Blood Glucose and Insulin Resistance

[chillier]

I bought a continuous glucose monitor a while ago thinking it could be interesting to try. @TamaraRC 's post has inspired to me to finally put it on.

Here's a trace from when I had 5 pieces of a medium pizza yesterday evening (peak on the right):



and a relative of mine eating exactly the same at the same time:



In my case the peak extends into what the app describes as the 'elevated' range, I think it peaked at something like 11.7mmol/L. Supposedly 2 hours after eating glucose levels should return to below 7.7mmol/L. Mine were over 9mmol/L at 2 hours and didn't dip below that until over 3 hours later. According to some online health websites this would place me firmly into a 'prediabetic' category.

I don't really know how to interpret these data so I'm not really sure if it's actually something that's abnormal or is actually very typical. I want to try this again after eating a big sugary desert, but I'm a bit concerned to do that because when I've eaten sweet food in the past it sometimes makes me feel quite ill.

@Jonathan Edwards in your experience do you know if this is in any way unusual?

There's been a few studies now arguing insulin resistance in ME (some mentioned in @TamaraRC 's video), I might put them together in this thread at some point to compare.

 

[Kitty]

I've always reacted badly to simple carbs since getting ill, so I find this an interesting idea. Trouble is, the sensors only last a couple of weeks and they're very expensive, so they're not easily accessible.

I know my long term blood glucose pattern's okay because I have regular HbA1c tests—probably more than average for a non-diabetic. I need regular blood tests anyway, I'm middle aged and at the top of the notional healthy BMI range, so they sometimes add a couple of other routine screenings to the lab form. They've all been fine.

 

[Yan]

The "pizza graph" from @chillier is similar to what I also get from for example eating a pizza. Actually I did test my blood glucose levels few days ago before and afer eating a pizza. Before it was 5.5mmol/L. 30 minutes after it was 8.1mmol/L. 90 minutes after it was 11.9mmol/L. Didn't take more tests because I started to feel better and thus it was obvious that the levels were going back down. In the past I've also noticed that at times I have the so called reactive hypoglycemia also. Sometimes 2-3 hours from meal my glucose level drops to around 3.5mmol/L also (causing different kind of symptoms) instead of stabilising back to normal right away.

I've also been "prediabetic" for over 15 years, though I believe that my situation has improved in the past years after I removed most of the foods that causes such large changes to my blood glucose level from my diet. And the same as @Kitty , my HbA1c has always been normal when tested. Last time it was even in the middle of the normal scale. As for the BMI, I'm in the low end, on the border of being underweight.

No idea if this has anything to do with my ME symptoms, but I strongly suspect that there's at least some correlation. I don't have any medical background so I can only guess though. I'm not sure if on my case a continuous blood glucose monitor would show much while I'm on my safe diet.

 

[TamaraRC]

I am just hypothesising and could be completely wrong but maybe it should be considered that the HbA1c might not fully capture certain forms of insulin resistance.

The HbA1c test measures the average blood glucose levels over approximately the last 2-3 months by assessing the percentage of glycated hemoglobin in the blood. While it could detect insulin receptor resistance caused by diet and androgen imbalance, there are situations where HbA1c might fail to reflect underlying insulin resistance accurately.

If a person has a genetic variant that causes prolonged or excessive insulin secretion from the pancreas, the persistent high levels of insulin could lead to insulin receptor resistance, particularly in tissues like muscle and liver.

However, if this prolonged insulin secretion lowers glucose levels during fasting and at night, this might balance out daytime spikes in glucose resulting in an average glucose level that appears normal or near-normal.

I am just hypothesising here, but it’s an interesting idea that the reason ME patients tests come back normal isn’t because there is nothing wrong but because the tests are not picking up on a problem.

In cases of prolonged insulin secretion due to genetic variants, doing a fasting insulin test and also insulin tests at one, two and three hours after a OGTT could be a better indication of a problem. Would need a large study and comparison to healthy controls.

