lucylocket61
Expert
- Messages
- 6,435
- Type of diabetes
- Type 2
- Treatment type
- Diet only
I do hope that, as this information sounds important, someone will translate it into easier language.
Interesting report on insulin and weight loss
- Thread starter Oldvatr
- Start Date
- Messages
- 8,470
- Type of diabetes
- Type 2
- Treatment type
- Tablets (oral)
I will have a go at describing it, but as you point out it is written in a style that gives the impression of describing everything in detail, but obfuscates it so as as to confuse the novitiate such as me.
I will be referring to the figures in the following page of the report
https://link.springer.com/article/10.1007/s00125-011-2204-7
Looking at Fig 2a, this shows the glucose levels that were measured in the blood as the test progressed.
There are two sets of results being displayed. The lower graph shows the non diabetic controls starting at the baseline 4.6 mmol/l at time (0) and the diabetic subjects starting at 7 mmol/l at time(0). at Time(0) both levels of glucose were raised by 2.8 mmol/l above their level at tim(0)., and the graph shows the average that each group reached according to the readings of blood plasma taken at the times stated in the text. The bars above and below the markers show the variation in the readings from the average value.
Looking at figure 2b this shows the insulin responses to the changes in glucose described in fig 2a above.
Fig 2b is showing the response from the non diabetics taken at baseline. This was the only time this group was tested.
The period from t(0) to t(10) show the fast sampling period to catch the first insulin phase response which normally only lasts 10 minutes. The time t(10) to t(20) is showing a slower sample rate. IMO if they had continued fast sampling here, then the fall off from the peak would have been sharper, but the 20 min delaty gives a slower decline that I believe is misleading. At t(30) the second step in glucose occurs and this second section also has the arginine added. The period from t(30) to t(40) should normally show another first phase response which these normal non diabetics should be showing, but for some reason it is missing.
The purpose of arginine is normally to suppress the second phase but allow the first phase through as normal. But it is missing even in the non diabetic group. The other thing to note is that the second stage response in the first step is also missing. I presume that because the second step is occurring too soon after the first part of the test, then it superimposes on top of the first part. So at time t(30) the beta cells are trying to give both the second stage from part 1 and also the first response to part 2. But we see neither occurring. What we see is that at t(60) the arginine gets stopped, and suddenly the beta cells are free to output whatever they have being held back, and it all comes out in a rush. So the peak of the second part is greater than the first part, and is artificially high (IMO). The peak at t(60) is short lived and seems to be a phase 1 response, and we do not see the phase 2 response to the second step because the measuring stops. We also do not see any phase 2 response from the first step. Note that a phase 2 response normally lasts 2 to 3 hours after a step change so this whole test has ignored or squeezed the second phase response into a super phase 1 response at t(60). I am not happy that this is a valid test. But it may just be showing that when the output gate opens at t(60) then it shows the dam burst and hence maximum possible output flooding out. Not convinced tht this is representing what happens under normal circumstances.
What figures 2c to 2f show is the same as fig 2b but for the diabetic subset averaged . but at different intervals of the trial. It does indeed show that the first response in insulin does improve for this group. What I take from this set is that since fig 2b has no first reponse either, then this set of graphs actually shows is NOT that beta cell production improves as claimed, but thaqt whatever stops the phase 1 response from happening has improved.
My reseach into the beta cell kinase continues, but from that I have learnt so far, the controlling enzymes for the phase 1 and phase 2 responses are different, and have different triggers. Phase 1 is controlled by potassium, and phase 2 is controlled by calcium. Different mechanisms. Arginine interferes with the calcium transfers, but not the potassium, so what happened to the normal people? Looking at a similar experiment by another team than ND show different results but they did not superimpose their tests like the ND did. Their results curves are very different.
I am beginning to think that the test method used in ND is suspect, and is producing artifacts that are being interpreted wrongly.
- Messages
- 8,470
- Type of diabetes
- Type 2
- Treatment type
- Tablets (oral)
Having researched several similar studies into beta cell function, my curiosity was aroused when I noticed that the units used by Roy Taylor in the ND trial to express Insulin Secretion Rate (ISR) were different from those used by others for the same parameter. He used [nmol min−1 m−2] whereas the others used [nmol min−1] . The difference is in the range of values, and the apparent extra division by what appears to be an area term
in an interview he gave he explained that the results were processed using a deconvolution corrector called Body Surface Area (BSA) to reduce the effect of obesity on the c=peptide results (as noted in a post I made above). Now during the actual clamp test part of the experiment that is a valid correction to make since during the hour or so of the test. this parameter will reflect the c-peptide measured at the time. It allows cross comparison between members of the test cohort
Where it falls down is if the BSA value changes during the whole study and any follow on re-tests. It is particularly important that it does not change as a result of the intervention If it does change over time, then this must be taken into consideration when making any claims for the intervention.
Having looked further into how BSA is evaluated, I found that there are three different formulae that can be used to calculate BSA. One thing these formulae have in common is that they multiply height by weight (similar to BMI calclulation) but express the term as "per square metre" as we see in the Taylor results for ISR.
