How Type 1 Diabetes Develops and May Be Prevented

Karsten Buschard^*, Rikke Thea, and Camilla Hartmann Friis Hansen

Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark.

*Corresponding Author: Karsten Buschard, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark.

Received: 24 June 2026; Accepted: 29 June 2026; Published: 21 July 2026

1. Introduction

Type 1 diabetes is an autoimmune disease affecting millions of people worldwide. Autoimmune diseases have various mechanisms and different clinical presentations, but they share the common features of immune-mediated damage to self-tissues and T cell involvement in all cases [1]. Certainly, if autoimmunity is initiated by a nontoxic virus, the acquired immune system is involved [2]. In this article, we describe the development of type 1 diabetes. A main recognition is that the pathogenesis is different in the initial phase, with autoantibody production, than in the later decisive phase, with malign insulitis and overt type 1 diabetes.

Insulin is a highly immunogenic compound, as it is a peptide secreted directly into the blood without any barriers. This is in opposition to the pituitary gland, which also produces peptide hormones but is situated behind the blood‒brain barrier. Other hormones secreted directly into the blood are typically small molecules, e.g., steroids, which are less immunogenic. We describe here, with respect to beta cells, that T-cell protection properties, such as sulfatide and Toll-like receptor 5 (TLR5), which are active locally at the cells to counterbalance the immunogenic effect of insulin, are essential.

2. Stage 1 of Development of Type 1 Diabetes

The first sign of developing type 1 diabetes is the presence of beta-cell autoantibodies (Table 1). These antibodies include IAA, GAD, IA-2, and ZNT8 antibodies [3]. If only one antibody is detectable, the type 1 diabetes risk is 15%, but if two, three, or even four antibodies are detected, the risk is substantially increased up to 100% [4].

Following a virus attack, the immune system generates not only virus-specific antibodies but typically also additional antibodies that may target other antigens in the physical or structural neighborhood [5,6]. In the pancreatic islets of Langerhans, the virus is often an enterovirus, which have been most investigated [7], although it might not be restricted to this [8]. Multiple studies have been made on virus etiology. These include especially Coxsackie virus B3 and B4. These viruses are most frequently seen during late summer which coincides in the northern hemisphere with a peak incidence of type 1 diabetes in the autumn months [9]. However, virus has been difficult to detect in full scale in patients. On the other hand, anti-viral drugs have been used in a trial with some effect after 1 year, but this was not present after 2 and 3 years [10].

The mentioned antibodies against beta cells have high value as diagnostic tools but have no importance for the pathogenesis of type 1 diabetes, besides one potential exception. Anti-sulfatide antibodies (ASAs) are present in healthy controls, but in pre-type 1 diabetes patients, the level of ASA is increased, but then returns to control values after diagnosis [11]. These ASAs may have a pathogenic effect by masking sulfatide at the beta-cell surface, since sulfatide is an important sphingolipid in type 1 diabetes, as will be discussed later. Other masking of sulfatide can be made by virus since sulfatide is a virus receptor [12].

Table 1: Stages of important events in the development of type 1 diabetes.

3. Stage 2 And 3 of Development of Type 1 Diabetes

As mentioned, classical beta-cell autoantibodies are not pathogenic and do not themselves cause the T-cell-driven autoimmune process leading to type 1 diabetes. However, the presence of beta-cell antibodies means that some T lymphocytes have been primed against certain beta-cell antigens. When T cells are activated again, the route toward beta-cell damage is shorter. This finding fits well with the fact that many studies (nPOD, DiViD) find only traces of virus left in the islets at diagnosis [19,20], as this initial trigger may have occurred months or years before the actual onset of type 1 diabetes [4].

In a recent study [16], we elucidated what might initiate T-cell-driven beta-cell destruction and thereby the autoimmune process. Toll-like receptor 5 (TLR5) is an important molecule (Table 2) in deciding whether innate immune cells, granulocytes, and macrophages, on the one hand, should be favored in a certain immune reaction or, on the other hand, T lymphocytes should be preferred [21,22]. TLR5 expression is stimulated by flagellin, a structural protein that composes the filaments of flagella in gram-negative bacteria [23]. Hence, in microbe-rich (“dirty”) surroundings, TLR5 is largely expressed but less so in very clean environments. This is found in mice in germ-free surroundings [24] but might also apply to humans in Scandinavia, especially Finland, where environmental hygiene standards are higher than those in Russian Karelia, which has a much lower incidence of type 1 diabetes [25]. Interestingly, we found that the mRNA levels of TLR5 in islets are one-third lower at the time of diagnosis of type 1 diabetes than during the phase of antibody positivity [16]. Additionally, TLR5 increases again after diagnosis [16]. Furthermore, we found an inverse correlation between T cells in the islets, which were less common in patients with higher TLR5 [16].

