Sciencemadness Discussion Board

Glycated hemoglobin, HbA1c levels

wg48temp9 - 30-10-2019 at 01:45

I am investigating how high blood glucose levels increase the level of glycated hemoglobin in blood cells as measured by a HbA1c test.

I can not find the relationship between them. My initial assumption is that it first order meaning the glycanation is proportional to time and glucose level for time intervals that are small compared to the average replacement time of red blood cells.

Does anyone have insights in to this they would like to share?

See wiki https://en.wikipedia.org/wiki/Glycated_hemoglobin

Metacelsus - 30-10-2019 at 03:27

The reaction is Schiff base formation followed by https://en.wikipedia.org/wiki/Amadori_rearrangement

It should be first order in glucose. See for example: https://pubs.acs.org/doi/pdf/10.1021/jf960458d

Fery - 30-10-2019 at 10:49

Glycated hemoglobin is long term marker of diabetes compensation. Glycaemia tells about last few hours, but glycated hemoglobing about last months. So if a patient disobeys diabetic diet, does not take peroral antidiabetics / insuline for months and follow them only the last day, doctor could find glycaemia within interval, but glycated hemoglobin too high. Healthy people have glycated hemoglobin less than 6% and when a patient with diabetes has is 10% it is still good result.
Biological halftime of erythrocyte is 120 days.

wg48temp9 - 30-10-2019 at 13:09

Quote: Originally posted by Fery  
Glycated hemoglobin is long term marker of diabetes compensation. Glycaemia tells about last few hours, but glycated hemoglobing about last months. So if a patient disobeys diabetic diet, does not take peroral antidiabetics / insuline for months and follow them only the last day, doctor could find glycaemia within interval, but glycated hemoglobin too high. Healthy people have glycated hemoglobin less than 6% and when a patient with diabetes has is 10% it is still good result.
Biological halftime of erythrocyte is 120 days.


Are the erythrocytes removed randomly or in response to aging?


I am a type 2 diabetic with diet and metformin medication to control it, however I have experienced a few hypos (low blood glucose levels) after my metform was increased based on my high HbA1c levels. I want to fully understand how my blood glucose levels relate to my HbA1c levels.

Now I suspect my hypos are simply the combined response of my doctor increasing my medication and my response of reducing my calorie intake in response to the high HbA1c level and lower activity levels due to a leg injury.

I think what I can assume for my model is that a fraction of the HbA1c is removed each day based on the replacement rate of the erythrocytes. That will produce an exponential decay in the HbA1c with step increase due to meals. Trying to relate the size of the step to the meal will be tricky. Perhaps measurements of blood glucose after a meal will help . I may have to add the effect of the liver releasing glucose too.

I need to find the paper that relates the HbA1c to a blood glucose level. It would also be useful to know what the dose related response to metformin is.

[Edited on 10/30/2019 by wg48temp9]

[Edited on 10/30/2019 by wg48temp9]

diddi - 30-10-2019 at 17:54

i am Type I for many years now. so the reason for my diabetes is different, but the symptoms and potential complications are the same over all. if you are newly diagnosed your HbA1c may be high. this is a reflection of the amount of glucose present when new red cells are being formed. because the red cells have a life of 3 or 4 months, you cannot really do anything on a short term scale to change A1c overnight. it is like a moving average so it only reflects change slowly.

If you are on metformin then your dr deems that the insulin pathway is impeded by fat cells and metformin reduces the way fats interact with insulin. in your case as a type II it is reasonable if you are under 50 years old that your pancreas works fine, but that the pathway is blocked.

The best ways to improve your outcomes are to generally reduce your carb intake (not just sugar intake) and to engage in some exercise. i walk for exercise because i am past the heavy sports and training. mind is willing but the body is reluctant :). after 3 months you should see improvement in A1c just by doing these 2 steps. you will find metformin may be totally withdrawn in patients who can achieve low carb intake and reduce their body weight. for me, a difference of 2-3kg is enough to effect how i am feeling. if the metformin is causing hypo then imo i would reduce dose (that is if you choose to try the 2 steps above)

in terms of blood testing, there is no point in checking until 2 hours after a meal. what you will need to do is test before and 2 hours after if you want to check the way your body deals with a particular meal. as i already said if you reduce carbs there will be an immediate and direct correlation between carb reduction and glucose levels @ 2 hours post meal.

happy to assist further or by PM if you like. Cheers!

