impair glucose-stimulated insulin secretion. Moreover, they detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells and cells close to the islets of Langerhans in full-body postmortem examinations of all 4 patients. Similarly, Steenblock et al. (42) detected SARS-CoV-2 viral infiltration of β cells in the islets and autopsy tissues of 11 patients who died of COVID-19.

Morphological and functional alterations of islets have been observed in patients infected with SARS-CoV-2, including a decrease in the number of insulin-secreting granules in β cells, loss of insulin gene transcription, damage to insulin secretion, and an increase in the number of both insulin- and glucagon-positive cells (41, 43, 44).

Regarding the distribution of SARS-CoV-2 in the pancreas, a mixed result was recognized. For instance, 1 study showed that SARS-CoV-2 particles were detected in cells containing insulin-secreting particles (42) and another study showed that SARS-CoV-2 particles were present in pancreatic ducts and endothelial cells (45). Some reports indicated that SARS-CoV-2 mRNA is present in insulin-positive cells and the ductal epithelium, but not in endocrine tissue (43, 46). However, other reports have shown that endocrine and exocrine tissues can be used to detect SARS-CoV-2 mRNA (41, 44, 45). Previous research (41) reported that SARS-CoV-2 positive cells were not randomly distributed throughout the pancreas but clustered in populations of infected cells. As a result, targeted viral diffusion occurred in the pancreas rather than being randomly disseminated in the pancreatic tissue. The discrepancies among these reports may be due to part of the difference in the expression levels of viral receptors among individuals. Moreover, staining methods for pancreatic hormones and viral antigens are different. SARS-CoV-2 may also affect the exocrine function of the pancreas. In COVID-19 patients, CD45-positive immune cells infiltrated pancreatic exocrine and endocrine tissues, indicating pancreatic inflammation (42). In contrast, there is no evidence of pancreatic inflammation with other patients (43, 47). This means that not all COVID-19 patients have pancreatic damage.

These studies provide evidence that SARS-CoV-2 directly infects β cells and affects β-cell function. However, not all autopsy samples interrogated in these studies showed clear evidence of viral particles in β cells (43, 46). According to Kusmartseva et al., SARS-CoV-2 nucleocapsid protein expression is primarily limited to the ducts (46). There are several explanations for these conflicting findings, such as spatial and temporal heterogeneity of viral spread, interindividual variations in the investigated donor tissue, and technical constraints, such as sample preservation and the detection assays used. Therefore, larger sample sizes, more stable detection techniques, and more refined analysis of interindividual differences may be required, as well as a better understanding of the clinical characteristics of individuals who may be more susceptible to SARS-CoV-2 viral infection. It is also necessary to investigate predisposing genetic factors, specifically HLA.

In addition, the propensity of SARS-CoV-2 to different tissues is controlled by cytokines expressed on target cells, such as the viral entry receptor angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) (48). Several studies have detected the expression of ACE2, TMPRSS, and other receptors and factors, such as dipeptidyl peptidase 4, HMBG1, and neuropilin 1 (NRP1), in islet β cells, which may facilitate SARS-CoV-2 entry (41, 42, 49).We discuss this in more detail in a subsequent section.

Structure of the SARS-CoV-2

SARS-CoV-2 is a coronavirus with a spherical morphology and a single-stranded RNA genome. SARS-CoV-2 and SARS-CoV share 79% homology with their genomes (47, 50). It is predicted that SARS-CoV-2 has at least 12 coding regions (49). Spike glycoproteins are involved in the crown-like appearance of coronavirus particles and play a key role in entry into the viral genome in host cells. Each spike consists of 3 monomers fused into trimers (51). The first key step in the entry SARS-CoV-2 into cells is the binding of the homologous trimer spike protein to its specific cellular receptor. This may trigger a series of proteolytic events that result in the fusion of the cell and the viral membrane. An in vitro–binding assay showed that the binding of SARS-CoV-2 protein to ACE 2 receptor was improved, and it was identified as the primary host receptor (52). The S protein contains 2 functionally distinct regions, S1 and S2, which are responsible for receptor binding and triggering of fusion events. Through the receptor binding domain of the S protein S1 unit, the virus can connect to the host cell receptor ACE2 and invade cells (48, 53, 54). Host cells then require TMPRSS2 activation (48). Other possible viral receptors and proteases that promote SARS-CoV-2 infection include disintegrin and metalloprotease 17, dipeptidyl peptidase 4, TMPRSS4, cathepsin L, FURIN, and NRP-1 (43, 49, 55-58). The multiple M glycoproteins in lipids are the largest component of virus particles, and it is also where the S-spike structure inserts and fixes. Interestingly, the coronavirus M protein is a polyhedral virus membrane (59), which was first described in the field of virology. Glycosylation plays a role in organ tropism and induces α-interferon production. The E protein of SARS-CoV-2 is a complete membrane protein, and the N protein is a phosphoprotein that combines the spiral core-shell structure with viral RNA to boost replication efficiency.