 

[Deanne NZ]

Pizza is not an ideal food to test your response because from what I understand the high fat content slows the digestion/absorption of the carbs & slows & prolongs the insulin response. It is a notoriously difficult food for Type 1 diabetics to dose for.
Try a similar test with boiled sweets or a sweet fizzy drink and away from a meal so that you are looking at the response purely to carbs.

 

[Yan]

Pizza is not an ideal food to test your response because from what I understand the high fat content slows the digestion/absorption of the carbs & slows & prolongs the insulin response. It is a notoriously difficult food for Type 1 diabetics to dose for.
Try a similar test with boiled sweets or a sweet fizzy drink and away from a meal so that you are looking at the response purely to carbs.

Mine was low fat. I made it 1/4 rye flour, 3/4 wheat flour. Tomato sauce, seafood and vegetable toppings. No cheese

 

[Jonathan Edwards]

@Jonathan Edwards in your experience do you know if this is in any way unusual?

You have managed to identify a subject on which I am totally ignorant.

Maybe we should discuss insulin resistance a bit more. There must be some experts here. It came up on Chris Ponting's proteomics study for ME/CFS.

 

[chillier]

Here are some of the pieces of relevant literature that I am aware of:

Beentjes and Ponting's recent preprint of blood factors in the UK biobank cohort. Many of the findings in the 'blood biochemistry' section are associated with insulin resistance including high(er) glucose, hba1c, and a high ratio of triglycerides to HDL cholesterol:

In this paper we feel quite far away from the raw data and it's been fairly pointed out that the signal could be coming from issues of specificity within the cohort. We can at least get a feel of the raw data for Triglyceride to HDL cholesterol ratio and TyG (a composite score of triglycerides and glucose) from these cumulative density plots:

The shift to the right of the curve for TyG for instance I think might suggest it's a population wide effect (whole normal distribution shifted to the right).

Precision life's genetic study on the UK biobank. 1 of the 14 identified genes is the insulin receptor INSR. Others are plausibly linked to insulin resistance. ATP9A and USP6NL for example are both involved in recycling RTK type receptors (which INSR is) from endosomes back to the plasma membrane:

This is from the same cohort as above so the same specificity concerns apply, however...

It's replicated in Precision life's long covid genetic study

 

[chillier]

In Armstrong et al 2015's metabolomics study (n=34 patients n=25 controls) in ME the only significantly elevated metabolite they see in the blood is glucose (phenylalanine/glutamate/hypoxanthine significantly low):


In Germain and Hanson 2022's 2 day CPET metabolomics study 1 of the 7 metabolites significant after multiple testing correction is 1,5 anhydroglucitol. (C = control, P = patient, left is total, middle female only, right male only)

Low levels indicates that an individual has had a hyperglycemic event in the previous 2 weeks. The molecule is metabolically inert and contained in food, but resembles glucose in structure. it competes with glucose for reabsorption into the blood in the kidney, such that if glucose levels are high, blood levels of 1,5 anhydroglucitol decrease.

In Hoel and Tronstadt 2021's metabolomics study they do not see high glucose levels, but do see high triglyceride levels. They also measure metabolism associated hormones and see high insulin, leptin and others:

 

[butter.]

ME patients can't utilize sugar and fats normally, are we surprised to find 'insuline resistance?' If you eat sugar, and your cells can't utilise it (for potentially a whole bunch of reasons) your BS will rise. Increased BS doesn't automatically indicate IR though, it also doesn't help that IR itself is poorly understood.

 

[Trish]

ME patients can't utilize sugar and fats normally

I haven't seen evidence of this.

 

[Amw66]

ME patients can't utilize sugar and fats normally, are we surprised to find 'insuline resistance?' If you eat sugar, and your cells can't utilise it (for potentially a whole bunch of reasons) your BS will rise. Increased BS doesn't automatically indicate IR though, it also doesn't help that IR itself is poorly understood.

I would turn that on it's head .
ME patients can't utilize glucose properly , which means the body has to workaround via either utilising fats, and / or protein.

