Possible Pharmacotherapeutic Effects of Immunomodulators in the Treatment of Diabetes Mellitus

The clinical pathology of diabetes is associated with impaired insulin secretion, insulin action, or a combination of both [1]. If the underlying pathology is not properly treated, the course may rapidly worsen, and also lead to potentially life-threatening short-term syndromes and long-term complications. Before the introduction of insulin by Banting and Best in 1922, diabetes historically remained a disease with a high mortality rate, and physicians did not have an effective clinical strategy to alleviate this disease. Intermittent fasting, diet, bland food, etc. In addition to prolonging the life of these patients, it also improved their quality of life [2]. Diabetes is a complex disease caused by genetic factors and many environmental factors. For example, sex differences in genetic and environmental factors such as sex hormones, sex chromosomes, and sex-specific epigenetic modifications lay the foundation for the development of diabetes [3]. Although there are multiple risk factors in the pathogenesis of diabetes, pancreatic β-cell dysfunction is a common feature of both type 1 diabetes (T1D) and type 2 diabetes (T2D). Genome-wide association studies have shown that T2D is a complex polygenic disease, with genetic factors estimated to account for 20% to 80% of the disease [4]. Pancreatic β-cells play an important role in regulating glucose homeostasis. They have molecular sensors that recognize elevated blood glucose levels and produce insulin to maintain blood glucose levels. Although pancreatic β-cell destruction leads to the development of T1D, T2D occurs when β-cells fail to secrete enough insulin to compensate for insulin resistance. Numerous studies have shown that multiple molecular mechanisms, including autoimmunity, inflammation, and metabolic stress, are risk factors for the development of β-cell deficiency. Autoimmune-mediated β-cell dysfunction is associated with β-cell autoantigens and immune cell infiltration of the pancreatic islets [5]. Type 1 diabetes (T1D) is characterized by insulin deficiency. Although some diagnosed patients have remarkable residual beta-cell function1, the deficiency soon becomes apparent and gradually resolves. [6] Although preschool-aged children lose almost all beta-cell function within a year of diagnosis, school-aged children or adolescents may have some insulin secretion for many years. In rare cases of T1D, beta-cell function improves dramatically soon after diagnosis, glucose metabolism normalizes, and insulin is not required during a period called complete remission [7].

Immunomodulatory pharmacotherapeutic approaches are widely used in medicine to correct many pathologies. In oncology practice, especially in the case of cancer that does not respond to known agents, antitumor immunotherapy significantly reduces mortality due to therapy with monoclonal antibodies (mAb) targeting immune cells and adoptive cell therapy (ACT) [8]. Also, by stimulating the relaxation of early inflammatory initiators such as reactive oxygen species, degranulation of tumor cells, inhibition of leukocyte infiltration, blocking inflammatory cytokines and inhibition of adaptive B and T lymphocytes, it has a positive effect and attracts attention in pharmacological practice. correction of cardiovascular diseases [9]. In nephrology practice, manipulations with the immune system of patients lead to regeneration of renal tissue, which reduces acute kidney injury without progression to chronic kidney disease and renal failure [10]. More specific immunotherapies have also been tested. The CD3 receptor is one of the important receptors that triggers the action of T cells as an antigen. It can be expected that monoclonal antibodies will at least modulate this receptor. Studies by North American and also French scientists have shown that the use of monoclonal anti-CD3 antibodies can block both the destructive autoimmune process and at least delay the decline in beta cell function [11]. From the treatment protocols used to date, it follows that the decrease in residual insulin secretion is delayed for only one year, since the C-peptide curve, which decreases one year after treatment, is similar to the curve in the placebo group. Further studies are ongoing to determine whether the effect can be prolonged with immunomodulators [12]. It is already recognized that type 1 diabetes is a specific autoimmune disease. Autoantibodies to pancreatic islets are used as diagnostic markers to predict pathogenesis in both laboratory mice and humans with diabetes [13]. These autoantibodies include insulin, glutamic acid decarboxylase (GAD), zinc transporter (ZnT8), and insulinoma antigen 2 (IA-2) in pancreatic islets. Although the molecular mechanisms of autoantigen processing are still unclear, a possible role for endoplasmic reticulum (ER) stress-related proteins in pancreatic β-cells in the formation of corresponding autoantigens has been suggested [14]. Against the background of the inflammatory process in adipocytes, the immune response is enhanced by apoptosis and macrophage infiltration, interaction of the pathogenic factor with CD4+ and CD8+ T cells, and CD11c+ M1 macrophages in adipose tissue enhance the inflammatory process in adipose tissue and peripheral insulin resistance [15]. As a result, pancreatic β-cells increase insulin production to compensate for peripheral insulin resistance, causing hyperinsulinemia [16]. However, in the long term, chronically progressive insulin resistance leads to β-cell depletion, which manifests as insulin deficiency. Persistent apoptosis ultimately leads to hyperglycemia and type II diabetes mellitus due to the induction of free fatty acids, amyloids and inflammatory cytokines by β-cells [17]. According to the results of some scientific studies, the level of tumor necrosis factor (TNF)-α in the adipose tissue of obese mice, as well as insulin resistance [18].

