Diabetes mellitus (DM) is one of the leading causes of death globally.1 DM is a metabolic disorder characterized by hyperglycemia resulting from a low level or complete deficiency of insulin hormone.1,2 Insulin, synthesized by the β cells of the pancreatic islets of Langerhans, plays a key role in modulating blood glucose levels.1,2 Type 1 DM (T1DM) is triggered by autoimmune destruction of pancreatic β cells, which leads to an absolute insulin deficiency,1,2 whereas type 2 DM (T2DM) typically is caused by insulin resistance along with insufficient insulin secretion.1,2
With a rapid rise in incidence during the last 50 years, T1DM is one of the most frequent autoimmune disorders in childhood and adolescence.3,4 T1DM is generally associated with a long prediabetic seroconversion period, during which autoantibodies to antigens of pancreatic β cells or insulin are produced.3,4 There are a few known factors that trigger autoimmunity during infancy, such as spontaneous cell death within the β-cell population, deposition of islet amyloid polypeptide aggregates, or viral infection that specifically targets pancreatic β cells and leads to islet cell death, which contribute to the formation of β-cell antigens, activation of dendritic cells, and antigen presentation.3,4 However, the exact etiopathogenesis remains poorly understood.
In general, patients with diabetes are more prone to microbial infections, which have been postulated to have a causal relationship with high blood glucose levels. However, it is little known about the role of therapeutic insulin administration on dissemination of infectious diseases in people with DM.2
Effect of Gut Microbiome
The increase in incidence of T1DM may not be solely a result of genetics and environmental factors, but also that of gut microbiota.3,4 Given the overarching influence of gut bacteria on human health, including its association with the functions of the body’s immune system and intestinal permeability, accumulating data suggest the gut microbiome may contribute to the pathogenesis of T1DM.3,4
The microbiota of the human intestinal tract is composed of bacteria, fungi, and eukaryotic and bacterial viruses (bacteriophages).3,4 Bacteria in the human gut live within surface-associated microbial communities, termed biofilms, which are characterized by the presence of self-produced extracellular matrix and a surface film that protects the microorganisms from the outer environment.3,4 Moreover, several studies have shown that the development of T1DM may be driven by some forms of bacteria.3,4
Among the aforementioned bacteria, the most common etiologic agent has been found to be Escherichia coli.3,4 Although E coli plays a protector role for the gut microbiome, E coli can affect all organs and systems and is a major cause of extraintestinal infections in patients with diabetes.3,4 E coli is the causative agent for 70% cases of patients with DM with an emphysematous urinary tract infection and in 40% of those with emphysematous cholecystitis.3,4 Moreover, high blood sugar levels have been linked to E coli’s rapid multiplication and ability to establish more severe form of the infection.3,4 Consequently, individuals with diabetes may be at higher risk for moderate or severe infection-related morbidity.
Association Between E coli and DM
A separate study conducted by Madacki-Todorovic and colleagues presented evidence for the direct effect of insulin on increased metabolic activity of E coli in an association with its biofilm-forming capability.5 Patients with DM are at high risk of developing microbial infections, which are believed to be triggered by the hyperglycemic physiologic status they have and can compromise components of the immune system.5 Pathogenic microorganisms can lead to disease as a result of suppression of the host immune mechanisms. Yet scant evidence has been reported on the role of therapeutic insulin administration on dissemination of infectious diseases in people with DM.