Fery - 31-10-2019 at 09:18

wg48temp9 old erythrocytes are detected because of their membrane and are removed from circulation when passing spleen, liver, lymphatic nodes
there is no need to obtain correlation between glucose blood level and glycated hemoglobin level - both of them must be examined
C-peptide before and after food tells whether pancreas is producing insulin or not and whether its level is increased after food (when there is insulin resistance the level of insulin could be even higher than in healthy people but its effect is blocked, in the beginning the pancreas tries to increase insulin level to compensate insulin resistance but then Langerhans cells of pancreas are exhausted)
also lactate should be examined when taking metformin
also vitamin B12 if you take metformin for years (risk of B12 hypovitaminosis is not well know fact)

wg48temp9 - 31-10-2019 at 23:19

Quote: Originally posted by diddi  
i am Type I for many years now. so the reason for my diabetes is different, but the symptoms and potential complications are the same over all. if you are newly diagnosed your HbA1c may be high. this is a reflection of the amount of glucose present when new red cells are being formed. because the red cells have a life of 3 or 4 months, you cannot really do anything on a short term scale to change A1c overnight. it is like a moving average so it only reflects change slowly.

If you are on metformin then your dr deems that the insulin pathway is impeded by fat cells and metformin reduces the way fats interact with insulin. in your case as a type II it is reasonable if you are under 50 years old that your pancreas works fine, but that the pathway is blocked.

The best ways to improve your outcomes are to generally reduce your carb intake (not just sugar intake) and to engage in some exercise. i walk for exercise because i am past the heavy sports and training. mind is willing but the body is reluctant :). after 3 months you should see improvement in A1c just by doing these 2 steps. you will find metformin may be totally withdrawn in patients who can achieve low carb intake and reduce their body weight. for me, a difference of 2-3kg is enough to effect how i am feeling. if the metformin is causing hypo then imo i would reduce dose (that is if you choose to try the 2 steps above)

in terms of blood testing, there is no point in checking until 2 hours after a meal. what you will need to do is test before and 2 hours after if you want to check the way your body deals with a particular meal. as i already said if you reduce carbs there will be an immediate and direct correlation between carb reduction and glucose levels @ 2 hours post meal.

happy to assist further or by PM if you like. Cheers!


Thanks for your input. No I am not newly diagnosed. I have been on metformin for about 5 years starting with 500mg per day of metformin then 1g per day and recently for 3 months 2g per day which was then reduced back to 1g per day no reason given. I am 70 years old ex workout, ex squash player, ex cyclist and now my dog will not do long walks due arthritis which is Ok with my knees as now they don't like long walks too. I have a BMI of 26 thats one over top end of the healthy range. I had been calculating my BMI using my wrong height apparently I have shrunk about 40mm. I need to loose about 5kg and that will improve my HbA1c levels. About 1.5kg of extra weight is my swollen knee. I have done the diabetic reading and day courses so I know all the usual advice but it does not hurt to be reminded.

TBC later, I am late for breakfast.

PS; Pre meal 6.4mmol/l that's in range. Below is a graph of my glucose over about the last week.
BG1.JPG - 24kB
The interval between vertical lines is a day. The green area is normal range, the horizontal central line of the green area is 6mmol/l, the interval between horizontal line is 2mmol/l, after the first hypo I stopped taking metformin pending discussion with my doctor. The peaks correspond to about 0.5h after a meal and the lows are usually before breakfast. There are missing data points probably my finger trouble.