So if any of these formulae are used, then there is a direct link to the main parameter being controlled by the intervention, namely body weight loss. So as body weight decreases over time, so the ISR will appear to increase by a factor directly tied to the change in weight.
For example, if the c-peptide rate is represented by Xn, and the BSA by Yn then during the actual day of the clamp test Xn/Yn will be valid for all the participants. A week later the test is repeated and we get a different X1/Y1, and when it is repeated a year later we get Xn/Yn.
Just assume for the moment that the beta cell output does not change at all over the 2 years, but the weight average drops by 15%, then there will be a change in Y that reflects this, so the ISR will be observed to have improved over time. If however, there is no weight change between year1 follow up, and year2 follow up, then there will be no change in ISR as a result, and this is indeed what Roy Taylor reports in the 2 year follow on report.
Since he reports that the weight did not change, and the ISR remained steady, then we can theorize that the ISR also remained unchanged. So does the apparent improvement in Beta Cell recovery show an actual real improvement, or is it simply due to weight loss due to the diet. In other words, is Roy Taylor making claims for Beta Cell recovery that are simply artifacts of his experimental method?
I am postulating this. I have no concrete evidence that they used any of the formulae for BSA as I have described above. But they did appear to use a software program called ISEC, and the writers of that package do confirm that along with c-peptide and time interval parameters, it does use height and body weight to adjust the results to give the Roy Taylor version of the ISR units.
I have manually cranked the BSA formuae to see what effect a 15% change in body weight with constant height will do to the result, and the results show a variance of between 6.6% and 8.02% for a person of 100kg and 1,7m height at start.
As I noted in other studies into c-peptide, the beta cell output also reduces with weight loss, but I cannot find any quantitative values to apply. This will have the effect of reducing the c-peptide, and also the ISR raw value before correction. so will conteract the error I reported above. So they couneract each other, but may not cancel out. We do see that the Table of macro values in the ND study do show that c-peptide reduced over time, but was this due to weight loss or improvement in insulin resistance (insulin sensitivity ) as also claimed in the ND study?
in an interview he gave he explained that the results were processed using a deconvolution corrector called Body Surface Area (BSA) to reduce the effect of obesity on the c=peptide results (as noted in a post I made above). Now during the actual clamp test part of the experiment that is a valid correction to make since during the hour or so of the test. this parameter will reflect the c-peptide measured at the time. It allows cross comparison between members of the test cohort
Where it falls down is if the BSA value changes during the whole study and any follow on re-tests. It is particularly important that it does not change as a result of the intervention If it does change over time, then this must be taken into consideration when making any claims for the intervention.
Having looked further into how BSA is evaluated, I found that there are three different formulae that can be used to calculate BSA. One thing these formulae have in common is that they multiply height by weight (similar to BMI calclulation) but express the term as "per square metre" as we see in the Taylor results for ISR.
So if any of these formulae are used, then there is a direct link to the main parameter being controlled by the intervention, namely body weight loss. So as body weight decreases over time, so the ISR will appear to increase by a factor directly tied to the change in weight.
For example, if the c-peptide rate is represented by Xn, and the BSA by Yn then during the actual day of the clamp test Xn/Yn will be valid for all the participants. A week later the test is repeated and we get a different X1/Y1, and when it is repeated a year later we get Xn/Yn.
Just assume for the moment that the beta cell output does not change at all over the 2 years, but the weight average drops by 15%, then there will be a change in Y that reflects this, so the ISR will be observed to have improved over time. If however, there is no weight change between year1 follow up, and year2 follow up, then there will be no change in ISR as a result, and this is indeed what Roy Taylor reports in the 2 year follow on report.
Since he reports that the weight did not change, and the ISR remained steady, then we can theorize that the ISR also remained unchanged. So does the apparent improvement in Beta Cell recovery show an actual real improvement, or is it simply due to weight loss due to the diet. In other words, is Roy Taylor making claims for Beta Cell recovery that are simply artifacts of his experimental method?
I am postulating this. I have no concrete evidence that they used any of the formulae for BSA as I have described above. But they did appear to use a software program called ISEC, and the writers of that package do confirm that along with c-peptide and time interval parameters, it does use height and body weight to adjust the results to give the Roy Taylor version of the ISR units.
I have manually cranked the BSA formuae to see what effect a 15% change in body weight with constant height will do to the result, and the results show a variance of between 6.6% and 8.02% for a person of 100kg and 1,7m height at start.
As I noted in other studies into c-peptide, the beta cell output also reduces with weight loss, but I cannot find any quantitative values to apply. This will have the effect of reducing the c-peptide, and also the ISR raw value before correction. so will conteract the error I reported above. So they couneract each other, but may not cancel out. We do see that the Table of macro values in the ND study do show that c-peptide reduced over time, but was this due to weight loss or improvement in insulin resistance (insulin sensitivity ) as also claimed in the ND study?
