Saudi Journal for Health Sciences

REVIEW ARTICLE
Year
: 2022  |  Volume : 11  |  Issue : 3  |  Page : 165--169

Primary understanding of type 1 diabetes as an autoimmune disease


Mohamd A Alblihed 
 Microbiology Department, College of Medicine, Taif University, Taif, Saudi Arabia

Correspondence Address:
Mohamd A Alblihed
Microbiology Department, College of Medicine, Taif University, Taif
Saudi Arabia

Abstract

Type 1 diabetes (T1D) is classified as an autoimmune disease affecting a wide range of people worldwide. Beta cells in the pancreatic islets of Langerhans in the pancreases are responsible for insulin productions, which help in the exchange of blood glucose into energy. These cells were destroyed by developing particular immune mechanisms. Some newly diagnosed patients with T1D have insignificant scientific understanding of their immune system condition. Importantly, scholars found a direct relationship between hypoglycemic and innate immune response. Therefore, this review was intended to elaborate a simple scientific explanation for T1D, including T1D etiology and pathogenesis, initiation of immune response against β-cell, and immunological impact of the best therapy, in addition to the newest understanding of the cell types and immune mechanisms involved in T1D. This review included articles published from 1997 to 2022 extracted from PubMed, Medline, and Google Scholar databases.



How to cite this article:
Alblihed MA. Primary understanding of type 1 diabetes as an autoimmune disease.Saudi J Health Sci 2022;11:165-169


How to cite this URL:
Alblihed MA. Primary understanding of type 1 diabetes as an autoimmune disease. Saudi J Health Sci [serial online] 2022 [cited 2023 Feb 7 ];11:165-169
Available from: https://www.saudijhealthsci.org/text.asp?2022/11/3/165/362378


Full Text



 Introduction



The chronic diseases are affecting people worldwide including Type 1 diabetes (T1D). T1D represents only 10% of diagnostic diabetes cases worldwide and mostly affects young generation.[1] T1D and T2D share common symptoms including excessive urination, thirstiness, weight loss, blurred vision, tiredness, fatigue, genital itching or thrush, and cuts and wounds take longer to heal. T1D symptoms can often appear quite quickly. The T1D is characterized as an autoimmune disease.[2] Beta cells (β-cells) in the pancreatic islets of Langerhans in the pancreases are responsible for the production of insulin in the body to help in the exchange of blood glucose (BG) into energy. In T1D conditions, β-cells will be targeted by particular immune mechanisms which lead to β-cells distractions and then lack of insulin production. The autoimmune disorder causes around 90% of β-cells deaths. The reason behind the immune system disorder is not fully known. It has been reported that T1D complications are associated with high levels of BG and proinflammatory responses. Unfortunately, there is no cure for T1D; however, several therapies have been developed to ensure that T1D patients can live close to normal BG.

T1D patients used different methods of insulin delivery, including multidaily injection, insulin pen, and insulin pumps.[3] Nonetheless, lacking of insulin directed the human body to convert fats to provide energy.[4] Behaviors and habits such as eating healthy are ideal in the management of the T1D. However, when patients diagnosed with T1D and the symptoms are observable, it may be difficult to cure the disease. Moreover, glycemic control remains difficult to be achieved by T1D patients, and complications are realized due to poor glycemic control. The most dangerous risk and complication for T1D is the diabetic ketoacidosis (DKA).[5] The DKA occurred when the body cannot use sugar and use fat instead as a source of energy. Once DKT started, ketones are released, and the blood becomes acidic (acidosis). The signs of DKA include high BG levels, thirsty, rapid breathing, abdominal pain, dehydration, and vomiting among other things.[6] Moreover, uncontrolled BG can lead to delay of wounds healing.[7]

Environmental factors, climate, and nutrition have been suggested as risk factors in developing T1D. Moreover, it has been suggested that the levels of Vitamin D may affect T1D disease development. Finally, susceptibility to T1D is resulted from a combination of both genetic and environmental factors.[8] Since immune system is responsible to protect the body from infections and inflammation, T1D classified as an autoimmune disease.[9] Immune system acts against by different mechanisms and then destroyed β-cells.[10] This review was intended to provide brief explanations for T1D, including T1D etiology and pathogenesis, initiation of immune response against β-cell, and immunological impact of the best therapy.

 Methods



Study selection

Literatures cited in Medline, PubMed, and Google Scholar were used in the current review of literature. The search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included the articles published between 1997 and 2022.

Search terms

A range of keywords were used, including T1D, diabetes, autoimmunity, and immunity. Combined keywords were used together with restricting the search engine to titles and abstracts.