In contrast to cellular immunity, humoral immunity is dependent on high or normal levels of TLR5 [26]. For type 1 diabetes, TLR5 expression in the initial disease phase of beta-cell antibody development differs from TLR5 expression in the phases of malignant insulitis and clinical type 1 diabetes [13]. Hence, there are two different pathogenic mechanisms involved in the initial and final phases of type 1 diabetes development. This may well be the reason why antibody-positive persons do not necessarily develop type 1 diabetes, and why type 1 diabetes patients, in about 10% of the cases, are diagnosed without any beta-cell antibodies [27]. In Africa type 1 diabetes is commonly seen without presence of beta-cell antibodies [28]. The etiology of this special diabetes might be (toxic) virus, agent that herd sphingolipid production such as fungi toxins (see below), Helicobacter bacteria, or other changes as described here.

High beta-cell activity can make beta cells vulnerable [29] since it might create defective ribosomal products (DRiPs), which are molecules encoded by an alternative open reading frame that is highly immunogenic [30]. Additionally, hybrid insulin peptides (HIPs), which are autoantigens that stimulate T cells, can also be generated under high beta-cell activity [31]. Interestingly, when beta cells are incubated with elevated levels of glucose, which induces high beta cell activity, the only TLR that increases is TLR5, which might function to protect against damage by T cells [32]. In contrast, NOD mice maintained in germ-free facilities (with no TLR5 stimulation) have the highest diabetes incidence, especially among male animals [33].

Another interesting aspect is the extent to which exogenous factors can influence TLR5 expression. As previously described, bacteria may invade the ductus pancreaticus via the papilla Vateri, which is also known to occur in the ductus choledochus. In fact, bacteria, including Staphylococcus aureus [34], which has previously been shown to inhibit the presence of TLR5 [35], can be present in the ductus pancreaticus in humans. Interestingly, fusidic acid, an antibiotic that targets Staphylococcus, has been found to reduce the incidence of diabetes in biobreeding (BB) rats [36], possibly due to diminished inhibition of TLR5. Another relevant bacteria present in the pancreatic environment is Helicobacter pylori, which has been associated with a 1.77-fold increase in type 1 diabetes in humans [37]. H. pylori can also inhibit TLR5 by masking its expression [38] and thereby may contribute to the development of type 1 diabetes. Therefore, at least two bacterial species commonly found near the pancreas are capable of downregulating TLR5 expression, potentially enhancing T-cell activity, in contrast to many other bacteria that increase TLR5 expression, as mentioned.

Regarding antibiotic treatment, it has recently been shown in a meta-analysis that administration to young individuals increases the risk of developing type 1 diabetes [39]. We have also found that antibiotic treatment using a combination of ampicillin, vancomycin, and neomycin decreases TLR5 expression in the pancreas of female BALB/c mice. Furthermore, in relation to the development of type 1 diabetes, it is of interest that flagellin can stimulate NLR family CARD domain-containing protein 4 (NLRC4), which may subsequently inhibit TLR5 and thereby activate T lymphocytes [40]. NLRC4 seems to be connected to type 1 diabetes through polymorphisms and the actual lowering in TLR5 expression may be due to this factor [41].

Among other agents that depress T cells is the sphingolipid sulfatide [17,42,43] (Table 2). Importantly at diagnosis, human type 1 diabetes islets represent only 23% of the normal sulfatide level [17]. Sulfatide is a highly interesting molecule composed of two fat chains, the amino acid L-serine, and a galactose group to which a sulfate is connected. If D-serine is present, e.g., after serine racemase activity [44], the amount of sulfatide is reduced due to its inhibitory effects on sulfatide production [45]. As recently outlined also by another research group, sulfatide is important for the function of beta cells [46]. In beta cells, sulfatide has several properties: it folds the insulin molecule; it preserves the insulin crystals at pH 5.5; at pH 7.4, it mediates hexa- and monomerization of the insulin molecules; it facilitates actual insulin secretion; and it is present at the surface of beta cells [47–49]. Also, sulfatide inhibits the potassium channel and after insulin release, and thereby sulfatide secretion, relaxes the individual beta-cell [50]. Verapamil influences the calcium channels and hence creates lower beta-cell activity and is thus a candidate for human medication [51]. The physiological properties are due to C16 sulfatide [50], whereas C24 sulfatide has immunological qualities [52], similarly to alpha-galactosylceramide, it diminishes the incidence of diabetes in NOD mice [52,53]. This finding fits well with the findings of Holm et al., who reported that long-chain sulfatide inhibits T cells [17]. As indicated by its name, C24 sulfatide is a long-chain fatty acid that requires special transporter proteins to be absorbed into beta cells. In a recent study, we found that long-chain fatty acid transporter proteins are reduced at the time of type 1 diabetes diagnosis [54].

