Richelle’s Thoughts & Musings

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My GIP Hypothesis

How it affects chronic illnesses like MECFS and Long Covid

The first time I really became aware of GIP was after I read a journal article on how it effects people with POTS. In this study they found it correlates with the exacerbation of POTS symptoms for at least 2 hours after oral glucose ingestion. The tachycardia really caught my attention, as I had postprandial tachycardia as one of the most problematic symptoms during my acute covid infection. It still was affecting me with every meal.

I was often postponing my meals as long as I could throughout the day, as I was often functional until I ate, and then all I could do was sit still and try not to move. I also would feel overall rather shitty, as my cognition would be sluggish and I just didn’t feel functional for at least several hours. GIP levels correlating with this feeling? I had to find out more.

GIP stands for Glucose-dependent Insulinotropic Polypeptide. It is an incretin (intestinal secretion) that is released when nutrients enter the stomach, especially carbohydrates. It then triggers the release of insulin to help keep blood glucose levels stable. It is deactivated (cleaved) by DPP-4, usually in less than 30 minutes, when everything is functioning correctly. Another incretin that works hand-in-hand with GIP is GLP-1 (Glucagon-Like Peptide-1). There are more incretins, too, like GLP-2, that are important, but that is for another day.

I search the research literature for more on GIP and found another interesting study. In this study, the researchers found that GIP works as a microvascular blood flow constrictor, especially in the skeletal muscles. When they administered glucose intravenously, the participants had little effect, except some dilation. When the glucose was administered orally, the participants skeletal muscles showed definite microvascular blood flow constriction. The researchers were able to attribute this to GIP.

Given this response, I wondered about the postprandial tachycardia. Did GIP affect the heart? I dove back into the literature looking for a possible connection. And, wow, was there ever! There are many studies where GIPR (GIP receptor) is studied. This one found a link between higher cardiac mortality and higher fasting levels of GIP. This article discusses how it is possibly tied to cardiovascular disease, especially with ties to endothelial tissue inflammation. And this one talks about how GIP triggers the release of osteopontin (OPN), which they say, “OPN concentrations are positively correlated in patients with critical limb ischemia.” There is quite a bit more on GIP and the vascular system and the heart specifically. There are ties to ceramides, NGF, and, interestingly, cortisol. (Plus many more systems that are still being identified.)

In Food-Dependent Cushing’s Syndrome, an abnormal response of the receptors for GIP in the adrenals, which causes an excess release of cortisol with the intake of food. (GIP also triggers some cortisol release!) There are so many other connections to GIP, and what might balance it. Usually it is release along with other incretins like GLP-1, so there must be some connection or imbalance, right?

In this study, they found GLP-1 has some protective effects for patients with different types of heart failure. This really piqued my interest, as I had heard Dr. Paul Cheney discuss how his MECFS patients often had what appeared to be a form of Heart Failure with Preserved Ejection Fraction (HFpEF). In another study, they wanted to raise the levels of hydrogen sulfate in order to increase GLP-1 levels.

I had a path for action, now. I started testing my blood pressure, glucose, and heart rate while fasting, and then after eating at the 1 hour, 2 hour, and 3 hour marks. I also started taking the chondroitin sulfate they used in the mice study as a prebiotic for the gut bacteria that produce hydrogen sulfate.

My readings were usually fairly stable in the fasting state, but then after eating my heart rate would increase at least 30 BPM, and my diastolic BP (the lower number) would increase about 5-10 points. The diastolic increase correlated with the general postprandial shitty feeling. My glucose readings would usually be close to 100 mg/dL when fasting, but then would jump after eating to 130-150 mg/dL. At the 3 hour mark the glucose would drop, usually no lower than 85 mg/dL.

After 90 days of taking the chondroitin sulfate, my heart rate stopped jumping after eating. It usually now would only go up about 5-10 BPM after eating. My blood glucose was (and still is!) erratic. But I could go back for seconds and feel pleasantly full, rather than eating tiny little portions hoping not to trigger the spike. Plus, the overall shitty feeling decreased. It isn’t completely gone, but I am functional after meals now!

Now my brain was really starting to wonder about everything else GIP might do. But why would it not be working right? Now we get into why it might be part of chronic illness.