[Edited on 11/1/2019 by wg48temp9]

diddi - 1-11-2019 at 02:45

seems you are high after your evening meal. i would consider your choices for that meal. also what time of day do you take metformin. it might be useful to ask doc about splitting dose? not sure as i am not on metformin

wg48temp9 - 2-11-2019 at 01:43

Quote: Originally posted by diddi  
seems you are high after your evening meal. i would consider your choices for that meal. also what time of day do you take metformin. it might be useful to ask doc about splitting dose? not sure as i am not on metformin


That hyper was caused by a baked potato partly as an experiment and partly because I like baked potatoes. I am not taking my metformin at the moment pending discussion with my doctor and to see what my glucose levels are with out it. Baked potatoes will probably be removed from my diet at least until I am back on metformin.

I suspected metformin reduces fasting glucose levels as some papers suggest it main action is to inhibit the release of glucose from the liver. It is also frequently stated that it has a low risk of hypos but its the release of glucose from the liver that maintains fasting glucose levels.

I found a paper that states metformin can reduce fasting glucose levels on average by 25% and up to 35% in some cases also confirmed by my pharmacist though I suspected she had been reading the same paper.

Though the usual advice on taking metformin is to take it with food in the mornings my doctor advised me to to take 500mg with breakfast and 500mg with my evening meal to reduce gastric side effects (diarrhea). I also note the average half life plasma levels are reached in 6.2 h while the half life in red blood cells ranges from 18.5 to 31.5 hours. If I go back on 1g of metformin I will try to take the 1g in the mornings to reduce the risk of morning hypos (before breakfast) from the 500mg evening dose the day before. i can not find that paper at the moment.


I also found a paper on the variability of blood glucose levels with time and the level of variability varies between individuals. It also confirmed that the HbA1c levels are determined by the time averaged glucose levels.
Attachment: Glucose-Variability-502.full.pdf (1.1MB)
This file has been downloaded 583 times

[/url]

Note: the HbA1c are the same for both but the variability is very different.
You must divide the vertical scale by 18 to convert it mmol/l .

[Edited on 11/2/2019 by wg48temp9]

wg48temp9 - 2-11-2019 at 02:52

Quote: Originally posted by Fery  
wg48temp9 old erythrocytes are detected because of their membrane and are removed from circulation when passing spleen, liver, lymphatic nodes
there is no need to obtain correlation between glucose blood level and glycated hemoglobin level - both of them must be examined
C-peptide before and after food tells whether pancreas is producing insulin or not and whether its level is increased after food (when there is insulin resistance the level of insulin could be even higher than in healthy people but its effect is blocked, in the beginning the pancreas tries to increase insulin level to compensate insulin resistance but then Langerhans cells of pancreas are exhausted)
also lactate should be examined when taking metformin
also vitamin B12 if you take metformin for years (risk of B12 hypovitaminosis is not well know fact)


My previous doctor actively discouraged my measuring my glucose levels. I agree with you that both HbA1c (glycated hemoglobin) should be measured.

I do want the relationship between my glucose blood level and HbA1c as my HbA1c levels are only tested one to two times a years which is too infrequent for me to judge how successful changes in diet exercise and medication is. Almost immediate negative feedback is more effective than having to wait upto a year

I don't think I have had a C peptide test. I will ask my doctor about it but then I have never had a glucose tolerance test by my doctor that I can remember. I plan on doing one myself .

Apparently I can hold my fasting glucose levels at about 6 mmol/l (not on metformin) but my islets of Langerhans cells are too exhausted to control the glucose highs and or I have insulin resistance.

I have at least a yearly blood tests I will check that it includes lactate and B12 tests. Thanks Fery.

Fery - 2-11-2019 at 09:57

Hi wg48temp9, glucose tolerance test is necessary when in doubts. When you had your glucose level like 10 mmol/l the diagnosis of diabetes mellitus was clear and then glucose tolerance test was unnecessary.
Testing B12 is not well known, the stock of this vitamin in liver is IIRC for about 5-10 years so the vitamin could be depleted after few years and metformin slightly increases the risk of B12 depletion.
Lactate is usually tested, metformin side effect of lactate acidosis is well known.

wg48temp9 - 4-11-2019 at 08:14

Here is paper describing a model of the glucose control system. I am unfamiliar terminology used in the paper but as I have a background in control systems I can probably understand it eventually. It may be useful to may understanding and control of the variability of my glucose levels,
Attachment: glumodel-cobelli2014.pdf (1.7MB)
This file has been downloaded 568 times

Can someone explain what the significance of adrenaline/epinephrine is in glucose control? I have not found it with a google search.