Another aspect of sulfatide is important and should be mentioned. Sulfatide promotes class II NKT cells which are inhibitory for development for type 1 diabetes [55]. Class II NKT cells are anti-inflammatory and are important for reducing diabetes incidence in NOD mice, but this system is less pronounced in humans [56].

Sulfatide also enhances regulatory T cells (Tregs) and low amount of Tregs has been found in patients with newly diagnosed type 1 diabetes [57,58]. Interestingly, Treg cells are reduced by galectin-3 [59] which is a molecule produced by macrophages, typically after a virus infection. These include, in mice, EMC virus [60] and, in humans, Coxsackie B3 virus [61]. Highly interestingly, both of these viruses have been connected to diabetes development [2,7]. Galectin-3 has been found to be upregulated in human serum of beta cell autoantibody-positive persons and type 1 diabetes patients [59], and in IL-1beta-exposed human and rat islets [62].

Beta-cell function progressively declines after the humoral phase, marked by antibody generation, leading to the clinical diagnosis of type 1 diabetes. This might be due to beta-cell stress-induced changes in ceramide-sphingomyelin levels caused by the activation of sphingomyelinase 2 (SMase2) [46], and the influence of cytokines may strengthen this process [46,63]. This may diminish the production of beta-galactosyl ceramide, which is the precursor of sulfatide [17]. Furthermore, for the initiating enzyme building sphingolipids, palmitoyl serine transferase, several polymorphisms exist against blood glucose parameters and type 1 diabetes [64]. Also, various fungi toxins can downregulate one of the building enzymes [65,66]; such one, Fumonisin B1, can be present in bread if grains have been less well stored [67]. This phenomenon is likely important both immunologically and functionally for beta cells.

Table 2: Factors associated with decreased sulfatide and TLR5 expression in type 1 diabetes pathogenesis.

In the last trimester of pregnancy, the incidence of diabetes is 3.8 times higher than that outside pregnancy [69]. During this period, there is considerable pressure on insulin production, which might play a role in this process. In spite of the ongoing diabetes process during the actual pregnancy, only 1 out of 55 of the fetuses of newly diagnosed type 1 diabetes mothers developed diabetes, and none of the healthy children displayed beta-cell autoantibodies [70]. This corresponds well with the fact that TLR5 is expressed in the human placenta [71,72], which is also biologically reasonable since the T cells of the mother must not reject the fetus, which partly presents foreign antigens.

Regarding immunological tolerance, there is a biological compromise during pregnancy. On the one hand, the prenatal beta cells should not be too mature and produce too much insulin, as this would lead to an overly large baby that is difficult to deliver [73]. On the other hand, more mature beta cells provide stronger immunological self-protection. Mothers with type 1 diabetes tend toward the latter, since these mothers display higher blood glucose values that stimulates the fetal beta cells to produce more insulin and to be more mature. This results in larger babies who often must be delivered by cesarean section or born preterm, but who have a lower risk of developing type 1 diabetes compared with children of fathers with type 1 diabetes [74]. Correspondingly, in a study using BB rats we stimulated neonatal beta-cell maturation and observed reduced diabetes incidence, likely due to improved self-tolerance [75].

In contrast to other autoimmune diseases, it is impossible to immunize mice in the periphery to induce type 1 diabetes by injecting beta cell homogenate with Freund’s adjuvants, etc., which will not create autoimmunity [76], most likely because of the local protection by TLR5 and sulfatide, as mentioned above. Furthermore, even in nondiabetic humans given repeatedly old-fashion insulin preparations (mean 59 injections) for psychiatric reasons to create insulin shock, no development of type 1 diabetes was observed [77]. In a later investigation, only two out of 27 examined former insulin-treated individuals displayed insulin antibodies. This is in accordance with the anticipation that these otherwise healthy nondiabetic persons have normal sulfatide levels and, in agreement with this, have no tendency to produce beta-cell-associated antibodies, such as those against insulin [77].