GIP and GLP-1 are moderated by DPP-4. DPP-4 (a glycoprotein) has another name, CD26. This gets us into the innate immune system and T-cells. CD26 is a costimulator of T-cell activation. (It is also present in synovial fluid, so I think there is likely a tie to Sjogren’s, but that’s a whole other post!) This study found that “the high expression of CD26 is accompanied by the differentiation of T lymphocytes into Th1 and Th17, indicating that CD26 plays a crucial role in regulating the immune response.” A dysregulated immune response might mean lower CD26/DPP-4, which leave less to regulate GIP and GLP-1.  GIP has twice the half life of GLP-1, so maybe there is enough to deactivate GLP-1, but not enough to deactivate the excess GIP, so it keeps attaching to its receptors, wreaking havoc in our bodies.

The cortisol-triggering effects of GIP might be part of this issue. Now I am really just getting into pure speculation, based on how my blood sugar responses are after eating. GIP can activate cortisol, which interferes with insulin. My hypothesis is that without enough DPP-4 (CD26), GIP stays in the systems much longer than the 30 minutes it is supposed to be elevated after meals. Without GLP-1 (which blocks glucagon release) blood sugar continues to rise. Insulin levels keep going up, but with the extra cortisol (maybe) and the glucagon releasing, the blood glucose keeps rising until GIP is finally regulated by DPP-4. This appears to take about 3 hours. At that point, insulin can suddenly do its job, so glucose suddenly is pulled out of the blood, causing hypoglycemia.

To test to see if this is the case in our patient population, I am proposing some patient-led research. We would test heart rate, blood pressure, blood glucose, and the overall postprandial shitty feeling (rated on a scale. There would need to be four measurements: Fasting, 1 hour post meal, 2 hours post meal, and 3 hours post meal. I would also suggest that diet interventions like being in ketosis be avoided in this study, as the ketones available would buffer many of the effects. Plus, we would need to test the reaction to carbohydrates.

After this data is gathered, then we can start looking at who might benefit from having insulin and cortisol tested at the timing of when the “shitty feeling” is most extreme, so as to have the likelihood of positive test results.

I have more thoughts on GIP and other incretins (I think they are also relevant in gastroparesis!), plus how it affects the brain and a link to the DOMS, but I will have to try describing all that in another post. Oh, one more article to reference, and that is this one connecting lower levels of CD26 with MECFS as a possible biomarker. I really wish I had a lab I could test this at, but this is not a typical one available at diagnostic labs, only research labs. Maybe one of these days we can all get together and find a way to test this ourselves, and show this link!

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ADHD, OCD, and MCAS

The many overlaps

By Richelle Sepulveda

(This is another stream of consciousness blog post, done late in the evening when I should be settling down for bed. If it feels erratic and jumps around, that’s why!)

For most of the last ten years, I was a psychology professor at a community college. I always did like to stay up on current research, and a field that was very intriguing for me was Affective Neuroscience. For my Psych 101 class I used an open source textbook, and it has a good chapter on it here. There is a lot of really interesting information in it, but one that I want to point out here is the Grief System. This is the system that feels “lonely” and “empty” and “loss”. It is constantly activating, and our energy must be expended to suppress it. Oxytocin, the bonding hormone, suppresses it, as does various endorphins. Since it is connected to the pain system, being ostracized can be physically felt as “pain” as well. This also means that many pain medications can suppress this system, too.

I bring up the Grief System because it has some connections to the Default Mode Network, too, which is relevant to understanding ADHD and OCD, or at least the tendencies towards those that people with MCAS have. Two other articles that are relevant are this one on ADHD and MCAS, and this one on mast cells and anxiety-like behavior. There’s more out there on ADHD and chronic pain, but I need to stay on topic!

Remember, I am not an expert, I am not a neuroscientist, I am just a person trying to figure out my health and mental well-being. If you find this interesting and relevant to you, I can connect you with more information that you can relate to yourself!

Anyways, I wanted to bring up affective neuroscience, as it is the way the brain processes and feels emotions, and how different states can be triggered by physical processes. And that is very relevant to how MCAS can affect our emotional states and thoughts.