The immune system

The first defense system in the body against invading pathogens is the immune system. Research indicates that T1D patients most likely to have a higher level of infection than normal people. Immune system protects the human body from infection by communicating an individual's well-being through a numerous complex immune network of interconnected cells and cytokines. However, when this system is uncontrolled, a negative autoimmune process will proceed. T1D is one of the autoimmune diseases caused by immune-mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans in the pancreases by reducing β-cells population and functionally suppressed by ongoing inflammation.

The β-cell destruction mechanism is still unclear. However, a number of proinflammatory cytokines have been shown to be significant for the development of T1D.[11] Other inflammatory proteins have been demonstrated to be critical for T1D development, including interleukin (IL) 2–7, IL-9, IL-11–13, IL-15, IL-21,[12] and signals through the JAK-STAT3 pathway that result in T-cell and B-cell proliferation and NK cells activation.[8]

T1D is similar to other inflammatory disease; T1D is not a homogeneous disease and there may be different etiologies. In some T1D patients, genetic factors could affect the magnitude of the immune responsiveness. In addition, involvement of environmental factors, mainly infectious causes, is assumed as possible driver for T1D. The recent finding of involving genetic human leukocyte antigen locus association with increased risk of T1D supported the theory that the T1D is immune mediated, which determines the specificity of αβ T-cells. T1D was found to be linked with gene constitution of IL-2 receptor, TCL antigen, nonreceptor type 22, and tyrosine phosphatase.[13] T1D is increasing at a faster rate worldwide, and both genetic and environmental factors are incriminated as predisposing or inducing factors.[14]

Infections activated event leading to T1D directly to β-cell, since many viruses[15],[16] are implicated for the induction of T1D either directly or indirectly through the inflammatory cytokines such as interferons-α (IFN-α).[17]

Pathogenesis of Type 1 diabetes

The well-characterized autoimmune disease is T1D. Nevertheless, the T1D mechanisms involved in the β-cell destruction are still not clear. The full understanding of T1D pathogenesis is challenging researchers, since most of the significant immunological actions have occurred before T1D patients diagnosed. Therefore, investigators are restricted to blood cells rather than islets or draining lymph nodes.[18],[19] Animal models have been involved widely, including NOD mice and BioBreeding (BB) rats. Several proposed susceptibility genes such as cytotoxic T-lymphocyte antigen 4, IL-2, and insulin were seen in the NOD mice.

The autoimmune process involved in the β-cell destruction includes macrophages, dendritic cells, B-lymphocytes, and T-lymphocytes. It has been recommended to identify which factors are causing the immune system to become unregulated and promote an autoimmune response.[20] Developing autoimmune disease T1D requested three fundamentals autoimmune development. First, activation of β-cell-reactive T-cells; second, the autoimmune response needs to be proinflammatory; and finally, immune regulation of autoreactive responses must fail.[8]

 Beta cells



β-cells can be infected and lyses through viruses' infections occurs such as cox-sackie B, rubella, and mumps. These infections can lead to the production of proinflammatory cytokines, mainly type I IFN, and increasing expression of MHC class I on β-cells.[17] Upregulating chemokines expression such as IL-8 and chemokine CC ligand (CCL)-5 can be due to the exposure to proinflammatory cytokines. In addition, β-cells can be affected by exposure to proinflammatory.[21] Arif and his team in 2011 indicating a possibility that around 50% of β-cells can share in their own death by interaction with its immunity.[21] Both T-cells from recent-onset T1D patients and islet cells express IL-22,[22] which signal transducer and activator of transcription (STAT3). Furthermore, IL-22 can lead to upregulate tissue protective gene transcription.[23] While β-cells exposure to IFN-α induces overexpression of NO synthesis by creation IL-22 receptor switch to signaling through STAT1.[24] Li, in 2011, confirmed that early blocking of IFN-α with the absence of an infection may delay the T1D development in NOD mice.[25]

When β-cell is destroyed by virus infection, viral antigen is presented in such cells[26] that leads to sensitization of the T cell-derived immune response to that antigens. Both CD8+ and B-cell immune responsiveness are activated with effector functions directed to the destruction of the infected cells.[8]

Efforts paid to identify the mechanisms behind β-cell destruction, as these efforts will lead to developing a cure for T1D. Sadly, about 90% of the β-cells were destructed when T1D patients were diagnosed. However, C-peptide is well known to realize an important function in insulin synthesis.