Type 1 diabetes is closely related to celiac disease, as they have the same tissue type preference [78,79]. We and others have shown that the gluten component gliadin, especially its 33-mer peptide, stimulates T cells [80,81]. In an animal study, this peptide has been shown to be present in islets and to activate tissue transglutaminase (tTG), which is a key component in celiac disease [80]. On the other hand, given a gluten-free diet, this peptide is of course not present in the islets, resulting in less T-cell stimulation. Interestingly, bakers who are chronically exposed to inhaled gliadin, which has been shown to be present in their nasal passages, develop regulatory T cells in the pancreatic lymph node and display a reduced incidence of type 1 diabetes [82].

The increased male incidence of type 1 diabetes is not always observed in low-incidence regions, where females may have a higher frequency – similar to patterns seen in other autoimmune diseases [83]. The male predominance is a rule in countries with high economic development and a modern (Western) lifestyle, likely due to more pronounced beta-cell stress.

Small beta-cell clusters may be part of non-fully developed islet, and it might be imagined to be a sign of modest islet volume. Such one must have more active beta cells and may then theoretically have a higher risk of diabetes development and especially destruction of the small clusters [84]. Actually, regarding anticipated small beta-cell volume in BB rats, the heaviest individuals with the lowest insulin production have double as high risk for developing early diabetes [85].

4. Prevention and Early Treatment

Owing to the abovementioned considerations, we suggest the following prevention strategies, which are shown in Table 3: 1) Before beta-cell damage, the TLR5 level should be increased by treatment with flagellin or flagellin compounds combined with pneumococcus [1]. Additionally, the environment should not be excessively clean, and exposure to nonpathological active bacteria should be encouraged. 2) Sulfatide can be enhanced by treatment with serine [86]. 3) A gluten-free diet is established in diabetic animal models. Additionally, nasal gliadin treatment could be instituted [87]. 4) The number of HIP and DRiP molecules should be decreased by avoiding beta-cell stress [31,88]. This can be accomplished by reducing the intake of refined carbohydrates (sugars, candy, and lemonade) and by engaging in a reasonable amount of exercise [89]. 5) Anti-CD3 T-cell antibodies have been approved and shown to inhibit type 1 diabetes development [90]. 6) The intestinal microbiota should include (i) short-chain fatty acid-producing bacteria [91], as these products, such as butyrate, are beneficial against autoimmune diseases, including type 1 diabetes [92]. (ii). Akkermansia muciniphila has been shown to reduce the incidence of diabetes in NOD mice [93]. (iii). Some Bacteroides fragilis can produce alpha-galactosyl ceramide [94], which has been shown to be beneficial against diabetes in NOD mice [52]. 7) Atopic diseases, including eczema, are less common in patients with type 1 diabetes [95]. By creating eczema artificially in NOD mice, the incidence of diabetes is reduced, and the mechanism seems to be related to an increased number of NKT cells [96]. Points 1, 3, 4, 5 and 7 have been proven or shown to be likely in human studies, whereas points 2, 3, 6, and 7 have so far only been supported by findings from animal studies. Finally, various pharmaceutical compounds that inhibit the acquired immune system, e.g. vitamin D [97] can be considered.

The reason why 90% of new type 1 diabetes cases do not have first degree relatives with the disease [98] might well be due to the difficult coincidence of events: reduced sulfatide, loss of TLR5, beta-cell stress, unlucky intestinal flora, etc.

Table 3: Contributors to type 1 diabetes (T1D) development and suggested preventive treatments.

Future Perspectives

The protection by TLR5 and sulfatide should be further substantiated both in animal and human studies; furthermore, falsification according to Popper should be attempted.

Due to the increasing preventive possibilities, screening for beta-cell autoantibodies in school-aged children should be performed two to three times while they are growing up to monitor the onset of autoimmune activity. The procedure is minimally invasive, requiring only 6 mL of blood from a fingertip, which can be tested by well-established high-throughput screening technologies. The primary problems are logistical and associated costs.

Conclusion

In conclusion, we describe how type 1 diabetes develops (Table 1 and 2). Importantly, the pathogenic mechanisms are different in the early antibody phase than in the later malignant insulitis phase in patients with clinical diabetes. We are aware that due to age and other factors the detailed manifests for type 1 diabetes may vary. However, as stated here the reduction of the two molecules TLR5 and sulfatide that inhibit T lymphocytes are decisive for the type 1 diabetes process, and prevention should include such a reduction not to happen. Thus, we hope that understanding the development of type 1 diabetes has now been outlined and that preventive treatments are within reach.

