T1D, Stress, Chronic Inflammation, & Sympathetic Overdrive

The relationship between autoimmunity, stress, & inflammation

The relationship among Type 1 diabetes, stress, and the autoimmune and inflammatory response has fascinated me for years.

For example, in 1972 I was an 11-year old kid recovering from the flu who never seemed to get better — and then I was diagnosed with Type 1 diabetes. Then, during my run across the USA in 2020-2021, as I crossed from Mississippi to Arkansas I met Evie, who had just been diagnosed with Type 1 diabetes after “recovering” from Covid-19.

In fact, there’s a fair bit of research suggesting that viral infections can trigger the latent autoimmune tendencies into full-blown immune system disorders – in effect, nature loads the gun, and something in our environment pulls the trigger.

But viral infections aren’t the only things that trigger inappropriate immune responses.

Physical stress plays a significant role. For instance, I’ve met a dozen or more runners in the ultrarunning and ultra-endurance communities on Facebook who were diagnosed with an autoimmune disorder shortly after finishing particularly grueling ultra-endurance events, like 100-mile runs.

The body can respond to the muscle damage caused by physical stress of prolonged exercise much as if it were an infection. Body temperatures rise, and aches, discomfort, and fatigue set in. Epinephrine and cortisol production rise to provide energy needed to “fight the invaders.” For folks like me, blood sugars also typically rise. Damaged myoglobins (“damage associated molecular patterns,” or DAMPs) are seen immunologically as foreign proteins, and the body tries to get rid of them in the same way.

Usually, that’s a good thing. Our bodies do need to fight off viruses and remove damaged cells.

But when this process gets permanently stuck in the “on” position, for instance, when physical stress and the associated inflammation trigger an underlying genetic predisposition to inappropriate immune reactions, it’s not a good thing at all.

For instance, with Type 1 diabetes, our bodies mistakenly identify our own insulin-producing beta cells as invaders. Auto-antigens prompt our immune system’s T-cells to go on the attack against those cells, and when they die, our ability to produce insulin dies along with them. And that’s just the beginning of the story.

Chronic inflammation and Type 1 diabetes

One of the least-understood aspects of autoimmune disorders is the chronic inflammation I mentioned above, and it’s probably the aspect most associated with long-term complications for us Type 1s.

The jury still seems to be out on whether anti-inflammatory meds can prevent or slow the development of T1D. Teplizumab/Tzield turns down the volume on the t-cell response, and has been shown to delay progression in folks with a genetic propensity to Type 1, for example. On the other hand, studies of NSAIDs showed no effect on beta cell preservation, and drugs that target cytokines have had mixed results.

Regardless, we need to think more broadly about what was going on before our bodies went on the warpath, going after insulin-producing cells. Why did we attack our own islet cells? What mechanism identified them as invaders in the first place?

I’m especially hopeful about recent research at Chicago’s Pritzker Institute which suggests that “inverse vaccines”–that is, “vaccines” that reassure our bodies that our beta cells aren’t foreign–may actually break the self-reinforcing connection between chronic inflammation and autoimmunity.

Why? Because these inverse vaccines work by instructing T cells to “call off the attack” for specific proteins that actually belong in the body, addressing the inflammatory and autoimmune response at its origin.

A problem that doesn’t go away on its own

Under normal circumstances, physical stress is transient and the inflammatory response operates normally to help the body naturally rebuild what’s been broken down by day-to-day life.

It promotes the production of cholesterol, which helps replace and maintain cells damaged by inflammation, especially following periods during which cells are subjected to shear stress, such as the muscle damage from prolonged exercise.

However, in autoimmune diseases like Type 1, chronic inflammation and the ongoing physiological stress it generates are lifelong factors that continue beyond the initial autoimmune response. Their effects can’t always be fully repaired by the body’s normal rebuilding processes.

This chronic inflammation and stress plays a significant role in the development of cardiovascular disease in Type 1. Unlike our “normal” counterparts, our bodies can’t stand down from a state of high immunological alert. This contributes to excess production of cholesterol and the slow formation of calcified plaques in blood vessels, known as atherosclerosis, as well as chronic high blood pressure and changes in even the tiniest blood vessels.

It’s like no matter what we do, we can’t switch out of that high-gear, all-hands-on-deck, this-is-not-a-drill, DEFCON-1 state associated with activation of the fight-or-flight instincts and the sympathetic nervous system. And this overwrought state has a name: sympathetic overdrive.

