I’m commenting about a commentary I wrote with some colleagues titled “Comment on Rhee et al. Association Between Glycemic Status and the Risk of Parkinson Disease: A Nationwide Population-Based Study.”.

Original Paper’s Findings

The paper we commented on was interested in the relationship between diabetes and Parkinson’s disease due to prior work suggesting that diabetes increases the risk of Parkinson’s ¹. For me, not being an expert in the field, I was quite surprised by this potential link between Parkinson’s and diabetes, which on the surface seem very dissimilar. So I was very curious to read what the paper had to say.

Parkinson’s is a brain disorder related to movement and leads to shaking, stiffness, and difficulty with walking, balance, and coordination.

Diabetes is a condition that affects how your body turns food into energy. The food you eat is broken down into sugar or glucose. The hormone insulin helps glucose from food get into your cells for use as energy. Diabetes occurs when your body doesn’t make enough insulin or can’t use insulin as well, leading to too much blood sugar staying in your bloodstream and not reaching your cells.

The authors had access to an impressive dataset of 50 million people who were part of the health care system in Korea. Of that sample, they used just 15 million people for their analyses. They found that Parkinson’s did increase with incidence of diabetes. Specifically, Parkinson’s diagnosis was related to the severity and duration of diabetes. They even found increased risk in people who weren’t yet diabetic but had higher than average levels of blood glucose. This means that the higher your blood glucose levels, the greater your risk for developing Parkinson’s, and the longer you have diabetes, the greater your risk for developing Parkinson’s.

Our Comments

The paper had some robust results but did not talk too much about potential mechanisms. In our commentary, we discussed that increased inflammation could be the common factor underlying both disorders and decreasing this inflammation could be a fruitful ‘cure’.

Inflammation is the body’s process of fighting against things that harm it. Chronic inflammation is when this response lingers so your body is constantly on alert even when there is nothing to fight. This can have negative impacts on your body.

The majority of people with diabetes (>90%) have type-2 diabetes, which is typically caused by obesity. Obesity and diabetes is characterized by chronic inflammation.

We researched the effects of anti-inflammatory drugs on Parkinson’s and diabetes. We focused on nicotine, which activates the anti-inflammatory cholinergic pathway by acting on the a7nAChR receptor. That just means that nicotine reduces inflammation. Nicotine was also found to to improve the response of insulin to sugar, and there was a negative correlation between nicotine (smoking) and the development of Parkinson’s. This suggests that by reducing the bodies inflammation response, one could reduce the risks for both diabetes and Parkinson’s. Since diabetes contributes to increased inflammation, this might be one factor for why diabetes increases the risk for Parkinson’s.

Just a note that obviously nicotine has many unpleasant side effects so we weren’t advocating for its use. But other safer medications that have the same underlying mechanisms would be important to research.

My Additional Comments

I think it is easier to see the connections between nicotine and inflammation by understanding the autonomic nervous system. This is “the part of the nervous system responsible for control of bodily functions not consciously directed, such as breathing, the heartbeat, and digestive processes” (Oxford Languages). It is composed of the sympathetic nervous system and the parasympathetic nervous system, which work in opposition to each other. They are like the Yin and Yang of the nervous system.

The sympathetic nervous system is like the Yang or active principle. It is responsible for priming the body for action such as during ‘flight or fight’. In our modern times, we are chronically stressed and hence frequently in the sympathetic state, ready to fight the next deadline or get activated by some insult on Twitter. Inflammation, as I mentioned earlier, is just like this where the body is fighting some threat. In cases like diabetes, it can lead to a chronic inflammation where the body is constantly in ‘flight or fight’ mood.

The parasympathetic nervous system is like the Yin or passive principle. It is responsible for conserving the body’s natural activity such as during ‘rest and digest’. Think about after you’ve eaten that nice meal or had a nice workout or had a nice time…in bed…and are now in a very relaxed state. These would be times where the parasympathetic system can shine. Because it is associated with relaxation, it leads to reduction in inflammation or has an anti-inflammatory response.

The image below borrowed from https://www.simplypsychology.org/parasympathetic-nervous-system.html illustrates the dichotomy well. For instance, note how heart rate goes up with sympathetic activity and heart rate goes down with parasympathetic activity.

So where is nicotine in all this? Well nicotine activates the cholinergic pathway which is part of the parasympathetic nervous system. That’s how it can have the effect to reduce inflammation, since nicotine activates the parasympathetic system which reduces inflammation. We don’t need to restrict ourselves to nicotine, of course, but could try other drugs that activate the parasympathetic system. Or we could also think of activities that might activate the parasympathetic system, and carry out some thought experiments on the effects on inflammation.