Diabetes Mellitus

Published by theTerrible on

I’m about to go down the rabbit hole so make sure the rope you tied around your waist that I’m pulling is also anchored at the entrance.

So I was reading this article: Autoantibodies in Diabetes

A person setting off firecrackers in a store and running away like how type 1 diabetes effects me

I WANNA KNOW WHO STARTED IT.

I get that GAD65, IA-2, and insulin are floating around trying to do their thing. I wanna know who pulled the fire alarm.

Who is the culprit in all these shenanigans? I get that GAD65, IA-2, or insulin might have gotten mislabeled as antigens, like how the intern mislabeled a piece of mail, but did they bump into the wrong person? Did some tyrant take over and persecute them?

“Modulation of GAD65 presentation to the T-cells by disease-associated GAD65Abs may be a possible mechanism for the breakdown of immunological tolerance to the pancreatic β-cells.”

Who is this GAD65Ab chick? Where did she come from? Who let you in this place??

“In this scenario, a particular GAD65Ab specificity present exclusively in pre-diabetic patients (not in GAD65Ab+ nondiabetic patients with other autoimmune diseases or in GAD65Ab+ nondiabetic control subjects) may therefore contribute to the initiation and/or perpetuation of the autoimmune process by altering the spectrum of T-cell determinants expressed by antigen-presenting cells and thus altering the focus of the T-cell response.”

Seriously?! You butt dialed the police!!!

Yes, I know that right there in the abstract it says, “A β-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity”.

Alright, so some autoantibodies (GAD65Ab) showed up. Who invited them? My genes? Some antibody put on the wrong pair of pants and wore a bad antigen-binding site? My hormones ran into a bad gang of isotypes and/or subtypes?

Genetics

Starting with genetics….. is me (get it?).

Environmental Risk Factors for Type 1 Diabetes

Ummmm… That’s literally everything. Let’s actually go to the others before dealing with this ‘head-phones that have been in my pocket all day’ tangled mess.

Antibody Isotypes and Subtypes

What about the isotypes? Who are the suspects here?

Human antibody isotypes or classes

WAS IT ONE OF YOU?

Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. | Diabetes Care (diabetesjournals.org)

IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less prevalent than IgG1 (P<0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. CONCLUSIONS: These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.

SERIOUSLY? ANOTHER ALARM? Someone activated my B-cell from a Th1-type immune response. What was the Th1 response for?

Th1 and Th2 responses: what are they? | The BMJ

“It is also hypothesized that those who go on to develop full blown allergies may be those who are born with a generally weaker Th1 response, although it is now apparent that babies with allergies produce weak Th1 and Th2 responses.”

Well, I have had really bad allergies for what feels like forever, even before the type 1 diabetes diagnosis, but it does point me in a new direction. What are things that can trigger immune responses? Well, yeah, duh, viruses.

Viral Factors

Quick recap: diabetes mellitus (type 1 diabetes) comes from an autoimmune response and we are tracing why that response exists.

Could there be a viral or bacterial bias that lead my immune system down the dark side?

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms (nih.gov)

The nice thing with this article is the table at the bottom where they are lining up the mechanisms in which autoimmunity exists AND for what disease! Here is what they say for type 1 diabetes:

Autoimmune DiseaseVirusOrganismProposed Mechanism
Induced type 1 diabetesEncephalomyocarditis-D virusMus musculusMolecular mimicry
Islet autoimmunityEnterovirusesHomo sapiensMolecular mimicry
Type 1 diabetes mellitusCoxsackievirusHomo sapiensMolecular mimicry
Type 1 diabetes mellitusCoxsackievirus B1Homo sapiensMolecular mimicry
Type 1 diabetes mellitusCytomegalovirusHomo sapiens
Type 1 diabetes mellitusRotavirusMus musculusBystander effect
Type 1 diabetes mellitusEnterovirusesHomo sapiens/Mus musculus

There are some plausible causes here! Molecular mimicry and bystander effect are on the menu boys!

Lord of the Rings orcs happy that meat is back on the menu like how proposed mechanisms for autoimmune diseases exist

Side note: any time I hear “occurs when CD8+ T, CD4+ T, or B cells are activated in an antigen-independent manner” (aka the bystander effect), my blood pressure goes up and my pupils dilate. For an immune system to start poppin’ off without any antigens is absolutely bonkers.

Viral Trigger for Type 1 Diabetes | Diabetes (diabetesjournals.org)

This article explores the hypothesis of the viral factor. There is a lot of back and forth on this within the article, and that back and forth makes sense! You’d think your immune system is your bro, your boo, your bestie, and that can be seen to be the case. On the other hand, it’s a case of malicious compliance.