Abbreviations

ASA: Anti-Sulfatide Antibody

BB: BioBreeding

DiViD: Diabetes Virus Detection

DRiP: Defective Ribosomal Product

HIP: Hybrid Insulin Peptide

NLRC4: NLR family CARD domain-containing protein 4

nPOD: network for Pancreatic Organ Donors with Diabetes

SMase2: Sphingomyelinase 2

T1D: Type 1 Diabetes

TLR5: Toll-Like Receptor 5

Tregs: Regulatory T cells

tTG: Tissue Transglutaminase

Author Contributions

The idea of the manuscript in the first draft, is conceptualized and written by Karsten Buschard, with input from Rikke Thea and Camilla Hartmann Friis Hansen. All authors confirm they had full access to all data behind the manuscript and accept responsibility for publication. All authors edited and approved the final manuscript.

Conflict of Interest

The authors declare that no conflict of interest exists.

References

1. Lim JS, Jeon EJ, Go HS, et al. Mucosal TLR5 activation controls healthspan and longevity. Nature Communications 15 (2024): 1-14.
2. Buschard K, Hastrup N, Rygaard J. Virus-induced diabetes mellitus in mice and the thymus-dependent immune system. Diabetologia 24 (1983): 42-46.
3. Kawasaki E. Anti-Islet Autoantibodies in Type 1 Diabetes. Int J Mol Sci 24 (2023).
4. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309 (2013): 2473-2479.
5. Getts DR, Chastain EML, Terry RL, et al. Virus infection, antiviral immunity, and autoimmunity. Immunol Rev 255 (2013): 197-209.
6. Miller SD, Vanderlugt CL, Begolka WS, et al. Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat Med 3 (1997): 1133-1136.
7. Wang K, Ye F, Chen Y, et al. Association Between Enterovirus Infection and Type 1 Diabetes Risk: A Meta-Analysis of 38 Case-Control Studies. Front Endocrinol (Lausanne) 12 (2021).
8. Morse ZJ, Horwitz MS. Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes. Front Immunol 12 (2021): 751337.
9. Gamble DR, Taylor KW. Seasonal incidence of diabetes mellitus. Br Med J 3 (1969): 631-633.
10. Mynarek IM, Krogvold L, Mørk FB, et al. Three-Year Follow-up After Antiviral Treatment in New-Onset Type 1 Diabetes: Results From the Diabetes Virus Detection and Intervention Trial. Diabetes Care 48 (2025): 481-488.
11. Buschard K, Josefsen K, Horn T, et al. Sulphatide and sulphatide antibodies in insulin-dependent diabetes mellitus. Lancet 342 (1993): 840.
12. Takahashi T, Kurebayashi Y, Suzuki T. Functional Analysis of Sulfatide in Influenza A Virus Infection and Replication. Methods Mol Biol 2556 (2022): 97-122.
13. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38 (2015): 1964-1974.
14. Evans-Molina C, Sims EK, DiMeglio LA, et al. β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis. JCI Insight 3 (2018).
15. Aamodt KI, Powers AC. The pathophysiology, presentation and classification of Type 1 diabetes. Diabetes Obes Metab 27 (2025).
16. Buschard K, Krogvold L, Pociot F, et al. TLR5 influences the development of type 1 diabetes. BMJ Open Diabetes Res Care 13 (2025).
17. Holm LJ, Krogvold L, Hasselby JP, et al. Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia 61 (2018): 1650-1661.
18. Regnell SE, Lernmark Å. Early prediction of autoimmune (type 1) diabetes. Diabetologia 60 (2017): 1370-1381.
19. Krogvold L, Genoni A, Puggioni A, et al. Live enteroviruses, but not other viruses, detected in human pancreas at the onset of type 1 diabetes in the DiViD study. Diabetologia 65 (2022): 2108-2120.
20. Rodriguez-Calvo T, Laiho JE, Oikarinen M, et al. Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes. Diabetologia 68 (2025): 1197-1210.
21. Letran SE, Lee SJ, Atif SM, et al. TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. Eur J Immunol 41 (2010): 29.
22. Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410 (2001): 1099-1103.
23. Feuillet V, Medjane S, Mondor I, et al. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci U S A 103 (2006): 12487-12492.
24. Huhta H, Helminen O, Kauppila JH, et al. The Expression of Toll-like Receptors in Normal Human and Murine Gastrointestinal Organs and the Effect of Microbiome and Cancer. Journal of Histochemistry and Cytochemistry 64 (2016): 470.
