Type1 Diabetes and COVID-19: A Systematic Review and Possible Management

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), remains a prominent global health concern. SARS-CoV-2 is an RNA virus belonging to the family Coronaviridae. There are different variants with unique mutations, which mainly affect the respiratory system, but can also damage the nervous system and endocrine organs. The clinical manifestations of COVID-19 vary from asymptomatic or mild disease to acute respiratory distress syndrome (ARDS), hospitalization and death [1]. The commonly reported endocrine complications are thyroid dysfunction and hyperglycemia [2]. The connection between COVID-19 and endocrine disorders such as Diabetes Mellitus (DM) is a nuanced area of research.

DM is a metabolic disorder characterized by dysfunctional insulin signaling, compromising the ability of cells to absorb glucose, causing hyperglycemia and other debilitating complications, including micro and macro vascular complications. The two main classifications of DM, namely type 1 DM (T1D) and type 2 DM (T2D), differ in that T1D consists of defective insulin production, whereas T2DM consists of inadequate cellular response to insulin signaling [3]. COVID-19 can potentially increase the incidence rate of T1D and T2D. T1D is routinely began by pancreatic cell damage, which is immune mediated and triggered by genetic or environmental factors. Viral infection, such as e enteroviruses and respiratory viruses, are probably responsible for autoimmunity against β-cell [4,5]. Generally, COVID-19 and T2DM appear to have a bidirectional relationship, but the relationship between COVID-19 and T1D remains to be controversial and multi-faceted [6].

Diabetic ketoacidosis (DKA) is a life-threatening complication that usually occurs in patients with T1D. In T1D, the absence of insulin promotes an excess breakdown of fats as an alternative source of energy, resulting in the buildup of acidic ketones and disrupting the organ functions. During the COVID-19 pandemic, there was a notable increase in the incidence and severity of DKA in patients with T1D, suggesting a possibility that COVID-19 and DKA are causally connected [7,8,9]. However, other studies found no evidence of a physiological association between DKA and SARS-CoV-2, implying that the surge in the incidence and severity of DKA during COVID-19 is best attributed to a diminished quality of care for diabetic patients due to an overburdened healthcare system [10,11,12]. Moreover, while the severity of symptoms of T1D may have been exacerbated during the pandemic (once again, arguably due to strains on the healthcare system), the overall incidence rate of T1D may not have necessarily been impacted [13]. Therefore, the interplay between COVID-19 and T1D is rather complex.

This review aims to elucidate the intricate relationship between COVID-19 and T1D, emphasizing the different aspects of epidemiology, pathophysiology, and prognosis. By providing a comprehensive review of the impact of COVID-19 on patients with T1D, this review also identifies potential therapeutic strategies to improve their outcomes and mitigate mortality and morbidity associated with both diseases.

2. Materials and Methods

This review aims to discuss the currently available data about COVID-19 infection in type 1 diabetic patients.

Data sources and searches. According to PRISMA guidelines [14], a systematic search was conducted in PubMed database and Google Scholar for relevant studies. Search dates were between January 2020 and December 2022. The following key words were applied for search: “T1D, T1DM, Type 1 DM or Type 1 Diabetes”, “Coronavirus, SARS-CoV-2 or COVID-19”.

Study selection: Two authors (KK and NA) reviewed abstracts and third author (KA) made a cross-check. We reviewed the references of relevant reviews to include further potentially relevant article. Two authors contributed to the selection process, data extraction and data collection independently of each other. The participants, study type, outcomes and interventions were used to select the relevant studies. The selected studies were discussed to resolve disagreements and a third author participated if needed. We included (1) clinical research articles, such as cohort, cross-sectional, case-control studies and case series, (2) review articles including mini-review, systematic review and meta-analysis, (3) opinion and commentary articles, like editorial, commentary, perspective, and letter to editor, that discuss the incidence, clinical characteristics, outcomes, complications, morbidity and mortality of T1D in COVID-19 patients or vice versa. Figure 1 shows the flowchart for the systematic review.

Duplicates were eliminated after a review of all recognized articles from the initial searches. The remaining papers were read in full. The publications were summarized in terms of the author, journal, year of publication, country of origin, study design, number of participants, type of intervention, age, gender, outcomes (death, DKA, or other complications), new onset diabetes or worsening of pre-existing diabetes, and other results in general.

3. Result

A total of 296 studies were found during the initial database searches. The exclusion process resulted in 21 eligible manuscripts for further investigation [7,8,9,10,11,12,13,15,16,17,18,19,20,21,22,23,24,25,26,27,28] (Table 1).

3.1. COVID-19 and T1D incidence

The incidence of new onset T1D in children was increased in Germany [16], Hungary [29], Romania [21], Turkey [23] and USA [28] but not in Australia [8], Israel [17], Poland [13,19,20], Saudi Arabia [22] and Turkey [30] during the COVID-19 pandemic. Furthermore, there was no significant increase in new onset autoantibody-negative type 1 diabetes in children, adolescents, and young adults in Germany [10] but new onset T1D and autoantibody positivity was higher in Turkey [23] during the pandemic.

3.2. Clinical outcomes and complications of T1D patients during COVID-19

DKA, hospitalization rate, and death were studied in selected studies. DKA incidence, prevalence or severity were increased in most studies [7,8,9,11,12,13,17,18,19,20,21,22,23,26,28] during the COVID-19 pandemic. However, there was no increased in DKA incidence in autoantibody-negative type 1 diabetes in Germany [10], or in new onset T1D in Israel [17]. There was also no increase in severe DKA in Israel [17] and no increase in DKA or severity in USA [25].