For years as I got sicker (before Covid) I was dealing with more and more anxiety. Sure, finances were tight, but this didn’t match the logic pathways I was using. I couldn’t shake this constant anxiety feeling. Plus, I was dealing with more and more depressive episodes. These weren’t usually severe, but they made life more difficult. My ADHD symptoms were harder to control, even with medication, and my anxiety would wake me up in the middle of the night, heart pounding, mind racing, an intrusive thought that activated the grief system (usually reliving some embarrassing or guilt-inducing event), as well as being too hot. Which really sucked, because I was always cold going to sleep, but then a couple of hours later I was way too hot. I couldn’t get a good night’s sleep, and the cycle of depression, anxiety, and poor sleep continued.

I had a student who was doing a project on OCD, something he had been diagnosed with when he was 3 years old. He wanted to know if his idiopathic urticaria (itchy skin without a clear reason) was connected, as he knew his OCD intrusive thoughts were worse any time his skin was itchier. I was learning about MCAS (Mast Cell Activation Syndrome) at the same time, and we both had a lightbulb go off. There was an overlap, and it shows up in the literature in many places. (PANDAS is one to consider for pathogen-triggered OCD, if you want to look it up.) It also made me interested in ADHD and the connection, as the Rejection Sensitivity Dysphoria in ADHD is so similar to the guilt in OCD.

Okay, I need to define a few things. OCD (Obsessive-Compulsive Disorder) is largely a disorder of the guilt system. This is an overactivation of the basic disgust system, which we are born with, which develops into guilt and morality by about year three, which is when OCD can be first diagnosed. (There’s some connection of the disgust system and sexuality, too, but that’s a post for another day.) To understand OCD, it helps to understand the Call of the Void, which is usually described as the desire to jump when on a balcony or the edge of a cliff. But it is not really about WANTING to jump, it is an intrusive thought where you picture what would happen if you did, or you leaned to far over the railing, or something like that. Often you will feel guilty at the same time, or embarrassed, and feel the urge (compulsion) to do behaviors that make the risk lower, like backing away from the edge, or grasping the railing until your knuckles are white.

Call of the Void can hit in many different situations, as it is part of our natural self-protection systems to picture what could be dangerous and what is necessary to avoid it. Another example, driving in two-way traffic and picturing swerving in front of a big truck, so you do what you need to do to make sure it never happens. Since this is part of the disgust system, you can also have disgust Call of the Void. Have you ever known someone who just CANNOT change a diaper? They might hold it at arms length and keep dramatically gagging. It looks so theatrical and dramatic. But they might be having an intrusive thought of disgust, picturing getting the contents in their mouth. And they cannot just stop thinking about it.

OCD and anxiety have a massive amount of symptomatic overlap, and anxiety does spike when mast cells degranulate, as described in the article I linked at the beginning of this blog. Any time you have a histamine dump, this can be triggered. The anxious thoughts that are more intrusive, as if someone is forcing you to think about something awful to you. Remember anaphylaxis is also a mast cell degranulation response, and one of the feelings in it is a feeling of doom. (In panic attacks as well, but again, a post for another day!)

Once I read about ADHD and the MCAS connection, I thought I would test it out on myself. A common symptom for me is the need to get work done, but I just don’t want to and I cannot start. I would often describe it as “difficulty getting going today.” To test the connection, I tried a Zyrtec and set a timer for when it would likely be kicking in. Sure enough, the barrier wall to getting started lowered, and I could begin to do the tasks I needed to. I also noticed that when I had ingested something that was a mast cell trigger for me, I would manifest more anxiety and struggled to concentrate on tasks. Again, a Zyrtec helped.

I also noticed that when I started serious MCAS treatment (so many different antihistamines!) that I was able to sleep through the night. I no longer woke up at 2 AM with the pounding heart and racing thoughts that I couldn’t control. My sleep was more refreshing. Not perfect, but much better than it had been. I also had an easier time falling asleep. Previously I had blamed it on my ADHD that I couldn’t settle my brain down to sleep. But once the MCAS was under better control, sleep actually came pretty easily.

Oh, yeah, Rejection Sensitivity Dysphoria! I almost forgot! RSD is a very difficult symptom in ADHD, but one few clinicians mention, partly because it is not easily measured. It is the feeling of humiliation and rejection for even the mildest criticism. An example I like to give is how one responds to being told “Your zipper is down.” A typical person might smile awkwardly, fix it, and say, “Wow, I wonder how long I have been walking around like that!”, then go on with their day. A person with implosive RSD may react by fleeing to the bathroom to fix it, then have the urge to get in their car and flee the area due to the humiliation feeling. It is dysphoric, as it is way outsized for the level of embarrassment one should have in such a situation. Explosive RSD can happen, too, where you become very angry with the person who pointed out your zipper is down. Implosive versus explosive often depends on the power dynamics of the relationship, so a parent with ADHD may react explosively to their child with ADHD, creating a pattern of generational trauma if they aren’t aware of the outsized reaction as not typical.