Sympathetic regulation and autoimmunity are closely related, and this relationship is one reason why people with type 1 diabetes and other inflammatory and autoimmune conditions such as lupus and rheumatoid arthritis are at greater risk of cardiovascular disease even when elements of disease maintenance such as blood sugar control are perfect.

That’s why it’s not enough to just keep our numbers “between the lines.”

Physical stress, endurance, and sympathetic overdrive

“Sympathetic overdrive,” also called “overactive sympathetic nervous system” or “sympathetic overload,” plays a leading role in the body’s overall stress response.

When I was doing my first 100-mile run in July 2017 at the Honey Badger 100 in Wichita, KS, overnight temps were in the 90s. On a lonely highway somewhere around midnight, an inexplicably enraged driver in a white pickup truck accelerated straight towards me and forced me into a ditch.

I climbed out of the ditch despite severely blistered feet, and over the next 30 miles, my blood sugar spiked and stayed near 300 mg/dl (17 mmol). As the night wore on into morning, I skipped fuel stops and kept trying to dose down the highs — only to watch my sugar rise back into the 300s and stay there — hour after endless hour.

This is sympathetic overdrive in action.

The usual advice at this point would be to stop exercising.

I kept going, but I was running on fumes.

The sun was already high in the sky when somewhere around mile 90, with only 10 miles to go, I simply had to eat, no matter what my sugar was.

So I finally sat down on the side of the road, ignored everything I knew about dealing with highs, and ate a fruit yogurt. I slurped down some Gatorade, and continued at a pace barely above a stumble. Leslie and I had agreed that given the high BGs, the best plan was to keep moving, but not to push myself more than I already was.

Then something strange happened.

My blood sugar started going down, steeply, despite little insulin on board and plenty of sugary yogurt.

That brief break and food activated the calming “rest and “digest” functions of my parasympathetic nervous system, ratcheting down the “fight or flight” reaction associated with sympathetic overdrive.

Getting “unstuck” from high gear

This is why I said earlier that it’s not enough to keep our numbers between the lines. We have to address the hyperactivation of the sympathetic nervous system.

“Sympathoinhibition” is the process of reducing the impact on the body of chronic stress and inflammation, especially related to the cardiovascular system.

This can be achieved through both medical and non-medical means.

For example, blood pressure drugs like ARBs and beta blockers have profound sympathoinhibitory effects, as do alpha-adrenergic blockers and other sympatholytics — drugs that help calm the sympathetic nervous system.

But medications can only do so much. Sometimes, the solutions you most need are within yourself — how you assess and respond to situations that trigger every fight or flight response in the book.

During my first full 140.6 triathlon, water conditions for the 2.4 mile swim were incredibly choppy, windy, and stormy. I had never seen, much less trained for, anything like that. In fact, half the swimmers eventually dropped out of the event.

As for me, in the first 400 yards I knew this situation was way more than I could handle. I had already aspirated a significant amount of water and tried to flag down the safety boat, only to watch in disbelief as the race’s only non-capsized vessel sped away to help someone else.

I had to force myself to stay calm, aim for the shore, and keep remembering that I had gotten myself into this situation, so I could most likely get myself out of it. I just had to think through it, consciously, one step at a time, and act.

Sergeant Hartman’s words from the movie Full Metal Jacket, “You best un-fuck yourself, soldier!” still echo in my head to this day.

Sometimes, getting your head on straight is your best tool for calming your sympathetic nervous system.

Learning to go “within”

Noted marathon swimmer Lynne Cox, famous for swimming from Alaska to Russia, wrote in her book Open Water Swimming Manual about her experiences training with Navy SEALs before she crossed the icy waters of the Bering Strait. She described how the SEALs used certain training exercises to determine what they were and weren’t physically capable of.

Then, if they couldn’t perform a task they knew they were physically capable of, any remaining problems were psychological. That meant they were addressable through focused assessment, preparation and rational acts of will.

By the time I finally got around to running across the US three years later, I had started learning to modulate my sympathetic “tone” through behavioral practices.

• I learned that exercising without triggering sympathetic overdrive can still produce the cardiovascular and other benefits of exercise.
• I learned to attend to my surroundings, mindfully stepping away from approaching traffic without anger, fear, frustration, or surprise.
• I learned to control some of my stress through yoga and deep breathing.
• I learned to meditate while running and aim for happiness amidst physical suffering.
• I learned, as the old poem says, to “move placidly amidst the noise and haste.”

I actually find all this helpful. Applying our minds to our physical and emotional stress is something we are all capable of, and it’s a good reminder that when we have to, we can do way more than we think.

Even with, and perhaps especially with, Type 1 diabetes.