How COVID-19 Triggers T1D

Virus-induced β-cell damage, immune-mediated loss of pancreatic β cells, and damage to β cells from the infection of surrounding cells were considered possible mechanisms that could lead to T1D (Fig. 1).

Cell-invasion gateways for SARS-CoV-2 viral entry mechanism

Coronavirus penetrates the cell interior using the host cell membrane protein receptor. The most well-known gateway for SARS-CoV-2 is ACE2 (48). Apart from ACE2, previous studies have proposed several proteases involved in coronavirus activation that can be expressed in β cells, including FURIN, NRP-1, and TMPRSS2 (49, 60, 61). To further understand the process of viral entry into cells, we offer an overview of the present findings on the SARS-CoV-2 receptor and host factors.

ACE2

When it comes to whether ACE2 is expressed in pancreatic β cells, different studies have reached different conclusions. RNA-sequencing and immunohistochemistry analyses of human pancreatic islets showed that ACE2 was expressed in human primary β cells (19, 39, 41, 62, 63). Conversely, some studies have shown extremely low ACE2 mRNA expression in the human pancreas, islets, and β cells (46, 64, 65). According to these studies, ACE 2 protein was not detected in β cells, but in the microvasculature, exocrine capillaries, islet ducts, and pericytes in both COVID-19 and non–COVID-19 patients (46, 63, 64). Possible reasons for these differences are as follows: the sample size is small, the sensitivity of the application method is low (44, 66), and sex and ethnic background differences (41, 44, 45) and methods of sample preparation or preservation are inconsistent (67), the effect of rapid autolysis of the pancreas on receptor detection (64), interindividual variation of the ACE2 subtype, antibodies specific for each subtype (41), and variable ACE2 expression associated with cytokine response (63).

TMPRSS2

TMPRSS2 is widely expressed in the epithelial cells (68).After SARS coronavirus binds to ACE2, it acts as an activator of SARS coronavirus spike proteins (69-71). In addition, TMPRSS2 increases viral intake by cleaving ACE2 at arginine residues 697-716 (72). However, TMPRSS2-deficient cells can still be infected with SARS-CoV-2, indicating that TMPRSS2 expression is not required for viral entry (44). Similar to ACE2, there are different results regarding the expression of TMPRSS2 in β cells. Some studies have shown the presence of TMPRSS2 in pancreatic endocrine cells (41, 42); on the other hand, others have not (43, 46, 64). Further research is necessary.

FURIN

SARS-CoV-2 homotrimer spikes, composed of S1 and S2 subunits, protrude from the surface of the virus and are essential for binding to membrane protein receptors. When SARS-CoV-2 enters the cell, the S glycoprotein must be cleaved by proteases at 2 different sites, S1/S2 and S2 (73). Recent studies have shown that when SARS-CoV-2 enters cells, viral entry is triggered by continuous cleavage of the viral S protein at the S1/S2 and S2 sites by FURIN and TMPRSS2, respectively, releasing the viral genome into target cells (74). Similarly, another study found that there is a FURIN cleavage site at the S1 and S2 subunits of the SARS-CoV-2 S glycoprotein. When the virus S protein binds to ACE2, FURIN cleaves the S protein between the S1 and S2 subunits, a process that is necessary for viral entry (75). Furthermore, according to a previous study, the increased level of FURIN in patients with diabetes may lead to an increased risk of SARS-CoV-2 infection in patients with diabetes (76).

NRP-1

NRP-1 is a cell surface receptor that plays vital roles in angiogenesis, vascular permeability regulation, and nervous system development (77). When the host protease FURIN cleaves the S glycoprotein into S1 and S2 parts, a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence is generated on S1, which conforms to the C-segment regular motif that binds to NRP1 and NRP2 receptors on the cell surface. James et al. demonstrated that the S1 C-segment regular instrument could be directly combined with NRP1 using X-ray crystallography and biochemical methods (49). SARS-CoV-2 is more infectious than SARS-CoV, which may be partly due to the binding of the C-terminal peptides NRP1 and S1. In addition, Cantuti et al. found that NRP1 could express ACE2 enhancers to promote viral host-cell interactions with low ACE2 expression (78). Moreover, the expression of NRP-1 is higher in β cells than in α cells (42-44). In vitro inhibition of pancreatic NRP-1 reduces SARS-CoV-2 infection efficiency and partially activates glucose to stimulate insulin secretion (43). Therefore, NRP-1 contributes to SARS-CoV-2 capacity to infect β cells (43, 44).