You can see how the guilt and intrusive thoughts of OCD and the RSD in ADHD could be connected by a similar underlying mechanism, right? And if part of that is trigger-happy mast cells, then MCAS can greatly exacerbate these emotional reactions, which is really problematic as emotional exertion is a trigger for PEM for many of us!

I am not saying I have OCD, but I do have tendencies in that direction. But when you add in MCAS, symptoms exacerbate. I feel guilty, that I am a burden on my loved ones, that I should be able to make myself better, that I could do more with my limited energy envelope, that I am just lazy, etc. I think many of us have had those thoughts. And they can be at least partially triggered by our illness itself. The BPS people get it so wrong when they try to connect the body symptoms with the thoughts. The path goes more the other way, with the physical illness causing the change in thoughts, not the other way around. And trying to change your thoughts when they are triggered by physical mechanisms is nearly impossible, but the guilt is already there, waiting for an excuse to prove you are just not trying hard enough.

How do your shake these thoughts. The only way out is through. You have to feel the feelings, but that is really hard, too. That’s a whole other post as well (one day I will tell you how I fatigued some pain receptors so I could walk on blistered feet, but it is not this day). That’s also a connection to the Grief System and the DMN. I also have some thoughts on overactivation of the DMN is why so many of us are aware of every subtle change in our bodies, but this one is already long enough.

(I should really do this one as a video, too. If so, I will also describe why and how it connects to sexuality and kinks. That was always a hit in Psych 101 classes!)

Posted on

My GIP Hypothesis

How it affects chronic illnesses like MECFS and Long Covid

The first time I really became aware of GIP was after I read a journal article on how it effects people with POTS. In this study they found it correlates with the exacerbation of POTS symptoms for at least 2 hours after oral glucose ingestion. The tachycardia really caught my attention, as I had postprandial tachycardia as one of the most problematic symptoms during my acute covid infection. It still was affecting me with every meal.

I was often postponing my meals as long as I could throughout the day, as I was often functional until I ate, and then all I could do was sit still and try not to move. I also would feel overall rather shitty, as my cognition would be sluggish and I just didn’t feel functional for at least several hours. GIP levels correlating with this feeling? I had to find out more.

GIP stands for Glucose-dependent Insulinotropic Polypeptide. It is an incretin (intestinal secretion) that is released when nutrients enter the stomach, especially carbohydrates. It then triggers the release of insulin to help keep blood glucose levels stable. It is deactivated (cleaved) by DPP-4, usually in less than 30 minutes, when everything is functioning correctly. Another incretin that works hand-in-hand with GIP is GLP-1 (Glucagon-Like Peptide-1). There are more incretins, too, like GLP-2, that are important, but that is for another day.

I search the research literature for more on GIP and found another interesting study. In this study, the researchers found that GIP works as a microvascular blood flow constrictor, especially in the skeletal muscles. When they administered glucose intravenously, the participants had little effect, except some dilation. When the glucose was administered orally, the participants skeletal muscles showed definite microvascular blood flow constriction. The researchers were able to attribute this to GIP.

Given this response, I wondered about the postprandial tachycardia. Did GIP affect the heart? I dove back into the literature looking for a possible connection. And, wow, was there ever! There are many studies where GIPR (GIP receptor) is studied. This one found a link between higher cardiac mortality and higher fasting levels of GIP. This article discusses how it is possibly tied to cardiovascular disease, especially with ties to endothelial tissue inflammation. And this one talks about how GIP triggers the release of osteopontin (OPN), which they say, “OPN concentrations are positively correlated in patients with critical limb ischemia.” There is quite a bit more on GIP and the vascular system and the heart specifically. There are ties to ceramides, NGF, and, interestingly, cortisol. (Plus many more systems that are still being identified.)

