Covid 19 and diabetes in children: advances and strategies

Increased COVID-19-related mortality has been linked not only to cardiovascular and renal complications of diabetes but also to glycemic control and body mass index. Several studies have indicated that adults with T1D face an elevated risk of COVID-19 complications. For instance, scientists discovered a correlation between elevated Glycosylated Hemoglobin, Type A1C (HbA1c) levels and increased COVID-19-related mortality and hospitality [23, 24]. Additionally, research involving adult diabetes patients has identified hyperglycemia as an independent factor associated with a severe prognosis in individuals hospitalized for COVID-19 [25, 26]. Conversely, some studies have reported contradictory findings. Roque Cardona-Hernandez and colleagues revealed that children with diabetes exhibited similar outcomes and prognosis to their non-diabetic peers across five centers [27]. Similarly, Revital Nimri and his colleagues found that young individuals with established T1D experienced mild COVID-19 infections in Israel. However, their research also suggested that elevated glucose levels during COVID-19 infection and older age were associated with a prolonged disease course [28].

The number of T1D children has increased sharply in recent years [29], how to face the risks from pandemic is a challenge for patients and their parents. A cross-sectional study involving 98 children and adolescents with T1D identified several key challenges faced by Iranian patients due to pandemic restrictions. These challenges included the necessity for increased insulin doses, reduced physical activity, insulin shortages, and missed morning insulin doses [30]. Other studies also noted weight gain, a significant rise in HbA1c levels, and an increase in daily insulin requirements among children with T1D during the pandemic [31, 32]. Furthermore, the mental health of children with diabetes has gained increased attention. A retrospective evaluation of 39 patients with T1D who experienced acute hospitalizations revealed that approximately 6 out of 11 (55%) patients hospitalized in 2021 had witnessed diabetes deterioration due to emotional distress, a phenomenon not prominently observed in the pre-COVID era [33]. Additionally, S. B. Koca and colleagues conducted a cross-sectional clinical and laboratory study, revealing a statistically significant positive correlation between HbA1c levels and Children’s Depression Inventory (CDI) scores, which serve as an indicator of depression status [34].

Conversely, María Sánchez Conejero and her colleagues reported contrasting results in an observational, retrospective study involving children and adolescents with T1D who utilized interstitial glucose monitoring systems. Their findings indicated that during a 2-week lockdown period, the glycemic control of children with T1D actually improved, particularly among those who had poorer baseline control [35]. Interestingly, another observational cohort study conducted by Namam Ali suggested improvements in glucometer data, including HbA1c and data from finger glucose monitoring (FGM) systems, among individuals with T1D during the COVID-19 pandemic and lockdown. Notably, FGM users demonstrated better outcomes [36]. Furthermore, dietary management has become increasingly crucial in diabetes treatment. A study involving 764 participants highlighted that eating habits were significantly worse among youths with diabetes compared to those without diabetes. This underscores the importance of lifestyle education during the pandemic [37].

Numerous reports and studies have explored the connection between viral infections and the onset of new diabetes cases. A compelling body of evidence has emerged from cases of robust type-1 diabetes characterized by the sudden onset of insulin-dependent hyperglycemia and, in some instances, ketoacidosis, even in individuals without detectable autoantibodies. Symptoms such as fever and cough have been identified as potential triggers for this new-onset diabetes. Virology studies have further detected RNA from enteroviruses in four patients afflicted with new-onset diabetes. Meta-analysis have provided substantial evidence linking enterovirus infections to the significant incidence of new-onset diabetes [38]. Furthermore, researchers have observed that individuals infected with Hepatitis C face an elevated risk of developing diabetes when compared to non-infected populations [39]. In vitro studies have also demonstrated that Coxsackie B virus can lead to beta cell dysfunction or even cell death [40].

During the acute phase of viral infection, the virus can replicate within pancreatic β cells, resulting in the direct destruction of these cells and triggering a cytotoxic immune response [41]. Following the acute phase, β cells within the islets are predominantly targeted by autoimmune processes and epitope diffusion. Sustained overexpression of major histocompatibility complex (MHC) molecules can expose β cell epitopes to the immune system, heightening the risk of autoimmune dysfunction. Another crucial mechanism of damage involves bystander effects, which are mediated by cytokines, particularly interferon-alpha (INF-α), interferon-beta (INF-β), interferon-gamma (IFN-γ), tumor necrosis factor (TNF), and interleukin-1beta (IL-1β). These cytokines can induce endoplasmic reticulum stress and trigger apoptosis in islet cells, as observed in animal models. Additional potential mechanisms include molecular mimicry and bystander activation, although their relevance to humans remains to be conclusively established.