Protein break down seemingly affects insulin requirements - diabetics may have to dose higher insulin for a protein rich diet than for a keto one . Keto can put type 2 into remission for some.

Tagging @mariovitali , as liver has a key role in all these scenarios .

 

[SNT Gatchaman]

Another potential tie-in with insulin resistance is The metabolic and physiologic impairments underlying long COVID associated exercise intolerance (2024, Pulmonary Circulation) —

Overall, the findings of the current study suggest that the increased reliance on anerobic metabolism during exercise extends beyond our current understanding of Long COVID pathobiology, which thus far, has primarily implicated abnormal mitochondrial oxidative phosphorylation.

We also demonstrated that peak venous succinate is significantly correlated with peak VO2 in long COVID patients (r = 0.68; p= 0.0008). Figure S2. While succinate release during exercise has been previously demonstrated, its mechanistic or prognostic significance is poorly understood. Few groups have provided a rationale and supportive data demonstrating this. 33 Reddy et al 34 demonstrated that succinate is significantly correlated with post‐exercise glucose tolerance in humans, which has important implications for linking succinate release at maximal exercise to glucose tolerance— suggesting a potential exercise‐related biomarker for severity of glucose intolerance. To our knowledge, our study demonstrates for the first time, the significant correlation between maximal exercise capacity and peak succinate release. This provides potential evidence for an exercise responsive, blood‐based biomarker for long COVID associated exercise intolerance.

Refs 33, 34 below.

Relevant portion of figure S2 is —



The orange dots are patients who had mild acute disease, green severe/hospitalised acute illness, but all similar LC status had normal results for their long Covid evaluations (mean 468 days from infection) —

All subjects had previously experienced acute SARS‐CoV‐2 infection confirmed by polymerase chain reaction testing and undergone investigative testing that did not explain their persistent exertional intolerance (i.e., unremarkable pulmonary function test, computed tomography chest, noninvasive CPET, cardiac stress testing, and echocardiogram).

[33] is Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel | PubMed Central (2022, Nature Chemical Biology)

[34] is pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise (2020, Cell) —

Notably, we found a significant correlation between peak exercise succinate concentration in muscle femoral vein during exercise and insulin sensitivity post-exercise. This association between peak venous succinate and insulin sensitivity was distinct among all covariates tested and occurred in the absence of correlations with maximum VO2 and peak muscle load. Based on these findings, we examined whether succinate-SUCNR1 signaling regulates post-exercise insulin sensitivity. We found that post-exercise insulin sensitivity was blunted in SUCNR1 KO mice, which also exhibited modest basal glucose insensitivity. Notably, previous examinations of SUCNR1 KO mice have established glucose insensitivity that depends on obesogenesis initiated by high-fat feeding, which occurs without changes in insulin tolerance. Therefore, the role of extracellular succinate-SUCNR1 signaling in insulin sensitivity observed here may be specific to the exercise response.

 

[alex3619]

Try a similar test with boiled sweets or a sweet fizzy drink and away from a meal so that you are looking at the response purely to carbs.

Current glycosylation testing is only for glucose, and fizzy drinks often contain a lot of fructose. Fructose is very much more glycating, and persists longer because only the liver can convert it. In doing so it damages the liver, using up ATP and resulting in uric acid. So be careful interpreting a high fructose meal and blood glucose. You can measure the glucose but not the fructose, and there is growing evidence that fructose is much more dangerous than glucose. New tests are apparently on the way to also measure fructose glycation, but I do not know how far away they are.

As a reminder, table sugar or sucrose is a compound of both glucose and fructose.

 

[alex3619]

In Armstrong et al 2015's metabolomics study (n=34 patients n=25 controls) in ME the only significantly elevated metabolite they see in the blood is glucose

I have been thinking about this a fair bit, but from another angle. I also have type 2 diabetes. If ME involves mitochondrial suppression, and elevated lactate release, then there are several problems.

First, energy demand will drive glycolysis and not the mitochondria. Limitations of blood supply will also impede glucose oxidation.