Fery - 4-11-2019 at 09:05

Hi wg48temp9, adrenaline increases blood glucose level. It is stress hormone which prepares human body to fight/escape.

wg48temp9 - 4-11-2019 at 10:03

Quote: Originally posted by Fery  
Hi wg48temp9, adrenaline increases blood glucose level. It is stress hormone which prepares human body to fight/escape.


Including "stress" in the search I found this on the subject:

https://dtc.ucsf.edu/types-of-diabetes/type2/understanding-t...

I did wounder how on occasions in the past, when I have had a hypo and did not know what it was, I could push through it and recover to some extent. I wounder if that was the stress response.

[Edited on 11/5/2019 by wg48temp9]

Fery - 5-11-2019 at 01:27

Hi wg48temp9, yes hypoglykemia leads into stress reaction, relasing adrenaline (and also other substances) so then the body normalises glykemia (relatively quickly from liver glycogen in case it is not already depleted). Most of the responses in human body are under back loop control.

wg48temp9 - 5-11-2019 at 03:09

Quote: Originally posted by Fery  
Hi wg48temp9, yes hypoglykemia leads into stress reaction, relasing adrenaline (and also other substances) so then the body normalises glykemia (relatively quickly from liver glycogen in case it is not already depleted). Most of the responses in human body are under back loop control.


Yes its fascinating, nested control loops usually each with a different response time that's required for loop stability and with back up systems. Even control loops at the cellular level of synthesis. Usually a very robust system until it runs out of control action or something critical goes wrong.

Hopefully I can tweak my glucose control loops with medication and by limiting the required control action stay close to homeostasis and stop testing my emergency back up systems.

wg48temp9 - 5-11-2019 at 23:49

My measured BG occasionally has small peaks and dips for no obvious reason. This morning I measured the same spot of blood three times.

The result was 7.2, 7.2 and 8.5 mmol/l. Ok no measurement is perfect but that's too large an error.

PS I should add the high reading was the last one by that time the spot of blood had been on my finger for about 30s.



[Edited on 11/6/2019 by wg48temp9]

Metacelsus - 6-11-2019 at 17:33

Hmmm, maybe some water was lost by the time of the third measurement, and the concentration was therefore higher?

wg48temp9 - 7-11-2019 at 01:59

Quote: Originally posted by Metacelsus  
Hmmm, maybe some water was lost by the time of the third measurement, and the concentration was therefore higher?


This morning I took two measurements from a single spot of blood about one minute apart, the result 6.5 and then 7.7 mmols/l. So something may be effecting the later reading.s Perhaps it is evaporation or temperature or a clotting reaction.

I did have a habit of pricking first and then getting a test strip out and sometimes I would fiddle about getting the test strip out of the container hence delaying the time to test the spot of blood. The test strips are moisture sensitive so I figured minimise the time they are out of the special container lined with desiccant.

I also had a problem yesterday using old urine test strips for ketones. Ouch death levels. Old strips quickly replaced by expensive new ones from a locale pharmacy (cheaper on ebay) who told me to go to hospital which I ignored. With the new strips, zero ketones on two tests.

Thinking about the ambient temperature in my test area. Its very variable first thing in the morning and I am near the air flow of a fan heater that may be on or off depending on the temperature. I will have to set the time switch to an early period and redirect the fan heater so the temperature is more stable and add a temperature display Oh and not use old opened test strips blood or urine.

PS: The test strips are supposed to be used between 10C to 40C. After a cold night first thing in the morning the temperature in my test area could be climbing rapidly from below 10C.

Fery - 7-11-2019 at 04:25

Personally if I was stung into my finger repeatedly, my blood glucose level would be certainly increasing progressively because feeling veeeeery uncomfortable and stressed. I hate any medical procedures concerning my body even I know they are necessary and I know and understand them into details. I realize that. Someone else maybe does not realize that but the stress could be there unaware.

wg48temp9 - 8-11-2019 at 03:40

Quote: Originally posted by Fery  
Personally if I was stung into my finger repeatedly, my blood glucose level would be certainly increasing progressively because feeling veeeeery uncomfortable and stressed. I hate any medical procedures concerning my body even I know they are necessary and I know and understand them into details. I realize that. Someone else maybe does not realize that but the stress could be there unaware.