- Messages
- 8,470
- Type of diabetes
- Type 2
- Treatment type
- Tablets (oral)
One other thing I discovered in the research papers using the glycemic insulin clamp GTT was that one paper found that the levels of insulin output response was more marked, had a sharper risetime, and longer decay time when the glucose was given in an oral test as compared to the intravenous infusion test. So the OGTT was better thsn the IVGTT for finding maximum secretion rates. This is why the arginine was needed to block the output of insulin to give a flood release effect when the arginine stopped. The researchers noted this difference, and considered thst the orsl metabolic route activates other glucose transporters other than just GLUT2 (there are at least 13 others) and also activates more incretin proteins such as GLP-1 and sulfonyl urea which happens in the normal real world.
So the insulin clamp is not reflecting real life and is an artificial construct to force a condition. It is the scientific way since an OGTT is difficult to control and repeat.
The other thing I note was that when arginine bolus is used, then the maximum insulin production mechanism only kicks into gear when the bgl rises to 16 mmol/l or above. The level Roy Taylor used was just over 10 mmol/l in the clamp which is the uusual (natural) trigger when carb causes the glucose step, but is held back by the arginine so the beta cells do not produce a proper response at all.
What I have found casts serious doubt on the claims being made for the Newcastle Diet in respect of Beta Cell recovery and GTT response characteristics.
The Diet itself is a useful and convenient method to lose some serious weight and to remove ectopic fat from the pancreas and liver, as demonstrated by the MRI scans. The diet seems to reboot the system, and if a proper maintenance regime is used for follow on, then the effect of the diet does seem to last a reasonable time. It is in effect just a short sharp shock to reset the metabolism and should be viewed as such. More work will be needed to unravel the full effects on the pancreas since the tests do not IMHO reflect real life events in vivo.
So the insulin clamp is not reflecting real life and is an artificial construct to force a condition. It is the scientific way since an OGTT is difficult to control and repeat.
The other thing I note was that when arginine bolus is used, then the maximum insulin production mechanism only kicks into gear when the bgl rises to 16 mmol/l or above. The level Roy Taylor used was just over 10 mmol/l in the clamp which is the uusual (natural) trigger when carb causes the glucose step, but is held back by the arginine so the beta cells do not produce a proper response at all.
What I have found casts serious doubt on the claims being made for the Newcastle Diet in respect of Beta Cell recovery and GTT response characteristics.
The Diet itself is a useful and convenient method to lose some serious weight and to remove ectopic fat from the pancreas and liver, as demonstrated by the MRI scans. The diet seems to reboot the system, and if a proper maintenance regime is used for follow on, then the effect of the diet does seem to last a reasonable time. It is in effect just a short sharp shock to reset the metabolism and should be viewed as such. More work will be needed to unravel the full effects on the pancreas since the tests do not IMHO reflect real life events in vivo.
- Messages
- 8,470
- Type of diabetes
- Type 2
- Treatment type
- Tablets (oral)
I have received a reply from Roy Taylor in reply to my email to him
"
Dear Martin,
Thank you for your thoughtful comments.
The use of body surface area is standard for this type of metabolic measurement. Weight loss will indeed decrease surface area although only by a small margin for the weight losses in DiRECT. Using data corrected for weight itself produces a greater effect. However, maximal insulin secretion is only slightly and non-significantly changed at 5 months when the weight loss was maximum (around 15kg). Maximal insulin secretion increased further and became significantly increased only at 12 months at which time weight regain had occurred (to around 12 kg below baseline). Weight increased further to 24 months but the insulin secretion remained steady and sufficient to maintain blood tests in the non-diabetic range.
i hope this is of interest to you and answers your question.
Best,
Roy Taylor
******************************************
Roy Taylor
Professor of Medicine and Metabolism
Magnetic Resonance Centre
Campus for Ageing and Vitality
Newcastle upon Tyne
NE4 5PL, UK
Tel 0191 208 1172
Website:
https://go.ncl.ac.uk/diabetes-reversal
"
I will be continuing my converstion with him, but I think this thread has reached a static position now so I will start a new thread to cover that progression from here..
"
Dear Martin,
Thank you for your thoughtful comments.
The use of body surface area is standard for this type of metabolic measurement. Weight loss will indeed decrease surface area although only by a small margin for the weight losses in DiRECT. Using data corrected for weight itself produces a greater effect. However, maximal insulin secretion is only slightly and non-significantly changed at 5 months when the weight loss was maximum (around 15kg). Maximal insulin secretion increased further and became significantly increased only at 12 months at which time weight regain had occurred (to around 12 kg below baseline). Weight increased further to 24 months but the insulin secretion remained steady and sufficient to maintain blood tests in the non-diabetic range.
i hope this is of interest to you and answers your question.
Best,
Roy Taylor
******************************************
Roy Taylor
Professor of Medicine and Metabolism
Magnetic Resonance Centre
Campus for Ageing and Vitality
Newcastle upon Tyne
NE4 5PL, UK
Tel 0191 208 1172
Website:
https://go.ncl.ac.uk/diabetes-reversal
"
I will be continuing my converstion with him, but I think this thread has reached a static position now so I will start a new thread to cover that progression from here..