In healthy people the lactate can be used by any tissue with a mitochondria, so not red blood cells. The brain can easily use it. If we have mitochondrial suppression in a range of tissues, then we will not rapidly clear the lactate. That means much more gets back to the liver. This will drive the Cori cycle, as the liver will convert lactate to glucose. It can then become converted to fat, so it may contribute to fatty liver, or raise blood sugar levels. Which then put pressure on glycolysis.

Also, keep in mind that vitamin C and glucose are both absorbed by the GLUT4 receptor if I recall correctly, though exercising muscle can bypass this. We don't exercise though. So we may need additional vitamin C if we want to protect our mitochondria from oxidative stress, though C works in combination with a minimum of 4 other compounds.

By the way, I have never heard of an ME patient with lactic acidosis. We seem to have elevated bicarbonate buffering to prevent this.

My big problem with type 2 diabetes is gluconeogenesis, I eat very low carbs. Since the pancreas in type 2 diabetes has uncoupling between alpha and beta cells we can make glucagon and insulin at the same time. Glucagon can induce gluconeogenesis. In most people this is mainly from glycerol. I suspect in us its greatly from lactate.

Mitochondrial suppression, if present, and elevated lactate, if present, might well drive glucose higher.

 

[Turtle]

30 years ago I had a 3 hour Glucose Tolerance Test. Started at 5,2 went up to 10,8. The doc suspected hypo glycaemia.
5 years ago I was diagnosed with diabetes II.
That took a long time to develop.

Succinate and Reverse Elektron Tansport in ischemia and reperfusion?
RET takes up to 5 times more energy, sounds (somewhat) familiar.

 

[Nightsong]

Another potential tie-in with insulin resistance is The metabolic and physiologic impairments underlying long COVID associated exercise intolerance (2024, Pulmonary Circulation) —

After seeing the Beentjes result, I've also been looking for signs of insulin resistance and related metabolic findings in patient populations that will likely include some pwME, such as Long COVID and POTS. In "Worsening Postural Tachycardia Syndrome Is Associated With Increased Glucose-Dependent Insulinotropic Polypeptide Secretion" (Hypertension, 2022) a POTS patient cohort was found to have greater insulin resistance than controls (Matsuda index 3.8 ± 1.0 vs 5.1 ± 1.3, p=0.009), along with higher levels of three gastrointestinal hormones (glucose-dependent insulinotropic peptide, peptide YY, pancreatic polypeptide). I don't recall any study assessing these in pwME.

This was mentioned in a very recent review in the Autonomic Neuroscience journal, which, while off-base in many respects, included references to this & a number of other interesting metabolic findings that I hadn't come across before.

 

[Yann04]

pancreatic polypeptide

I think this one can be influenced by diet.

Ie. Bütler 2024

 

[Murph]

I got a continuous glucose monitor ($15 introductory price) and so far (only 48h so far) it has been fascinating. I don't seem to have glucose problems in the day or when I eat a bunch of carbs. But at night if I wake up feeling thirsty apparently my blood sugar is low.

I wake up, visit the bathroom, drink water, fall back asleep and my blood sugar ... recovers! from water alone!

My take: this is a dysautonomia thing - I drink salty water all day but at night I don't, my blood pressure falls, and **somehow** that circulatory problem also leads to a blood sugar slump.

anyone got any insights on dysautonomia and blood glucose?

 

[Amw66]

I got a continuous glucose monitor ($15 introductory price) and so far (only 48h so far) it has been fascinating. I don't seem to have glucose problems in the day or when I eat a bunch of carbs. But at night if I wake up feeling thirsty apparently my blood sugar is low.

I wake up, visit the bathroom, drink water, fall back asleep and my blood sugar ... recovers! from water alone!

My take: this is a dysautonomia thing - I drink salty water all day but at night I don't, my blood pressure falls, and **somehow** that circulatory problem also leads to a blood sugar slump.

anyone got any insights on dysautonomia and blood glucose?

At night your body is fasting so glucose has to come from the liver . Slightly different process