The infection process is illustrated in Fig. 1. COVID-19, a positive-sense single-stranded RNA coronavirus, comprises four essential protein components: membrane (M), envelope (E), nucleocapsid (N), and spike (S) proteins. During the cellular entry process, the S protein interacts with angiotensin-converting enzyme 2 (ACE2), which is widely expressed in the human respiratory system. Subsequently, the virus undergoes endocytosis, leading to the fusion of the virus with the host cell membrane. Simultaneously, the bound S protein is cleaved by the membrane-bound serine protease Transmembrane Serine Protease 2 (TMPRSS2), activating the endocytic process and enabling the virus to enter the host cell. In this context, the RNA within the virus directly engages with ribosomes to initiate replication and translation processes, resulting in the production of viral proteins and RNAs. Following modification, assembly, and packaging, the virus is released from the host cell through exocytosis, subsequently infecting other cells.

Pancreatic β cells, responsible for insulin synthesis and secretion, play a pivotal role in regulating glucose levels within the human body. In the context of COVID-19 infection, the ACE2 receptor assumes a central role. Analyses of public databases have demonstrated the expression of ACE2 receptors not only in exocrine glands but also in islets, including β cells, with higher expression levels compared to the lungs [42]. Besides, the expression of ACE2, TMPRSS, Dipeptidyl peptidase 4 (DPP4), high molecular group box 1 (HMBG1), and Neuropilin-1 receptor (NRP1) on the membrane of islet β cells, also facilitates viral entry. The investigation into the impact of COVID-19 on islet β-cells initially stemmed from autopsy reports, where scientists observed pancreatic tissue degradation in three patients who succumbed to COVID-19 infection. A study in Wuhan, China, further identified elevated levels of amylase and lipase in COVID-19 patients, even in cases with mild symptoms, with more significant elevations seen in severe cases. Computed tomography scans of severely infected COVID-19 individuals indicated pancreatic changes such as pancreas enlargement or pancreatic duct dilation, without signs of acute necrosis [42]. Syairah Hanan Shaharuddin and colleagues conducted a study utilizing live human pancreatic cultures and postmortem pancreatic tissue from COVID-19 patients, revealing the virus’s ability to infect pancreatic tissues, encompassing endocrine islets, exocrine acinar cells, and ductal cells within the pancreas [43].

In infected human islets, both insulin content and glucose-stimulated insulin secretion experienced significant decreases when compared to mock-treated islets, implying a detrimental impact on islet function. Janis A Müller and colleagues found following infection, endocrine cells exhibited subcellular and functional damage, including dilation and vacuolization of the endoplasmic reticulum (ER)-Golgi apparatus complex, as well as a loss of the ability to transition from high glucose levels to low glucose levels [44]. Transcriptional analysis revealed defects in protein secretion, a loss of cell identity, and an enrichment of IFN type 1 response [44]. Additionally, in another study, by staining for autopsy tissue from COVID-19 patients and normal individuals, the scientists suggested that COVID-19 infiltration induces the expression of phosphorylation of mixed linage kinase domain-like protein (pMLKL), which may be considered a signal of necroptosis [45]. Besides, scientists observed that infection induced apoptosis in β-cells. Through the application of global phosphoproteomics, substrate-based kinase activity prediction, along with kinase set enrichment analysis and gene set enrichment analysis, they unveiled an upregulation of stress-response Mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK)/p38 (MAPK8/11), and cytoskeleton-reorganizing p21-activated kinases (PAK), both of which can trigger cell death through apoptosis pathways. Furthermore, several members of the protein kinase C (PKC) family exhibited downregulation [4].

In pancreatic tissues, there exist two types of islet cells, β cell plays a more important role in glucose metabolism, however, is more vulnerable in damage of infection. In a separate study that centered on pancreatic tissue from donors who had not been infected by COVID-19, scientists discovered that ACE2 and TMPRSS2 were generally expressed in both β-cells and α-cells but at low protein levels. However, two other receptors, NRP1 and transferrin receptor protein 1 (TFRC), displayed robust expression specifically in β-cells, not in α-cells. This suggests a potential mechanism for COVID-19’s tropism for β-cells [4]. In another in-vitro study, the efficiency of COVID-19 infection significantly decreased in the following co-treatment with the small molecule EG00229, a selective NRP1 antagonist [4].