They have this sweet figure to illustrate:

Interplay between virus- and host-intrinsic properties dictates whether enhancement or abrogation of type 1 diabetes occurs. β = β cells. Teff, effector (autoreactive) T-cells.
Enhancement vs Abrogation

“While molecular mimicry might activate autoreactive T-cells, it could also segregate these cells away from the islets and/or induce the activation of protective Tregs. While inflammatory cytokines might promote bystander activation of APCs and autoreactive T-cells, infection could occur at a time where inflammation will induce the relocation or demise of these cells. Whereas β-cell lysis and presentation of islet antigen might promote activation of autoreactive T-cells, it could also suppress the function of these cells by promoting Treg activity. Whereas repeated/sustained infections might lead to the accumulation of autoreactive T-cells within the memory pool, they could also induce suppressor mechanisms that will hinder autoimmunity.”

Two kids from the Simpsons on a teeter totter to emphasize how viruses are good and bad for the immune system

Well we net zeroed on that one, but the article has a section called Certain viruses might promote autoimmunity and the quite extensive list of findings is very interesting. You should take a look and see if you had one of those viruses before your diagnosis of type 1 diabetes. It might be a dot worth connecting.

OR as they have the other subheading: Viruses may be wrongly accused. It’s akin to the fable of Keyser Söze. They hurt, they help, they’re the good guy, they’re the bad guy.

It ends with this: “Based on current evidence, it thus appears impossible to assess the capacity of viruses to modulate type 1 diabetes without knowledge of the state of advancement of autoimmunity and infection history of affected individuals.”

*Sigh*

BUT, we aren’t back to the drawing board.

Most important is the indication from animal studies that modulation of autoimmunity during viral infection does not depend merely on inherent properties of the virus, but also significantly on intrinsic factors of the host. The close interplay between the two will dictate whether enhancement or abrogation of autoimmune diabetes occurs.

Looks like we are back to genetics.

Back to Genetics

Genetic Testing of Newborns for Type 1 Diabetes Susceptibility – The MIDIA Study | IntechOpen

First off: “However, no single pathogenic environmental agent has been identified that explain all cases. In all likelihood, T1D develops by various combinations of pathways in response to commonly encountered environmental exposures.” That’s pretty interesting. You’ll be told it’s the milk, the root vegetables, the cereals (I’m looking at you chart from earlier). All these things are causing type 1 diabetes as fast as epigenetics is throwing methyl groups at my DNA.

Dodge balls berating me like how methyl groups hop onto DNA

It comes full circle here. The Results section of the article poke at nutrition-related factors, viruses, and mothers. Despite having to stop the study and mentioning the need for other organizations to contribute to the data pool they were trying to build here, some progress is better than no progress.

You’ll also notice that this is a Norwegian study. The second article, Viral Trigger for Type 1 Diabetes, from the previous section on Viral Factors had this to say:

“There exists a geographical north-south gradient indicative of an inverse correlation between “hygiene” and incidence of autoimmune disease (as well as allergy). Countries such as Finland versus Venezuela/China, or wider regions such as Northern versus Southern Europe (with the exception of Sardinia), represent areas where socioeconomics correlate closely with type 1 diabetes prevalence. Reduced type 1 diabetes incidence is observed in countries of lower socioeconomic status, which is associated with a higher rate of infection. This phenomenon may also be related to the use of particular vaccine strategies in countries exhibiting different sanitary standards. It is also interesting to note that many type 1 diabetic patients are first born of large families, possibly indicative of lower exposure to infections. In addition, while congenital infections have been proposed to account for type 1 diabetes development in the offspring, the use of antimicrobials by mothers before pregnancy and subsequently by the child was suggested to be associated with higher risk for type 1 diabetes.”

This hygiene hypothesis is pretty interesting. More and more countries are reporting more and more children with autoimmune diseases.

If you can escape the infectious diseases, you won’t be escaping the autoimmune diseases.

The genetic factor and how your environment can effect it goes on ad infinitum. It’s a piece of hay in the needle stack.

Conclusion

It seems this is where the road begins and ends. I mean really. Any time you search ‘why I gots the first diabetes’, you get the entrance to the rabbit hole.

You aren’t alone in the autoimmune battle. There are tons of autoimmune diseases and based on some of those articles they have red strings connecting them. When you start to study the origin of one, you wind up studying the origin of them all. That’s the battle.

Hopefully, you can be at peace knowing there is a wealth of information out there on this stuff. Specifically with type 1 diabetes, I was just tired of the generic/vague answers to my questions about the disease.

Although I do expect the MDs walking around to have some specifics on these inquiries, the amount of specializing specialists have to specialize in is pretty nuts. It’s coming at you at all angles. You’ve now become the conspiracy theorist against everything because that’s pretty much what caused your autoimmune disease… Everything.

Categories: Good Grief