Saudi Journal for Health Sciences

: 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


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

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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
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Full Text


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.


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.


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.

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Conflicts of interest

There are no conflicts of interest.


1Uchigata Y. Can restoring immune balance be the ultimate therapy for type 1 diabetes? J Diabetes Investig 2016;7:819-21.
2Khosravi-Maharlooei M, Madley R, Borsotti C, Ferreira LM, Sharp RC, Brehm MA, et al. Modeling human T1D-associated autoimmune processes. Mol Metab 2022;56:101417.
3Health AIO. Insulin pump use in Australia. Aust Prescr 2012;41:186-90.
4Chantelau EA, Prätor R, Prätor J. Insulin-induced localized lipoatrophy preceded by shingles (herpes zoster): A case report. J Med Case Rep 2014;8:223.
5Razavi Z. Frequency of ketoacidosis in newly diagnosed type 1 diabetic children. Oman Med J 2010;25:114-7.
6Onyiriuka AN, Ifebi E. Ketoacidosis at diagnosis of type 1 diabetes in children and adolescents: Frequency and clinical characteristics. J Diabetes Metab Disord 2013;12:47.
7Sarikonda G, Pettus J, Sachithanantham S, Phatak S, Miller JF, Ganesan L, et al. Temporal intra-individual variation of immunological biomarkers in type 1 diabetes patients: Implications for future use in cross-sectional assessment. PLoS One 2013;8:e79383.
8Wållberg M, Cooke A. Immune mechanisms in type 1 diabetes. Trends Immunol 2013;34:583-91.
9Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab 2012;16 Suppl 1:S27-36.
10Hassan GA, Sliem HA, Ellethy AT, Salama Mel-S. Role of immune system modulation in prevention of type 1 diabetes mellitus. Indian J Endocrinol Metab 2012;16:904-9.
11Chiang JL, Kirkman MS, Laffel LM, Peters AL, Type 1 Diabetes Sourcebook Authors. Type 1 diabetes through the life span: A position statement of the American diabetes association. Diabetes Care 2014;37:2034-54.
12Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000;408:57-63.
13Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009;41:703-7.
14Imkampe AK, Gulliford MC. Trends in type 1 diabetes incidence in the UK in 0- to 14-year-olds and in 15- to 34-year-olds, 1991-2008. Diabet Med 2011;28:811-4.
15Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 2009;52:1143-51.
16Richardson SJ, Leete P, Bone AJ, Foulis AK, Morgan NG. Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1. Diabetologia 2013;56:185-93.
17von Herrath M. Can we learn from viruses how to prevent type 1 diabetes? The role of viral infections in the pathogenesis of type 1 diabetes and the development of novel combination therapies. Diabetes 2009;58:2-11.
18Vehik K, Fiske SW, Logan CA, Agardh D, Cilio CM, Hagopian W, et al. Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY. Diabetes Metab Res Rev 2013;29:557-67.
19Campbell-Thompson M, Wasserfall C, Kaddis J, Albanese-O'Neill A, Staeva T, Nierras C, et al. Network for pancreatic organ donors with diabetes (nPOD): Developing a tissue biobank for type 1 diabetes. Diabetes Metab Res Rev 2012;28:608-17.
20Lernmark Å. Environmental factors in the etiology of type 1 diabetes, celiac disease, and narcolepsy. Pediatr Diabetes 2016;17 Suppl 22:65-72.
21Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, et al. The human pancreatic islet transcriptome: Expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet 2012;8:e1002552.
22Arif S, Moore F, Marks K, Bouckenooghe T, Dayan CM, Planas R, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death. Diabetes 2011;60:2112-9.
23Singh B, Nikoopour E, Huszarik K, Elliott JF, Jevnikar AM. Immunomodulation and regeneration of islet beta cells by cytokines in autoimmune type 1 diabetes. J Interferon Cytokine Res 2011;31:711-9.
24Bachmann M, Ulziibat S, Härdle L, Pfeilschifter J, Mühl H. IFNα converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets. Biochem Pharmacol 2013;85:396-403.
25Li Q, McDevitt HO. The role of interferon alpha in initiation of type I diabetes in the NOD mouse. Clin Immunol 2011;140:3-7.
26Calderon B, Unanue ER. Antigen presentation events in autoimmune diabetes. Curr Opin Immunol 2012;24:119-28.
27Luppi P, Kallas Å, Wahren J. Can C-peptide mediated anti-inflammatory effects retard the development of microvascular complications of type 1 diabetes? Diabetes Metab Res Rev 2013;29:357-62.
28Pfleger C, Mortensen HB, Hansen L, Herder C, Roep BO, Hoey H, et al. Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes. Diabetes 2008;57:929-37.
29Pham MN, Kolb H, Battelino T, Ludvigsson J, Pozzilli P, Zivehe F, et al. Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes. Diabetologia 2013;56:1356-63.
30Kaas A, Pfleger C, Kharagjitsingh AV, Schloot NC, Hansen L, Buschard K, et al. Association between age, IL-10, IFNγ, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes. Diabet Med 2012;29:734-41.
31Sima AA, Zhang W, Kreipke CW, Rafols JA, Hoffman WH. Inflammation in diabetic encephalopathy is prevented by C-peptide. Rev Diabet Stud 2009;6:37-42.
32Joshua IG, Zhang Q, Falcone JC, Bratcher AP, Rodriguez WE, Tyagi SC. Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C-peptide. J Cell Biochem 2005;96:1149-56.
33Lim YC, Bhatt MP, Kwon MH, Park D, Na S, Kim YM, et al. Proinsulin C-peptide prevents impaired wound healing by activating angiogenesis in diabetes. J Invest Dermatol 2015;135:269-78.
34Walsh J, Roberts R. Pumping Insulin: Everything you need for Success on a Smart Insulin Pump. San Diego: Torrey Pines Press; 2006.
35Rodgers J. Using Insulin Pumps in Diabetes: A Guide for Nurses and other Health Professionals. Wiley: John Wiley & Sons; 2008.
36Klonoff DC. Technological advances in the treatment of diabetes mellitus: Better bioengineering begets benefits in glucose measurement, the artificial pancreas, and insulin delivery. Pediatr Endocrinol Rev 2003;1:94-100.
37Cobert B, Cobert J. 100 Questions & Answers about your Child's Obesity. Sudbury, Massachusetts: Jones & Bartlett Learning; 2009.
38Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol 1999;26:259-65.
39Wijsman CA, Mooijaart SP, Westendorp RG, Maier AB. Responsiveness of the innate immune system and glucose concentrations in the oldest old. Age (Dordr) 2012;34:983-6.
40Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010;5:e9085.
41Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med 1997;14:29-34.
42Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 2004;286:E234-8.
43van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67.
44Keim C, Kazadi D, Rothschild G, Basu U. Regulation of AID, the B-cell genome mutator. Genes Dev 2013;27:1-17.
45Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 2006;107:3639-46.