In Food-Dependent Cushing’s Syndrome, an abnormal response of the receptors for GIP in the adrenals, which causes an excess release of cortisol with the intake of food. (GIP also triggers some cortisol release!) There are so many other connections to GIP, and what might balance it. Usually it is release along with other incretins like GLP-1, so there must be some connection or imbalance, right?

In this study, they found GLP-1 has some protective effects for patients with different types of heart failure. This really piqued my interest, as I had heard Dr. Paul Cheney discuss how his MECFS patients often had what appeared to be a form of Heart Failure with Preserved Ejection Fraction (HFpEF). In another study, they wanted to raise the levels of hydrogen sulfate in order to increase GLP-1 levels.

I had a path for action, now. I started testing my blood pressure, glucose, and heart rate while fasting, and then after eating at the 1 hour, 2 hour, and 3 hour marks. I also started taking the chondroitin sulfate they used in the mice study as a prebiotic for the gut bacteria that produce hydrogen sulfate.

My readings were usually fairly stable in the fasting state, but then after eating my heart rate would increase at least 30 BPM, and my diastolic BP (the lower number) would increase about 5-10 points. The diastolic increase correlated with the general postprandial shitty feeling. My glucose readings would usually be close to 100 mg/dL when fasting, but then would jump after eating to 130-150 mg/dL. At the 3 hour mark the glucose would drop, usually no lower than 85 mg/dL.

After 90 days of taking the chondroitin sulfate, my heart rate stopped jumping after eating. It usually now would only go up about 5-10 BPM after eating. My blood glucose was (and still is!) erratic. But I could go back for seconds and feel pleasantly full, rather than eating tiny little portions hoping not to trigger the spike. Plus, the overall shitty feeling decreased. It isn’t completely gone, but I am functional after meals now!

Now my brain was really starting to wonder about everything else GIP might do. But why would it not be working right? Now we get into why it might be part of chronic illness.

GIP and GLP-1 are moderated by DPP-4. DPP-4 (a glycoprotein) has another name, CD26. This gets us into the innate immune system and T-cells. CD26 is a costimulator of T-cell activation. (It is also present in synovial fluid, so I think there is likely a tie to Sjogren’s, but that’s a whole other post!) This study found that “the high expression of CD26 is accompanied by the differentiation of T lymphocytes into Th1 and Th17, indicating that CD26 plays a crucial role in regulating the immune response.” A dysregulated immune response might mean lower CD26/DPP-4, which leave less to regulate GIP and GLP-1.  GIP has twice the half life of GLP-1, so maybe there is enough to deactivate GLP-1, but not enough to deactivate the excess GIP, so it keeps attaching to its receptors, wreaking havoc in our bodies.

The cortisol-triggering effects of GIP might be part of this issue. Now I am really just getting into pure speculation, based on how my blood sugar responses are after eating. GIP can activate cortisol, which interferes with insulin. My hypothesis is that without enough DPP-4 (CD26), GIP stays in the systems much longer than the 30 minutes it is supposed to be elevated after meals. Without GLP-1 (which blocks glucagon release) blood sugar continues to rise. Insulin levels keep going up, but with the extra cortisol (maybe) and the glucagon releasing, the blood glucose keeps rising until GIP is finally regulated by DPP-4. This appears to take about 3 hours. At that point, insulin can suddenly do its job, so glucose suddenly is pulled out of the blood, causing hypoglycemia.

To test to see if this is the case in our patient population, I am proposing some patient-led research. We would test heart rate, blood pressure, blood glucose, and the overall postprandial shitty feeling (rated on a scale. There would need to be four measurements: Fasting, 1 hour post meal, 2 hours post meal, and 3 hours post meal. I would also suggest that diet interventions like being in ketosis be avoided in this study, as the ketones available would buffer many of the effects. Plus, we would need to test the reaction to carbohydrates.

After this data is gathered, then we can start looking at who might benefit from having insulin and cortisol tested at the timing of when the “shitty feeling” is most extreme, so as to have the likelihood of positive test results.

I have more thoughts on GIP and other incretins (I think they are also relevant in gastroparesis!), plus how it affects the brain and a link to the DOMS, but I will have to try describing all that in another post. Oh, one more article to reference, and that is this one connecting lower levels of CD26 with MECFS as a possible biomarker. I really wish I had a lab I could test this at, but this is not a typical one available at diagnostic labs, only research labs. Maybe one of these days we can all get together and find a way to test this ourselves, and show this link!