As mentioned, the levels of β-cell receptors and proteins in the pancreas are inconsistent. However, that SARS-CoV-2 may infect β cells and other pancreatic cells seems to have been recognized by some research groups and was confirmed by hPSC-derived cells/organoids. This indicates that the pancreas is one of the SARS-CoV-2 target organs. However, the entry mechanism of SARS-CoV-2 requires further investigation (39).

COVID-19 triggers autoimmune β-cell disorders: autoimmune mechanism

Autoimmune diseases are characterized by the presence of autoantibodies, loss of immune tolerance, and permanent inflammatory response caused by immune system imbalance, resulting in target organ damage and dysfunction. This immune-induced damage is also present in patients with COVID-19. Wang et al. (79) used a high-throughput autoantibody discovery technique to screen a cohort of 194 individuals infected with SARS-CoV-2 and found that patients with COVID-19 exhibited marked increases in autoantibody reactivity compared with uninfected individuals and showed a high prevalence of autoantibodies against immunomodulatory proteins, which increased disease severity in a mouse model of SARS-CoV-2 infection. In addition to immune-targeting autoantibodies, they observed a high prevalence of tissue-associated autoantibodies in patients with COVID-19. These autoantibodies were directed against vascular cells, coagulation factors and platelets, connective tissue, extracellular matrix components, and various organ systems, including the lung, central nervous system, skin, gastrointestinal tract, and other tissues. Bastard et al. (80) reported that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G autoantibodies against interferon-ω (IFN-ω; 13 patients), 13 types of IFN-α (36 patients), or both (52 patients) at the onset of critical disease. Another team (81) characterized the immunologic underpinning of emerging primary autoreactivity in COVID-19 and found that extrafollicular B-cell activation is a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity. Further research identified extrafollicular B-cell activation as a dominant feature of severe and critical COVID-19 and highlighted the immunological consequences of uncensored EF expansion of autoreactive naive B cells in severe COVID-19 infection.

Although there was no mention of islet related antibodies in these studies, this suggests that SARS-CoV-2 may induce autoimmune diseases. SARS-CoV-2 infection can cause autoimmune pancreatitis and destruction of islet β cells through a variety of mechanisms (82), including epitope spreading, molecular mimicry, and bystander activation (83), but the mechanisms of generation and chronic pathogenic potential remain to be understood. Therefore, it is necessary to further understand the molecular mechanisms by which viruses such as SARS-CoV-2, can induce autoimmunity.

Epitope spreading

In the acute phase of infection, the virus targeting pancreatic β cells replicates in the cells, directly leading to the destruction of β cells and inducing a cytotoxic immune response until the immune system stops viral replication; only then are the β cells no longer lost (83). In the process of continuous immune response to the pathogen, the number of epitopes in the pathogen that generate the body's immune response is increasing. It has also been proposed that COVID-19 leads to the production of neoepitopes via posttranslationally modified proteins, which can trigger islet cell autoimmunity in genetically susceptible individuals (84). In a persistent viral infection, there is increased cytokine secretion by dying cells, specifically IFN-γ and perforin, which could enhance major histocompatibility complex I expression and the presentation of new self-antigens. These new self-antigens are presented by antigen-presenting cells (APCs) to CD4+ and CD8+ T cells to generate antibodies aimed at self-antigens, inducing autoimmunity and further tissue and organ damage (85). This suggests that the autoimmune response is amplified, and there is β-cell damage and continuous failure of T-cell regulation. In the presence of persistent inflammation and autoreactive CD4+ and CD8+ T cells, β cells are destroyed and insulin replacement therapy is required for SARS-CoV-2-initiated autoimmunity; therefore, SARS-CoV-2 induced autoimmunity may lead to chronic and progressive islet β-cell damage.