25. Kondrashova A, Seiskari T, Ilonen J, et al. The “Hygiene hypothesis” and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS 121 (2013): 478-493.
26. Oh JZ, Ravindran R, Chassaing B, et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41 (2014): 478-492.
27. Bravis V, Kaur A, Walkey HC, et al. Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort. BMJ Open 8 (2018).
28. Katte JC, McDonald TJ, Sobngwi E, et al. The phenotype of type 1 diabetes in sub-Saharan Africa. Front Public Health 11 (2023).
29. Thea R, Buschard K. Beta-cell activity and development of Type 1 diabetes. APMIS 133 (2025).
30. Thomaidou S, Munoz Garcia A, de Lange S, et al. IFNɣ but not IFNα increases recognition of insulin defective ribosomal product-derived antigen to amplify islet autoimmunity. Diabetologia 66 (2023): 2075-2086.
31. Baker RL, Rihanek M, Hohenstein AC, et al. Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes 68 (2019): 1830-1840.
32. Weile C, Josefsen K, Buschard K. Glucose activation of islets of Langerhans up-regulates Toll-like receptor 5: possible mechanism of protection. Clin Exp Immunol 166 (2011): 251-257.
33. Yurkovetskiy L, Burrows M, Khan AA, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39 (2013): 400-412.
34. Korsgren S, Molin Y, Salmela K, et al. On the etiology of type 1 diabetes: a new animal model signifying a decisive role for bacteria eliciting an adverse innate immunity response. Am J Pathol 181 (2012): 1735-1748.
35. Patot S, Imbert P, Baude J, et al. The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility. PLoS Pathog 13 (2017).
36. Buschard K, Pedersen C, Hansen S V., et al. Anti-diabetogenic effect of fusidic acid in diabetes prone BB rats. Autoimmunity 14 (1992): 101-104.
37. Chua WK, Hong YK, Hu SW, et al. A Significant Association between Type 1 Diabetes and Helicobacter pylori Infection: A Meta-Analysis Study. Medicina (Kaunas) 60 (2024).
38. Pachathundikandi SK, Tegtmeyer N, Backert S. Masking of typical TLR4 and TLR5 ligands modulates inflammation and resolution by Helicobacter pylori. Trends Microbiol 31 (2023): 903-915.
39. Ram S, Corbin M, ’t Mannetje A, Douwes J, Kvalsvig A, Eng A. Antibiotic Exposure in Early Life and Risk of Type 1 Diabetes: A Meta-Analysis. Diabetes Obes Metab 28 (2026).
40. Li W, Yang J, Zhang E, et al. Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. Cell Mol Immunol 13 (2016): 514-523.
41. Xu L, Sun X, Xia Y, et al. Polymorphisms of the NLRC4 Gene are Associated with the Onset Age, Positive Rate of GADA and 2-h Postprandial C-Peptide in Patients with Type 1 Diabetes. Diabetes Metab Syndr Obes 13 (2020): 811-818.
42. Buschard K, Schloot NC, Kaas A, et al. Inhibition of insulin-specific autoreactive T-cells by sulphatide which is variably expressed in beta cells. Diabetologia 42 (1999): 1212-1218.
43. Hamatani M, Ochi H, Kimura K, et al. T cells from MS Patients with High Disease Severity Are Insensitive to an Immune-Suppressive Effect of Sulfatide. Mol Neurobiol 59 (2022): 5276-5283.
44. Lockridge AD, Baumann DC, Akhaphong B, et al. Serine racemase is expressed in islets and contributes to the regulation of glucose homeostasis. Islets 8 (2016): 195-206.
45. Hanada K, Hara T, Nishijima M. D-Serine inhibits serine palmitoyltransferase, the enzyme catalyzing the initial step of sphingolipid biosynthesis. FEBS Lett 474 (2000): 63-65.
46. Xu J, Amalaraj I, Oliveira A De, et al. Proinflammatory Stress Activates Neutral Sphingomyelinase 2–Based Generation of a Ceramide-Enriched β-Cell EV Subpopulation. Diabetes 74 (2025): 1964-1975.
47. Fredman P, Månsson JE, Rynmark BM, et al. The glycosphingolipid sulfatide in the islets of Langerhans in rat pancreas is processed through recycling: possible involvement in insulin trafficking. Glycobiology 10 (2000): 39-50.
48. Osterbye T, Jórgensen KH, Fredman P, et al. Sulfatide promotes the folding of proinsulin, preserves insulin crystals, and mediates its monomerization. Glycobiology 11 (2001): 473-479.
