Sunday, August 16, 2015

Diabetic Autonomic Neuropathy: where variability is a good thing.

Diabetic Autonomic Neuropathy: where variability is a good thing.

We are all familiar with the most spectacular complications of Type 1 Diabetes: cardio-vascular damage, nephropathy, neuropathy, diabetic retinopathy, etc... That's part of the basic information package every newly diagnosed patient receives, the Damocles sword that motivates us to control blood sugar. Most of them are, to a significant extent, linked to the glycation of proteins. They are typically called “advanced glycation end products” (AGEs) in the literature. In many cases, AGE have been directly linked to the damage observed. This is also the main reason why HbA1c, as an AGE, is such a good control indicator: it is a proxy for what happens elsewhere in your body. Good blood glucose control is the tool of choice to prevent or minimize a lot of the complications we are facing.

However, things aren't that simple. Diabetic neuropathy is often understood as peripheral neuropathy as in
“Uncle Jim lost sensations in his foot, he had blisters, they became infected and did not heal because his arteries were bad too. They had to cut his leg.”

That is not the whole story... enter the autonomic nervous system.

Our nervous system does not consist only of a cortex, a sensory sub-system and a motor sub-system. There's a thing called the autonomic nervous system that controls, mostly unconsciously and without our intervention, the basic functionality of our bodies: the rhythm of our heart, our respiration, vasodilation, vasoconstriction, the behaviour of our stomach, intestines and bladder, our reaction to exercise and stress, even sexual arousal...

While it is mostly invisible, the autonomic nervous system is what keeps us comfortably alive.

A detailed explanation of how the system works is, of course, outside the scope of a mere blog post. But one simple way to visualize the autonomic nervous system is to think of two separate controllers called the sympathetic and parasympathetic systems.
  • The sympathetic system would be most active in a “fight or flight” situation (increases heart rate, sends blood to muscle, redirects blood flow away from secondary functions, etc...).
  • The parasympathetic system would be most active in a “read and digest” situation (sends blood to intestines, increases peristalsis, decreases heart rate). 
Here is an illustration of the ramifications of the system (marked as free for non commercial use by Google Image search - do not hesitated contacting me if any of the republished illustrations are in violation of anything)

Most of the time, in healthy people, the systems are said to be “balanced”. The concept is a bit fuzzy: it basically means that the systems do what they have to do in an appropriate way. When the balance is lost through diabetic autonomic neuropathy, life can be hell. This often cited paper gives a good overview of the ton of severe issues it is directly responsible for. Warning: do not read it if you are the type of person that worries endlessly.


Roughly speaking, most of the wiring of the system goes through two big nerves: the vagus nerve and the splanchnic nerve. Some other smaller nerves such as spinal nerves serve other territories. The type of wire that goes into each nerve is a complex topic in itself, especially since the heart is a special case. No worries though, we won't need to go into details for our purposes.

If you have read the paper above, you have seen that, in diabetes, this system can be badly damaged. And to add insult to injury, while poor control has the obvious deleterious effects, it can be damaged very soon in the course of the disease and, apparently, somewhat independently of your blood glucose control.  How does that happen? Well, we don't really know. Just as we don't know why some nerves seem to be impacted more than others. Glycation as usual. Auto-immune reactions and inflammation do play a role, but beyond that, looking at the literature, it is again a depressing case of “probably affects”, “deserves further attention”, “seems to be implicated”...
It is the main actor behind gastroparesis, the delayed, inconsistent emptying of the stomach that can wreak havoc on the best control strategy. But it can also lead to orthostatic hypotension (low blood pressure when standing up from sitting), dizzyness, erectile disfunction, lack of exercise adaptation, etc... 

Unfortunately, the heart is also a target, so much that it deserves its own acronym: CAN for cardiac autonomic neuropathy ( CAN is also suspected to play a role in sudden death (certain for Type 2 Diabetics, may play a role in Type 1 Diabetics although ionic and pH disturbances my be enough by themselves)

The heart of the matter

Our heart runs a natural pacemaker, called the sinoatrial node. It triggers roughly 60-70 times per minute: that is, if you want, our natural spontaneous rhythm. Its activity is modulated by the sympathetic – parasympathetic balance. The parasympathetic impulses reaching the sinoatrial node through the vagus nerve tend to lower the rate at which the natural pacemaker fires. The sympathetic impulses, traveling through the spinal nerves, increase the firing rate and the strength of the ventricular contraction, for example when we exercise. In a healthy subject, the systems are ideally balanced.

However, if the vagus nerve is severely damaged, an imbalance is introduced: the sympathetic system will work almost as it should but the parasympathetic activity will be lower. At the extreme, an old diabetic will have resting heart rate higher than an healthy individual and will not adapt as easily to exercise or even suddenly standing up from a sitting position.

And that slowly brings us to the fancy world of tachograms and RR interval analysis

A healthy S/PS balance is always ready to react almost instantly to any change of conditions. The sinoatrial node is normally in a very unstable “trigger happy” state. Mere emotions can accelerate our firing rate within seconds. At the peripheral level, sudden vasodilation can make us faint. Run five steps, your heart responds at once.

That instability is highly desirable (an unusual concept for diabetics) as it reflects our ability to adapt to changes in life. You do positively want to have a constantly unstable heart. That variability can be quantified in a myriad of ways. It is loved by researchers as it gives them plenty of opportunities to publish papers on the correlation between dozens of indicators with dozens of outcomes under a dozen of circumstances such as post myocardial infarction, aging, exercise recovery, or even our propensity to socialize (where's free will anyway?) etc...

As far as the T1D patient is concerned, the story begins around 1975 when DJ Ewing  and others looked at RR variability (basically how unstable your cardiac rhythm is) and published this paper  which can be summarized by this figure
The hearts of diabetics did not seem, on average, to behave like the hearts of healthy controls.

Very quickly, lots of people jumped on the concept, confirmed the findings (here for example, here) and the concept was used as a mortality predictor (here for example) and as a tool to detect early asymptomatic autonomic neuropathy (see again the Vinik paper for explanation and links).

As a T1D parent, I am always a bit paranoid. Once I learned that diabetic autonomic neuropathy could potentially exist at the time of diagnosis, I absolutely, totally and utterly needed to know if my son was affected. On the basis of that paper that, armed with an ECG device, I embarked on what I expected to be a simple check and ultimately was dragged into a tricky journey in the very muddy waters of RR Interval Analysis, tachograms, power bands and clinical protocols (or the lack of them)

That will be for the next post.

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