I used to faint at the sight of my blood but I am now old enough to have collided with the sharp corners of reality frequently enough to have toughened up or become desensitized

My new doctor is a disappointment. Having just handed me a sheet for a HbA1c blood test I asked if the blood tests include a B12 test. She took the sheet back and while writing on it said "Oh I suppose we should be checking that". Its called a B12/folate test which reminded me I have had one such test previously. Prior to that test I was asked to stop taking any vitamin supplements that contain folate for a month (from memory) prior to the test. My new doctor did not tell me that. My sister says general practice doctors are the useless doctors that can not get jobs in hospitals. I also asked about a C peptide test and alternatives to metformin that will not give me hypos but my time was up "Ok lets not worry about that now goodbye"

On a vaguely related subject I had an appointment with podiatrist yesterday. A brand new one fresh from uni. She checked the blood flow to my big toes with a ultrasound doppler device. I asked her a question about the 1, 2 or 3 sounds thing. Wow she was delighted to explain it to me and let me listen again to the sounds. I will be seeing her again when she will be pulling the fungi ingrowing nail off my big toe and using phenol to kill the nail bed, crude but allegedly effective. Ouch !! when I got phenol on my hand it hurt for weeks.

Tsjerk - 8-11-2019 at 04:25

Quote: Originally posted by wg48temp9  


On a vaguely related subject I had an appointment with podiatrist yesterday. A brand new one fresh from uni. She checked the blood flow to my big toes with a ultrasound doppler device. I asked her a question about the 1, 2 or 3 sounds thing. Wow she was delighted to explain it to me and let me listen again to the sounds. I will be seeing her again when she will be pulling the fungi ingrowing nail off my big toe and using phenol to kill the nail bed, crude but allegedly effective. Ouch !! when I got phenol on my hand it hurt for weeks.



Phenol works like a charm, but don't worry about the pain, I guess it will be much better than the pain of the nail. I had no problems with it after a couple of paracetamols.

wg48temp9 - 8-11-2019 at 04:54

Quote: Originally posted by Tsjerk  
Quote: Originally posted by wg48temp9  


On a vaguely related subject I had an appointment with podiatrist yesterday. A brand new one fresh from uni. She checked the blood flow to my big toes with a ultrasound doppler device. I asked her a question about the 1, 2 or 3 sounds thing. Wow she was delighted to explain it to me and let me listen again to the sounds. I will be seeing her again when she will be pulling the fungi ingrowing nail off my big toe and using phenol to kill the nail bed, crude but allegedly effective. Ouch !! when I got phenol on my hand it hurt for weeks.


Phenol works like a charm, but don't worry about the pain, I guess it will be much better than the pain of the nail. I had no problems with it after a couple of paracetamols.


You must be made of stronger stuff than me. Paracetamol for me only if it comes with 60mg of codeine or better yet oxycodone.

wg48temp9 - 9-11-2019 at 01:42

Oh WTF. Apparently I should expect a normal test solution to read between
5.9 to 9 mmol/l and a high test solution to read 15.1 to 22.8 mmol/l !!!

wg48temp9 - 14-11-2019 at 02:32

I have been careful to have a more constant temperature in my test area. But Apparently its not having much effect. One reading was 2.8mmols/l which I assume was wrong as I did not feel like I was in a coma LOL. When I repeated the test it was 7.1.

So I fired up an old meter to compare results, 8.4 on one of them 6.1 on the other. The test strips for the old meter were a year out of date so I can not draw any conclusions other than I have a measurement problem.

There are semi continuous reading devices available such as FreeStyle Libre but its about 50 pounds for the sensor that only works for 20 days which is actually less than the cost of the test strips I presently would use over the same period. But I can not find any info on the accuracy.

I think I will talk to help line of the meter manufacturer.