Glucose metabolism plays a crucial role in the mechanisms of diabetes. Catabolic processes like glycolysis occur in the liver, muscle, and nearly all peripheral tissues, while anabolic stages include gluconeogenesis and glycogen synthesis. These pathways collectively regulate glucose levels within the body. Any impairment in glucose metabolism within these pathways can result in glucose level dysfunction. Multiple studies have identified elevated blood glucose levels as a significant independent risk factor for severe infection and worse outcomes. Ana Campos Codo and her colleagues conducted a study focusing on monocytes and macrophages, which are believed to play an essential role in the disease’s pathogenesis. They discovered that these cells undergo a shift towards heightened glycolysis after infection, facilitating COVID-19 replication [52]. In vitro studies further demonstrated that increasing glucose levels in culture led to a significant rise in viral load, as well as the expression of ACE2 and IL-1β in monocytes infected by COVID-19. Elevated glucose levels also trigger the secretion of cytokines, including TNF-α, IL-6, IFN α, β, and λ. Monocytes isolated from tissues of diabetes patients exhibited a higher viral load compared to normal controls [52]. Proteomic studies suggested an upregulation of glycolysis-related pathways after infection, indicating that increased glycolysis could be a distinctive feature of COVID-19 infection compared to other respiratory viruses [52]. Additionally, further research based on bronchoalveolar lavage (BAL) monocytes from severe COVID-19 patients found that metabolic state changes were promoted by hypoxia-inducible factor-1α (HIF-1α), which was stabilized by mitochondrial reactive oxygen species (ROS) production triggered by infection [52].

The most prevalent pathophysiological change observed in the organs of COVID-19 patients is uncontrolled inflammation. Key manifestations include widespread damage to the alveoli, infiltration of inflammatory cells in hyaline membranes, as well as inflammation in the liver, myocardium, and brain. Jérôme Hadjadj and colleagues conducted an integrated immune analysis on a cohort of 50 COVID-19 patients with varying disease severity. They discovered a significant impairment in the interferon (IFN) type I response, which was associated with persistent viral load in the bloodstream and an exacerbated inflammatory response. However, the inflammation is primarily driven by increased production and signaling of TNF-α and IL-6 [53]. In addition to changes in immune types, severe COVID-19 patients also experience cytokine storms, which can pose a life-threatening risk. A retrospective study conducted in Wuhan indicated alterations in immune types in patients following COVID-19 infection [47]. Furthermore, the researchers identified IL-6 and lactate dehydrogenase (LDH) as independent parameters for predicting the severity of COVID-19. In innate immunity, IL-6 plays a crucial role as a pro-inflammatory factor, capable of causing damage to proteins, lipids, and DNA in organs and tissues, ultimately affecting the body’s structure and function [54]. Elevated inflammatory biomarkers like IL-6 have been linked to an increased risk of both microvascular and macrovascular complications due to low-grade vascular inflammation, which could contribute to the severity of diabetes [55].

Insulin resistance plays a critical role in the development and progression of diabetes, particularly in type 2 diabetes. However, insulin resistance following COVID-19 infection differs from diet-induced insulin resistance, as it is primarily driven by inflammation affecting metabolic organs or the entire body. Elettra Barberis and her colleagues utilized metabolomic approaches to identify lipid biomarkers in COVID-19 patients, providing evidence of insulin resistance development post-infection [56]. Moritz Reiterer and his colleagues observed a frequent association between hyperglycemia and severe respiratory syndrome in COVID-19 patients, with insulin resistance identified as a leading factor. Their research also revealed lower levels of adiponectin in COVID-19 patients. Subsequent studies indicated that COVID-19 has the capacity to replicate in hamster adipose tissue and modify adipokine expression, particularly leading to a reduction in adiponectin expression [57].

In addition to adipose tissue, the metabolic condition of skeletal muscle also plays a role in the severity of insulin resistance. Marko Šestan and colleagues discovered that the virus-induced IFN-γ can reduce the expression of insulin receptors in skeletal muscle, resulting in a state of hyperinsulinemia. This state can further boost antiviral immunity by directly stimulating the function of CD8 + effector T cells. Consequently, viral infection may accelerate the development of diabetes in individuals with pre-existing insulin resistance conditions, such as obesity or fatty liver diseases [58].

As a state of endocrine dysfunction, the interplay between organs holds significant implications for the development and severity of diseases. Endocrine hormones serve as crucial bridges between these organs. In light of the evidence indicating hyperglycemia following COVID-19 infection, researchers have identified a glucogenic hormone known as GP73 [59]. GP73 is secreted by various tissues during fasting and is notably elevated in lung, liver, and kidney tissues post COVID-19 infection. Experiments with cultured cells have shown that GP73 secretion increases following COVID-19 infection or overexpression of COVID-19 nucleocapsid and spike proteins in a dose and time-dependent manner [59]. Studies on mice have revealed that after GP73 injection, these molecules are primarily transported to the liver and kidneys, with higher accumulation observed after 30 min. Additionally, researchers have demonstrated that GP73 can enhance the expression of key gluconeogenic enzymes, intracellular cAMP levels, and PKA kinase activity, thereby increasing glucogenesis. Subsequent investigations have indicated that blocking GP73 can inhibit excessive glucogenesis and reduce elevated glucose levels during fasting stages after COVID-19 infection in vitro and in vivo [59]. As detection technologies advance, more hormones remain to be discovered, potentially serving as therapeutic targets in the future.