In addition, an increase in plasma interleukin (IL)-6, C-reactive protein, plasminogen activator inhibitor and other inflammatory mediators was recorded in the blood plasma of the corresponding animals. [19]. TNF-α, free fatty acids, diacylglyceride, ceramide, reactive oxygen species (ROS), hypoxia activate Iҡβα kinase β (IKKβ) and N-terminal kinase I c-Jun (JNK1) in adipose tissue and insulin receptor substrate (IRS-1) is induced by the inhibitor [20]. In addition, TNF-α induces insulin resistance [21]. The revolution in biomedical research that has occurred over the past three decades has attracted worldwide attention in this direction. Attempts at immunological intervention as a preventive method for people with diabetes aim to overcome the limitations of exogenous insulin therapy and reduce the risk of morbidity and mortality associated with the disease. Current immunomodulatory strategies in diabetes are classified into stages: primary immunomodulation - aimed at preventing diabetes, autoimmunogenesis before the formation of β-cell autoantibodies; secondary immunomodulation to prevent pathogenesis after the formation of β-cell autoantibodies; tertiary immunomodulation aimed at preventing symptomatic pathoregression after the diagnosis of the disease. Most studies have focused on tertiary immunomodulation aimed at easily identifying new patients with T1DM [22]. The use of immunomodulatory drugs alters the response of the immune system by increasing or decreasing the production of serum antibodies using immunostimulants and immunosuppressants, respectively. Immunostimulants are used to enhance the immune response to infectious diseases, malignancies, primary or secondary immunodeficiency, and to alter antibody transmission. However, immunosuppressants are used to reduce the immune response to transplanted organs and to treat autoimmune diseases [23]. Immunomodulatory pharmacotherapeutic approaches are designed to disrupt the proinflammatory process through various mechanisms, including the ability to modulate the immune system's response to diseases, the action of antioxidants, disruption of bacterial flora, monoclonal antibodies, cytokines and extracellular immune mediators, and extracellular immune signals [24]. Thus, it selectively either inhibits or activates certain cell populations and subpopulations responsible for the immune response. Kunisaki et al. in their experiments [25] showed normalization of retinal blood flow and PKC activity in vascular tissue upon administration of vitamin E to diabetic rats. In addition, two other short-term experimental studies have shown that high doses of vitamin C and lipoic acid improve some aspects of endothelial dysfunction in diabetes [26]. Furthermore, recent studies have shown that vitamin E has the ability to reduce oxidative stress accumulated in macrophages in diabetic mice [27]. Finally, other studies have been able to find a preventive effect of vitamin E in patients with heart failure and type 1 diabetes. They were able to show that “supplementation of streptozotocin (STZ)-induced diabetic rats with 2000 IU vitamin E/kg diet provides significant protection against T1DM-induced cardiac dysfunction, which begins immediately after induction of hyperglycemia and continues for 8 weeks. ” [28].

Treatment with several monoclonal antibodies targeting T lymphocytes has been successfully tested in newly diagnosed patients with CD. Rituximab (anti-CD20) lowers HbA1c and normalizes insulin secretion, thereby providing a therapeutic effect in patients with diabetes mellitus [29]. However, in patients receiving long-term treatment with rituximab, the improvement was transient and the monoclonal antibodies remained unchanged [30]. In contrast, although teplizumab (anti-CD3) prevents the progression of type 1 diabetes in clinically high-risk individuals [31], the effect of the corresponding drug in patients with the HLA-DR3 allele or anti-ZnT8 antibodies was not satisfactory, reflecting the heterogeneity of diabetes. Proinflammatory cytokines play an important role in the development of diabetes, and cytokine administration has been found to induce important cytoprotective changes in the pancreas [32]. Interleukins (ILs) are potent immunomodulators that have significant effects on the immune system, exerting cytostatic, pronecrotic and proapoptotic inhibitory effects, which is very important given the pathogenesis of diabetes mellitus [33]. Studies of pharmacological IL-1 antagonism and monoclonal blockade have shown that IL-1 inhibition can protect pancreatic tissue when combined with adjunctive therapy [34]. CD4+ T- and CD8+ effector T-cells are key factors in the destruction of pancreatic β-cells and the development of overt T1D. Thus, anti-CD3 monoclonal antibodies (mAbs) targeting T-cells are one of the promising therapeutic approaches, given that targeting T-cells is the most effective approach to the development of diabetes. Although the exact mechanism of action of anti-CD3 monoclonal antibodies is unclear, it is believed that they deplete autoreactive T cells and preserve the activity of regulatory T cells [35]. Diabetes is a multifactorial disease caused by genetic and environmental factors that affect abnormal immune modulation, leading to dysfunction and destruction of pancreatic β-cells. Although the mechanisms of altered immune responses are not yet fully understood. The focus of immunotherapeutic approaches to the prevention of diabetes is on the effector CD4+ T cells and CD8+ T cells. Currently, uncontrolled inflammatory signaling pathways are considered to be the main factors in the pathogenesis of diabetes. As reported above, the pathogenesis of diabetes mellitus is accompanied by many components of the immune system including T helper cells, cytotoxic T cells, regulatory T cells, etc. As a result of the above scientific analysis, the use of immunomodulators can be considered appropriate for the purpose of pharmacological correction of both types of diabetes, protection of the pancreas from damage, and prevention of the progression of the corresponding disease, which requires preclinical and clinical series of studies.

Decleration: No conflict of interest