49. Buschard K, Høy M, Bokvist K, et al. Sulfatide controls insulin secretion by modulation of ATP-sensitive K(+)-channel activity and Ca(2+)-dependent exocytosis in rat pancreatic beta-cells. Diabetes 51 (2002): 2514-2521.
50. Buschard K, Blomqvist M, Månsson JE, et al. C16:0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of KATP channels to ATP inhibition. Diabetes 55 (2006): 2826-2834.
51. Forlenza GP, McVean J, Beck RW, et al. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA 329 (2023): 990-999.
52. Subramanian L, Blumenfeld H, Tohn R, et al. NKT cells stimulated by long fatty acyl chain sulfatides significantly reduce the incidence of type 1 diabetes in nonobese diabetic mice [corrected]. PLoS One 7 (2012).
53. Buschard K, Hanspers K, Fredman P, et al. Treatment with sulfatide or its precursor, galactosylceramide, prevents diabetes in NOD mice. Autoimmunity 34 (2001): 9-17.
54. Buschard K, Krogvold L, Thea R, et al. Genes Involved in Cellular Uptake of Long-Chain C24 Sulfatide in Relation to Pathogenesis of Type 1 Diabetes. Fortune Journal of Health Sciences 9 (2026): 256-261.
55. Ni H, Lin Q, Zhong J, et al. Role of sulfatide-reactive vNKT cells in promoting lung Treg cells via dendritic cell modulation in asthma models. Eur J Pharmacol 970 (2024).
56. Lee PT, Putnam A, Benlagha K, et al. Testing the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest 110 (2002): 793-800.
57. Buschard K, Madsbad S, Rygaard J. Depressed suppressor cell activity in patients with newly diagnosed insulin-dependent diabetes mellitus. Clin Exp Immunol 41 (1980): 25.
58. Ryba-Stanisławowska M, Skrzypkowska M, MyŚliwiec M, et al. Loss of the balance between CD4(+)Foxp3(+) regulatory T cells and CD4(+)IL17A(+) Th17 cells in patients with type 1 diabetes. Hum Immunol 74 (2013): 701-707.
59. Xie L, Zhang R, Zou H, et al. Galectin-3 exacerbates autoimmune diabetes by limiting regulatory T cell differentiation and function. Sci Adv 12 (2026).
60. Kobayashi K, Niwa M, Hoshi M, et al. Early microlesion of viral encephalitis confirmed by galectin-3 expression after a virus inoculation. Neurosci Lett 592 (2015): 107-112.
61. De Giusti CJ, Ure AE, Rivadeneyra L, et al. Macrophages and galectin 3 play critical roles in CVB3-induced murine acute myocarditis and chronic fibrosis. J Mol Cell Cardiol 85 (2015): 58-70.
62. Karlsen AE, Størling ZM, Sparre T, et al. Immune-mediated β-cell destruction in vitro and in vivo—A pivotal role for galectin-3. Biochem Biophys Res Commun 344 (2006): 406-415.
63. Bendtzen K, Mandrup-Poulsen T, Nerup J, et al. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232 (1986): 1545-1547.
64. Buschard K, Josefsen K, Krogvold L, et al. Influence of sphingolipid enzymes on blood glucose levels, development of diabetes, and involvement of pericytes. Diabetes Metab Res Rev 40 (2024).
65. Abbas HK, Tanaka T, Duke SO, et al. Fumonisin- and AAL-Toxin-Induced Disruption of Sphingolipid Metabolism with Accumulation of Free Sphingoid Bases. Plant Physiol 106 (1994): 1085-1093.
66. Delgado A, Casas J, Llebaria A, et al. Inhibitors of sphingolipid metabolism enzymes. Biochim Biophys Acta 1758 (2006): 1957-1977.
67. Chen J, Wen J, Tang Y, et al. Research Progress on Fumonisin B1 Contamination and Toxicity: A Review. Molecules 26 (2021).
68. Xu J, Harris-Kawano A, Enriquez JR, Mirmira RG, Sims EK. Proinflammatory stress activates neutral sphingomyelinase 2 based generation of a ceramide-enriched β cell EV subpopulation. Diabetes 20 (2025).
69. Buschard K, Buch I, Molsted-Pedersen L, et al. Increased incidence of true type I diabetes acquired during pregnancy. Br Med J (Clin Res Ed) 294 (1987): 275-279.
70. Buschard K, Molsted-Pedersen L, Palmer J, et al. Investigations in children who were in utero at onset of insulin-dependent diabetes in their mothers. Lancet 1 (1989): 811-814.
71. Patni S, Wynen LP, Seager AL, et al. Expression and activity of Toll-like receptors 1-9 in the human term placenta and changes associated with labor at term. Biol Reprod 80 (2009): 243-248.
72. Pudney J, He X, Masheeb Z, et al. Differential expression of toll-like receptors in the human placenta across early gestation. Placenta 46 (2016): 1-10.
