Type 1 diabetes (T1D) is an autoimmune disease characterized by immune-mediated destruction of beta cells. Beta cells are responsible for generating insulin, a critical hormone that regulates blood glucose levels in the human body. Susceptible individuals are influenced by a combination of high-risk specific genetic allele factors such as HLA genes and environmental elements like viral infections or dietary factors, with the consequence of inciting an aberrant immune response. In the initial steps of T1D development, beta cells release islet autoantigens as a result of cellular turnover or damage. These antigens are then subsequently presented to T helper cells (CD4+). In response, macrophages and dendritic cells infiltrate the pancreatic islets with beta cell polypeptides. Interleukin (IL)-12 released from the infiltrating cells activates CD4+ T cells, which have already been pre-programmed as helper cells. CD4+ T cell activation induces the secretion of IL-2, which in turns activates beta cell antigen-specific CD8+ T cells, which have been pre-programmed as cytotoxic cells. Consequently, the coordination of type 1 T helper (Th1) CD4+ T cells and CD8+ cytotoxic T cells leads to the elimination of existing beta cells. The Th1 CD4+ T cells release pro-inflammatory cytokines, such as interferon-gamma (IFN-γ), which further enhance the activation and cytotoxicity of CD8+ T cells. Henceforth the CD8+ T cells, armed with cytokinesis molecules, can directly target and destroy beta cells, exacerbating the loss of islet mass. In addition, one crucial aspect regarding the pathogenetic development of T1D is the dysregulation of two types of T cells: regulatory T cells (Tregs) and effector T cells. Tregs are prominent in maintaining immune tolerance and preventing autoimmune attacks; effector T cells are usually activated by the lack of Tregs and designated to attack all foreign molecules. However, in T1D, there is often an imbalance between both the quantity and function of Tregs. This leads to impaired Treg activity, resulting in a loss of immune tolerance and an unchecked immune response by effector T cells targeting beta cells, henceforth releasing cytotoxic mediators, recruit macrophages, and orchestrate an inflammatory cascade within the islets. Consequently, beta cells undergo apoptosis and progressive decline, leading to reduced insulin secretion. The clinical presentation manifests as polydipsia, polyuria, unexplained weight loss, fatigue, and visual disturbances. The etiology of T1D necessitates a comprehensive exploration of the underlying genetic, immunological, and environmental intricacies to advance therapeutic interventions and preventive strategies.
Insulin plays a vital role in regulating the glucose level in the blood. This destruction process leads to severe insulin depletion hence hyperglycemia, the condition of having persistent high blood sugar level. Insulin deficiency can cause fatty acid oxidation, fat breakdown, and produce an excessive amount of ketones. Hyperglycemia can inflict various health implications, including diabetic ketoacidosis, where the absence of insulin drives the rapid breakdown of fats for energy, and is potentially lethal. Long-term hyperglycemia can result in microvascular and macrovascular complications. The former primarily affect small blood vessels, causing complications such as diabetic retinopathy, permanent damage to eyes and eyesight, and peripheral neuropathy, enduring harm to nerves in the extremities of human limbs. Macrovascular complications, on the other hand, affect larger blood vessels. These implications include high blood pressure, arterial stiffness, and kidney disease. Until now, while certain genetic and environmental risk factors are implicated, the exact cause of this lethal disease is still unknown, and it has no effective solution beyond timely and frequently injected insulin.
Currently, exogenous insulin replacement therapy is the standard of care for T1D. New developments such as hybrid closed-loop systems, which are automated pumps that are able to deliver insulin based on detected bloodstream glucose levels, mainly aim for regulating insulin delivery and long-acting insulins. Aside from external aids, multiple studies on the prevention of T1D complications emphasize the importance of early treatment and blood glucose control. Another current solution is the transplantation of primary islets. However, the effectiveness of this method is hindered by factors such as an insufficient supply of islet cells, extensive death of islet cells by autoimmune attacks on these “foreign” transplants, and poor vascular engraftment of islets. As such, more research on stem cell-based therapy is required before islet transplantations can be considered a fully effective method to overcome T1D. This renders current T1D treatments to simply increasing insulin intake to resolve the insufficiency caused by beta cell destruction.
Since TID is caused by the destruction of beta cells, one proposed method in treating T1D involves protecting beta cells. The primary literature review reveals the renalase (RNLS) gene, which can also be found in mice; as a promising candidate, RNLS is a flavoprotein oxidase and was identified in Genome Wide Association Study (GWAS) of T1D Cai et al. (2020). According to Cai et al (2020), mutations in the RNLS gene protect beta cells. First, RNLS mutation allows cells to withstand greater levels of endoplasmic reticulum (ER) stress. Moreover, RNLS mutation is associated with reduced activity of autoreactive CD8+ T cells, which may result in less frequent assault on insulin-producing beta cells. For our project, we will manipulate RNLS expression through selective promoter usage and different mutations. The crystal structure of human RNLS has been solved. It is also known that RNLS uses a flavin adenine dinucleotide (FAD) cofactor for catalysis and is structurally related to other flavoprotein oxidases. Combining these preliminary knowledge, the authors of the study noted that a drug approved by the Food and Drug Administration (FDA) meant to treat moderate to severe hypertension, pargyline, replicates the effects of RNLS mutation by inhibiting the protein’s activity. In addition to protecting beta cells from being attacked by T cells, we can regenerate beta cells to maintain insulin production in T1D patients. Reg3-ʏ is a promising genetic target for stimulating beta cell regeneration (Xia et al., 2016). Reg3-ʏ gene, which facilitates lectin secretion, confers beneficial effects on beta cell regeneration. Upon the overexpression of Reg3-ʏ gene in pancreatic cells, the Janus kinase 2/signal transducer and activator of transcription 3/nuclear factor κB signaling pathway will be activated. Janus kinase includes two domains, the catalytic domain and a kinase domain. Once its receptor binds with ligands, the dimerization of the receptor happens and activates the Janus kinase. Activated Janus kinase initiates trans-phosphorylation on specific tyrosine residues, and becomes a docking site for recruitment of latent cytoplasmic transcription factors. Janus kinase-signal transducer and activator of transcription is essential for signal transduction from cell membrane to nucleus, which is important to some cytokines and growth factor. This signal pathway enhances the regeneration of beta-cells and thus increases the amount of beta-cells, which can produce insulin. On top of that, the expression of Reg3-ʏ expression gene attenuates lymphocyte infiltration, which ease the attack from immune cells, leading to the recovery of insulin production. To explain the decline in lymphocyte infiltrate, Xia et al (2016) shows that Reg3-ʏ gene boosts the differentiation of CD4+ and CD25+ T cells, which are both T-cells crucial in protecting target organs from autoimmune disease and in maintaining immune tolerance. By overexpressing Reg3-ʏ gene, autoimmunity can be attenuated and the the body can achieve immune homeostasis.
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