C-peptide

T1D is characterized by C-peptide deficiency, elevated levels of proinflammatory cytokines, and hyperglycemia. C-peptide is also named as connecting peptide; it is short 31-amino-acid polypeptide. C-peptide connects insulin's A-chain to its B-chain in the proinsulin molecule. C-peptide is well known to realize an important function in insulin synthesis, and it is useful as an indicator of β-cell function. Furthermore, C-peptide levels, used as a marker for serum insulin concentration, assess the β-cell function and also the autoimmune attack on pancreatic β-cells.

Immunologically, reducing plasma secretion and concentration of cytokines IL-1 and IL-6 and chemokines and protection against TNF-induced in T1D are associated with C-peptide activity.[27]

Researchers show the association of C-peptide and anti-inflammatory cytokine like IL-1 receptor antagonist (IL-1ra). IL-1ra elevated in patients with increased C-peptide secretion, which means improving β-cell function (stimulated C-peptide) in T1D patients. However, IL-1 β is negatively associated with C-peptide. Proinflammatory including IL-6 was elevated in patients with increased C-peptide secretion.[28]

Moreover, proinflammatory cytokines such as TNF-α were associated with increased fasting and stimulated C-peptide concentrations. Anti-inflammatory IL-10, transforming growth factor-β1 (TGF-β1), and TGF-β2 increased and associated with lower fasting and stimulated C-peptide level.[29] Chemokines including CCL2, CCL3, CCL4, and CCL5 concentrations negatively associated with C-peptide level.[28],[30]

Replacement of insulinomimetic C-peptide in T1D significantly prevents and corrects the upregulation of receptor for advanced glycation end products (RAGE) and NF-κB activation with downstream beneficial effects on proinflammatory factors such as TNF-α and ILs. Moreover, the interaction between RAGE and its ligands is thought to result in proinflammatory gene activation. The development of diabetic encephalopathy is the result of activation of innate immune responses, and this can be prevented through the replacement of insulinomimetic C-peptide.[31] Exclusively, microvascular complications in T1D can be improved by the supplementation of C-peptide.[32] Insulinomimetic C-peptide speeds wound healing in T1D by reducing inflammation and angiogenesis stimulation.[33]

Type 1 diabetes treatment

Managing T1D is controlling the level of BG close to normal, between 4.0 and 5.4 mmol/L (72–99 mg/dL) when fasting, and up to 7.8 mmol/L (140 mg/dL) 2 h after eating, to prevent diabetes complications.[34] T1D treatments aim to ensure that there is a constant supply of insulin in the body by taking insulin, healthy eating, and management of weight.[35] Frequently, people who have lived with T1D manage their BG regardless of types of insulin treatments including rapid acting, long lasting, and intermediate insulin.[36] Since the stomach enzymes affect externally administered insulin, insulin intervention cannot be administered orally. These types of insulin can be injected through multidaily injection through a needle and syringe or advanced equipment like insulin pen or insulin pumps. With controlled diet, research found three injections daily that provide good glycemic control for people with T1D.[1] Insulin pump is highly recommended for T1D, as it is comfortable, reduces neuropathy pain, eliminates insulin resistance, controls glycemia, and reduces the risk of diabetes complications. However, in case of the pump failure, patients are at risk of ketoacidosis.[37] The use of pumps can interfere with the preservation of C-peptide.

Immunological impacts of controlling the blood glucose

T1D patients are at risk of having lower immunity levels compared to people without T1D. However, controlling the BG close to normal leads to the improvement of immune system. Failure to supply required insulin may lead to several defects of the innate immune system.[38] There is a lack of clear relationship between BG and immune system.

Some researchers indicated that the T1D patients increased risk of disturbances in innate immunity, infection, and sepsis. Nondiabetic with higher glucose concentrations are at high risk with lower innate immune response.[39] Delamaire et al. in 1997 and Andreasen in 2010 hypothesized that high BG negatively influences cytokine production and neutrophil function.[40],[41] In 2012, researcher found significant negative association between BG concentrations, but not HbA1c, and cytokine response capacity in TNF-α, IL-6, IL-1 β, and IL-10. However, in vitro applying of different BG concentrations on innate immunity have yielded conflicting results.[38]

In nondiabetic, cytokine response was not reduced when induction of hyperglycemia and lipopolysaccharide (LPS) stimulation in vivo.[42] Moreover, no association was found between HbA1c and cytokines levels in response to LPS-stimulation. Nevertheless, in nondiabetic patients, stress-induced hyperglycemia is with high risk of sepsis and increased morbidity and mortality.[43]

The relationship between hyperglycemia and low cytokine response could lead to clinical significance. The disorders in glucose and insulin metabolism may lead to reduced β-cell function and decreased insulin action.[44],[45] Importantly, scholars found a direct relationship between glucose concentration and innate immune response.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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