Aside from human insulin’s influence on the growth kinetic of E coli, little is known about other effects of insulin on E coli in the course of systemic infection, and there is a lack of data on how insulin may affect metabolic activity of this pathogen and its ability to become a biofilm former. Consequently, the researchers of this study investigated the effect of hormone insulin on the expression of enzymatic virulent factors of E coli as the most common pathogen associated with morbimortality in patients with diabetes.5 Three strains of E coli (E coli-C1, E coli-C2, and E coli-C3) with robust biofilm-forming ability, together with nonbiofilm-former E coli strain (E coli-Ref) as the control, were isolated from clinical samples of patients by using conventional microbiologic identification and isolation methods.5
A key defining characteristic of microorganisms such as E coli is their ability to grow and multiply in different environments if they have all necessary nutritive supplements. Therefore, all E coli strains were incubated in growth media at 37 °C for different incubation times with the addition of human insulin in dosing concentration of 2.5 U/mL.5 The results demonstrated that insulin administration had a significant stimulatory effect on E coli proliferation of all tested E coli strains, serving as an autoinducer or stimulatory agent for E coli infection and pathogenicity compared with control strains that were not supplemented with insulin and showed a significantly lower proliferation rate at all incubation times.5
Moreover, microbial proteases also play a crucial role in cell viability and virulence status of the microbe, and protease genes are new potential therapeutic targets in treatment of infectious diseases.5 Aspartyl proteinase of E coli is a catalytic type of enzyme that is released from the cell at higher concentration during the infection process of the host. Compared with control strains that were not supplemented with insulin, the presence of insulin also stimulated expression of E coli virulent factor enzyme aspartyl proteinase, which in synergism with human insulin served as signal molecules for bacterial quorum sensing and biofilm formation.5 This study demonstrated that human hormone insulin, even in this low concentration, not only had significant stimulatory effect on proliferation of bacterial cells but also significantly affected metabolic activity of E coli and acted as an autoinducer for biofilm formation.5 Based on these findings, the researcher reasonably identified human insulin as potential risk factor for dissemination of E coli infections and for the increase of related pathogenicity because of its stimulatory effect on the expression of aspartyl proteinase genes.5
A multidrug-resistant bacterium with biofilm-forming capacity can commonly cause devastating complications in patients with DM, including diabetic foot ulcers and diabetic foot infections.5 Results of this study also underline the need for development of alternative catheter materials that will not allow biofilm formation and guidelines in choice of catheters for patients with diabetes.5
Association between E coli and T1DM
A study conducted by Tetz et al revealed that there may be a correlation between a high level of amyloid-producing E coli in the intestinal tract, followed by their depletion resulting from prophage induction and the initiation of autoimmunity, and T1DM progression.3 In humans, pathologic depositions of insoluble amyloid aggregates have been shown to be associated with the development of T1DM, where an increased islet amyloid polypeptide concentration may constitute a risk factor for β-cell destruction.3
As the gut microbiota is known to play a role in T1DM, Tetz and colleagues at the Human Microbiology Institute in New York City analyzed data from a prospective longitudinal microbiome cohort study by Kostic et al of 16 children (aged 0-3 years) with human leukocyte antigens (HLA)-susceptibility to T1DM, using an algorithm focusing on amyloid-producing bacteria.3,4 High-throughput shotgun sequencing was performed on the Illumina HiSeq500 platform for microbiota sequencing and processing.3 This analysis revealed an overlooked association between autoimmunity and the dynamics of gut amyloid-producing E coli.3
The findings demonstrated a different, dynamic relationship in children with HLA-conferred susceptibility to T1DM.3 E coli tended to disappear over time in patients with T1DM and patients who were seroconverters, whereas it increased and did not change significantly over time in children without HLA-conferred susceptibility to T1DM.3 E coli depletion was found before the appearance of antibodies, suggesting a role of E coli in disease onset.3 Moreover, their “in vitro study revealed a highly immunogenic complex (amyloid curli-DNA composites) released from E coli biofilms upon prophage induction, which triggered the production of type I interferons through the TLR2/9 stimulation of β-cells and DCs, and autoimmune cascade through the TLR-2-MyD88-NF-kB pathway.” 3
This suggests that a leaky gut allows E coli amyloid-DNA complexes to pass to the lamina propria and trigger autoimmunity and T1DM progression.3 The researchers concluded that “that E coli biofilm-derived highly immunogenic amyloid curly-DNA complexes might be involved in the activation of a prodiabetic pathway in children who are at a risk of T1DM.” 3
In conclusion, E coli is a notorious pathogen with a broad spectrum of associated illnesses, including the progression of diabetes. These findings suggest that insulin may potentially be a risk factor for increased E coli virulence. Determining the exact role of E coli in the progression of diabetes may lead to novel diagnostics and interventional approaches; however, further detailed studies are required.
1. Baena-Diez JM, Penafiel J, Subirana I, Ramos R, Elosua R, Marin-Ibanez A, et al. Risk of cause-specific death in individuals with diabetes: A competing risks analysis. Diabetes Care. 2016;39(11):1987-1995.
2. Suri RS, Mahon JL, Clark WF, Moist LM, Salvadori M, Garg AX. Relationship between Escherichia coli O157:H7 and diabetes mellitus. Kidney International. 2009;75(Suppl 112):S44-S46.
3. Tetz G, Brown SM, Hao Y, Tetz V. Type 1 Diabetes: An association between autoimmunity, the dynamics of gut amyloid producing E. coli and their phages. Scientific Reports. 2019,9:9685.
4. Kostic AD, Gevers D, Siljander H, et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host & Microbe. 2015;17(2):260-273.
5. Madacki-Todorovic K, Eminovic I, Mehmedinovic NI, Ibirisimovic M. Insulin acts as stimulatory agent in diabetes-related Escherichia coli pathogenesis. Int J Diabetes Clin Res. 2018;5(4):098.