The hospitalization rate of new onset T1D during the pandemic seems to be stable in French [27]. Nevertheless, the data about death rate is not consistent, as increase in death reported in China [9] and USA [24,26], but no increase in death seen in French [15].

4. Discussion

SARS-CoV-2 enters human cells mainly through the ACE2 receptor. There are other receptors that may mediate SARS-CoV-2 entry into human cells, including dipeptidyl peptidase 4 (DPP-4 or CD26), CD147, neuropilin-1, lectins, CD209L, and tyrosine-protein kinase receptor UFO (AXL). The host proteases, such as transmembrane protease serine 2 (TMPRSS2), furin, trypsin, elastase and cathepsin L, are also involved in the process of SARS-CoV-2 entry into cells. ACE2 on cell membrane has other responsibilities against inflammation, proliferation and fibrosis. Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is indirectly involved in the process of SARS-CoV-2 entrance and tissue damage by shedding ACE2 from the cell membrane [31,32,33]. ACE2 expression in the GI tract and pancreas is relatively remarkable. It is also expressed in essential metabolic tissues, such as liver, kidney, adipocytes and vasculature [34]. Coronavirus can potentially target the metabolic tissues, especially the pancreas, which leads to islet cell damage [35], insulin resistance [36] and hyperglycemia (Figure 2). The current information about incidence of new onset T1D in children during the pandemic is not consistent across the countries. This could be due to differences in outcomes of treatment modalities, accessibility to effective treatment and speed of conducting a successful approach. However, COVID-19 was associated with increased incidence and severity of DKA in different countries. Furthermore, there are few case reports or case series including euglycemic DKA [37], known T1D and DKA [38], or new onset T1D with or without DKA [39,40,41,42,43,44,45,46,47] following COVID-19 infection or vaccination [48,49], which raises concern over not only a possible causal relationship between COVID-19 and T1D, but also the beneficial roles of early and practical treatment. In addition, it should be emphasized that the occurrence of new SARS-CoV-2 strains with unique mutations can potentially render resistance to the current antivirals that are routinely used, such as Paxlovid, Remdesivir and Molnupiravir [50,51].

Therefore, considering other medications with the potential capability of targeting SARS-CoV-2 receptor, reducing virus entry into the cells and alleviating inflammation may improve clinical outcomes better than antivirals. They may also assist in reducing the risk of hyperglycemia and new onset diabetes. Ursodeoxycholic acid (UDCA) reduces farnesoid X receptor (FXR) signaling, downregulates ACE2 expression in respiratory tract and diminishes susceptibility to SARS-CoV-2 infection. It was associated with reduced hospitalization, ICU admission and death of COVID-19 patients [52]. UDCA was also shown to reduce COVID-19 infectivity and severity in cirrhotic patients [53]. Antiandrogens downregulate TMPRSS2 and ACE2, which reduce SARS-CoV-2 entry into the cells [54]. They lower mortality, hospitalization rate and duration of SARS-CoV-2 infection [55]. Spironolactone, an aldosterone receptor antagonist with anti-androgenic effects, antagonizes TMPRSS2 and ADAM17, reduces virus entry into the cells, and diminishes SARS-CoV-2-mediated endothelial damage [56,57]. It has been reported that spironolactone improves the clinical scores and reduces mortality, ICU admission, intubation and end orang damage in hospitalized COVID-19 patients [57]. Metformin activates AMP-activated protein kinase (AMPK), which leads to phosphorylation of ACE2. ACE2 phosphorylation enhances ACE2 stability on cell membrane, increases Ang (angiotensin) 1-7 and endothelial nitric oxide synthase bioavailability, and therefore provides lung protection by preserving endothelial function. The phosphorylation of ACE2 may affect virus entry into the cells too. Metformin also inhibits mammalian target of rapamycin (mTOR) pathway and modulates the immune response against the infection [58,59,60]. Generally, metformin seems to be helpful by reducing SARS-CoV-2-related tissue injury. Metformin could not improve the clinical outcomes of COVID-19 patients impressively [61] but it could reduce the incidence of long COVID [62]. DPP4 inhibitors have immunomodulatory roles and possibly blunt the alternative route of virus entry through DPP4 receptors [32]. They can alleviate SARS-CoV-2 cytokine storm and injury to the organs. The use of DPP4 inhibitors in patients with SARS-CoV-2 infection was associated with improvement of glucose levels in diabetic patients and clinical improvement and reduction of inflammatory markers in diabetic and non-diabetic patients [57,63,64].

5. Conclusion

Based on the collected evidence, the effect of SARS-CoV-2 infection on the incidence of new onset T1D is controversial. However, COVID-19 increases the incidence and severity of DKA in T1D patients. Antivirals seems to be helpful but not completely protective against SARS-CoV-2-induced tissue injuries. An alternative therapeutic approach includes targeting SARS-CoV-2 receptor, blocking virus entry and alleviating inflammation, especially by combining medications with different beneficial characteristics, to tackle SARS-CoV-2 infection and associated complications. Flooring the path for future clinical trials that investigate the protective role of this alternative approach would be reasonable, as it is shown that combination of spironolactone and sitagliptin could reduce hospitalization rate and duration of disease [65].