73. Tuch BE, Jones A, Turtle JR. Maturation of the response of human fetal pancreatic explants to glucose. Diabetologia 28 (1985): 28-31.
74. Warram JH, Krolewski AS, Gottlieb MS, et al. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 311 (1984): 149-152.
75. Buschard K, Jorgensen M, Aaen K, et al. Prevention of diabetes mellitus in BB rats by neonatal stimulation of beta cells. Lancet 335 (1990): 134-135.
76. Nerup J, Andersen OO, Bendixen G, et al. Cell-mediated immunity in diabetes mellitus. Proc R Soc Med 67 (1974): 506-513.
77. Bock T, Pedersen CR, Josefsen K, et al. No risk of diabetes after insulin-shock treatment. Lancet 339 (1992): 1504-1506.
78. Nerup J, Platz P, Andersen OO, et al. HL-A antigens and diabetes mellitus. Lancet 2 (1974): 864-866.
79. Goodwin G. Type 1 Diabetes Mellitus and Celiac Disease: Distinct Autoimmune Disorders That Share Common Pathogenic Mechanisms. Horm Res Paediatr 92 (2019): 285-292.
80. Dall M, Calloe K, Haupt-Jorgensen M, et al. Gliadin fragments and a specific gliadin 33-mer peptide close KATP channels and induce insulin secretion in INS-1E cells and rat islets of langerhans. PLoS One 8 (2013).
81. Hansen CHF, Krych Ł, Buschard K, et al. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice. Diabetes 63 (2014): 2821-2832.
82. Haupt-Jorgensen M, Nielsen E, Engkilde K, et al. Occupation with grain crops is associated with lower type 1 diabetes incidence: Registry-based case-control study. PLoS One 12 (2017).
83. Alizadeh A, Alizadeh C. A Review of Incidence and Prevalence Rates of Type 1 Diabetes (T1D) Worldwide: 2000-2022. CEOS Family Med Communi Health 3 (2025): 101.
84. Murrall K, Luckett T, Lekka C, et al. Small things matter: Lack of extraislet β cells in type 1 diabetes. Sci Adv 11 (2025).
85. Pedersen CR, Bock T, Hanse S V., et al. High juvenile body weight and low insulin levels as markers preceding early diabetes in the BB rat. Autoimmunity 17 (1994): 261-269.
86. Holm LJ, Buschard K. L-serine: a neglected amino acid with a potential therapeutic role in diabetes. APMIS 127 (2019): 655-659.
87. Funda DP, Fundova P, Hansen AK, et al. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice. PLoS One 9 (2014).
88. Pach N, Basler M. Cellular stress increases DRIP production and MHC Class I antigen presentation. Front Immunol 15 (2024): 1445338.
89. Lin Y, Fan R, Hao Z, et al. The Association Between Physical Activity and Insulin Level Under Different Levels of Lipid Indices and Serum Uric Acid. Front Physiol 13 (2022): 809669.
90. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 381 (2019): 603-613.
91. Fusco W, Lorenzo MB, Cintoni M, et al. Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients 15 (2023): 2211.
92. Golpour F, Abbasi-Alaei M, Babaei F, et al. Short chain fatty acids, a possible treatment option for autoimmune diseases. Biomed Pharmacother 163 (2023).
93. Hansen CHF, Krych L, Nielsen DS, et al. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55 (2012): 2285-2294.
94. Hansen CHF, Jozipovic D, Zachariassen LF, et al. Probiotic treatment with viable α-galactosylceramide-producing Bacteroides fragilis reduces diabetes incidence in female nonobese diabetic mice. J Diabetes 16 (2024).
95. Rosenbauer J, Herzig P, Giani G. Atopic eczema in early childhood could be protective against Type 1 diabetes. Diabetologia 46 (2003): 784-788.
96. Engkilde K, Johansen JD, Hansen AK, et al. Prevention of type 1 diabetes by inducing subclinical dermatitis on a small area. Diabetes Metab Res Rev 27 (2011): 954-958.
97. Vanherwegen AS, Eelen G, Ferreira GB, et al. Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism. J Steroid Biochem Mol Biol 187 (2019): 134-145.
98. Sims EK, Besser REJ, Dayan C, et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes 71 (2022): 610-623.
99. Strachan DP. Hay fever, hygiene, and household size. BMJ 299 (1989): 1259-1260.
100. Aaen K, Rygaard J, Josefsen K, et al. Dependence of antigen expression on functional state of beta-cells. Diabetes 39 (1990): 697-701.