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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