Molecular mimicry

The molecular mimicry hypothesis suggests that T and B lymphocytes are activated because of the structural similarity between pathogen antigens and their own antigens, which leads to potential cross-reactions, leading to autoimmune diseases. Homology between pancreatic autoantigens and viral proteins has been predicted, such as cytomegalovirus, rotavirus, and coxsackie B-like enteroviruses (86-88). Similarly, molecular mimicry is believed to be responsible for the autoimmune reaction in COVID-19 (89-91). Venkatakrishnan et al. (92) reported that different 8-mer and 9-mer peptides have potential cross-reactivity between the human reference proteome and SARS-CoV-2. Daria et al. analyzed the shared relationship between the sequence of the minimum epitopes of SARS-CoV-2 and human proteomes, and many immunoreactivity epitopes shared with human proteins were recorded. These results suggest that various clinical manifestations and pathologies after SARS-CoV-2 infection may explain diseases, including different organs and systems (93). In addition, the viral protein was compared with the human molecular chaperone by Marino Gammazza et al. (94), assuming that chaperones were involved in the molecular mimic phenomenon after SARS-CoV-2 infection. Insulin in the β cells of COVID-19 patients and molecular similarity between SARS-CoV-2 and autoantigen associated with cells has not been confirmed yet.

Bystander activation

Another hypothesized mechanism is bystander activation. The innate immune system, the body's first line of defense, responds strongly to SARS-CoV-2, leading to increased levels of proinflammatory cytokines. This overactive immune response creates a “cytokine storm,” the nonspecific, overreactive antiviral immune response that produces a local inflammatory environment. During cell infection (95) near β cells, dendritic cells secrete pro-inflammatory cytokines that initiate self-tissue damage while producing self-antigens that mimic COVID-19 antigens. These self-antigens are eventually picked up and presented by APCs to stimulate nearby, previously unresponsive, self-responding T cells, thereby inducing autoimmunity (96, 97). For instance, studies have shown that pancreatitis leads to damage to exocrine and endocrine cells and diabetes (98, 99). The association between COVID-19 pancreatic damage and pancreatitis has been repeatedly demonstrated (100-102). Infection is often accompanied by elevated amylase and lipase levels (103, 104).

SARS-CoV-2 effects on microvasculature: indirect damage mechanism

Another means that COVID-19 leads to tissue damage in the pancreas is the destruction of pancreatic blood vessels. Qadir et al. (45) reported that SARS-CoV-2 could infect pancreatic islets, ducts, and endothelial cells in nonhuman primates and humans, and that SARS-CoV-2 infection is related to disseminated pancreatic endotheliitis, fibrosis, microthrombi, and new-onset hyperglycemia, suggesting that COVID-19 causes new-onset diabetes. Kusmartseva et al. (46) observed multiple thrombotic lesions in pancreatic slices of COVID-19 patients. COVID-19 causes microvascular inflammation, hypercoagulable state, and thrombosis (105, 106). Endothelial injury can result in systemic inflammation and the heap up of prediabetic metabolites through the activation of immune cells and inflammatory responses in tissues, ultimately leading to β-cell injury. This is another possible mechanism for the islet damage associated with SARS-CoV-2 infection (107, 108).

Conclusions and Future Directions

The COVID-19 outbreak in 2019 has placed an enormous burden on humanity. We are still in the early stages of the disease, but unfortunately, its effects can be long-range, especially as a possible trigger for autoimmune disease. The possibility that COVID-19 infection might contribute to damage within the pancreas is supported by diverse data. The mechanisms involved include direct cytopathic effects of SARS-CoV-2 replication, systemic and local inflammatory responses, and long-term autoimmune damage. Given that the development of autoimmune diseases is often a chronic, long-term process, it is difficult to draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area requires us to focus on the long-term outcomes. More comprehensive studies with larger cohorts of patients with different demographics, ethnicities, and geographic locations and long-term clinical follow-up are needed, involving C-peptide, insulin, and anti-islet antibodies, especially in pediatric patients, together with more comprehensive long-term histopathological analysis of the patient's biological samples. Genetic susceptibility of individual patients should also be considered.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by “the National Natural Science Foundation of China” (81900384, 81900701) and “Natural Science Foundation of Jilin Province” (YDZJ202201ZYTS036).

Disclosures

The authors have no conflicts of interest relevant to this article to disclose.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

Abbreviations

 
• ACE2

  angiotensin-converting enzyme 2

 
• APC

  antigen-presenting cell

 
• DKA

  diabetic ketoacidosis

 
• IFN

  interferon

 
• iPSC

  induced pluripotent stem cell

 
• NRP-1

  neuropilin 1

 
• OR

  odds ratio

 
• T1D

  type 1 diabetes

 
• TMPRSS2

  transmembrane serine protease 2