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Beta Cell De-Differentiation?

Discussion in 'Diabetes Soapbox - Have Your Say' started by Oldvatr, Feb 13, 2022.

  1. Oldvatr

    Oldvatr Type 2 · Expert

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    De-Differentiation became a buzzword last year, and it entered and nearly derailed a few threads here in the Forum, so I feel it deserves its own topic thread. I have placed it in the Soapbox section because discussion on this topic can become quite heated, The purpose of this thread is to discuss and learn about the subject, not win points.

    When i was diagnosed some 30 years ago as a nascent T2D (Newbie) I was informed by the experts at that time that the condition is progressive, and will lead to needing insulin treatment within 10 years at most. i was informed that my beta cells will suffer apoptosis and fail. The cause of T2D in those days was believed to be insulin resistance in the muscle tissue, which could only be overcome by massive excess of insulin in the manner of a sledgehammer cracking a nut. I have learnt since that this is only part of the story, and that management of the condition has improved.

    We do know that beta cell output does deplete with T2D, and that beta cell mass does change as the condition progresses, but recent experiments have demonstrated that for some T2D it is possible to recover beta cell output to the point of not requiring diabtic medications. So beta cells do not always die, some just go off the radar but can be recovered apparently through the intervention via a diet that mimics bariatric surgery outcomes. At present only one diet has been recognised as being suitable, and that is the very low calorie diet(VLC). However the study that proved this used a diet that was not only calorie restricted, but was also a low carb diet at the same time. So there are IMHO potentially 2 diets that may have this effect

    The old theory of beta cell death through exhaustion does not exlain how beta cells that stopped output can suddenly recover almost full output just through losing some weight. This is where de-differentiation raises its head, as a theory (so far) that can explain what the beta cells do when they are not on duty.

    Let me start by looking at what differentiation means in terms of the beta cell (in all cell actually). It is a term used by endocrinologists (called endo's henceforth) that describe the process that occurs shortly after conception whereby nascent stem cells get programmed by the DNA to perform their different tasks, i,e the RNA formula that they use to control their activities.

    There is no evidence found so far that any cell in our body gets reprogrmmed to perform a different function or revert back to being a stem cell. Yes, some cells do change, but this is what we call cancer. Damaged cells such as happens all the time from toxin, radiation, virus etc are detected by our immune system and are removed naturally as they occur. So cancer cells are damaged cells that have an altered DNA, but which are not detected as alien to our body. Cancer cells seem to serve no function except replicate and grow,

    Beta cells do not get replaced unlike most of the other cells in our body. The pancreas starts its work from the get-go with a full set of beta cells within the first month following conception.

    So what is de-differentiation? There are currently two definitions. The original definition as used by the endo' is that sometimes cell lose some or all of their programming info (their RNA code) and stop providing their original function. They remain identified as being part of our body so do not get removed by the immune system, and they do not replicate like cancer. It is akin to the Microsoft BSOD condition, where something significant needs to be done to reboot them back into useful function. Until that happens, they could be described as being dormant. A recent study has shown that the pancreas does contain dormant beta cells, and that under certain (surgical) conditions, they can become active again. this is a by product of pancreatic surgery.

    But Prof Roy Taylor has taken this a step further in relation to beta cells. He is currently seeking funding for research to investigate his theory which in essence is that instead of becoming dormant, the de-differentiation of the beta cell is such that it takes on the function of an Alpha cell instead (i.e. is reprogrammed as an Alpha) and starts producing glucagon instead of insulin. For it to do this it would have to be damaged in such a way as to replace the RNA code for insulin by that for glucagon. Thus it requires our bodies to engineer a gene splicing within the cell when it gets distressed by T2D. Not too sure if this is possible, and I am unaware of any other cell in the body changing its function like this.

    What is even more astounding is the claim by Roy in his application paper that the VLC diet that leads to 15% weight loss also induces the same process, but in reverse to turn the cell back into a Beta. In my mind this is not logical, so it will be interesting to see what his research finds.
    https://pubmed.ncbi.nlm.nih.gov/27926891/

    In my laymans mind, I see a simpler explanation that does not need de-differentiation at all.

    If weight loss improves the beta cell function (not yet proven since all tests in vivo so far are on the panceras output not individual cell outputs) then if weight in the form of ectopic fat within the pancreas can repair the damage when it is removed, then probably the same weight gain in the pancreas organ is causing a problem. Now maybe the fat is blocking a pathway for the enzyme demand signal, or is stopping calcium getting into the cell (required to give the switch on voltage that starts insulin production), or is simply blocking the output portal of the beta cell so insulin is not stored or released then these are mechanisms that make sense. I would personally plump for the calcium being interferred with but a blocked drain also does it for me.
     
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    #1 Oldvatr, Feb 13, 2022 at 3:24 PM
    Last edited: Feb 13, 2022
  2. Bubbleblower

    Bubbleblower LADA · BANNED

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    I don’t like the term dedifferentiation either because we don’t know what is happening, some scientists proposed to use the term altered identity instead. There are studies showing high glucose changes the alpha to beta cell ratio, but it is complicated;

    Dynamic Change of β to α Ratio in Islets of Chinese People With Prediabetes and Type 2 Diabetes Mellitus
    The β to α ratio in islets (β/α) in PreD was significantly higher than that in ND, resulting from an increase of β cells and a decrease of α cells per islet, but that in T2D was significantly lower than that in ND, resulting from a decrease of β cells and an increase of α cells per islet. The β-cell percentage and β/α ratio positively correlated and α-cell percentage negatively correlated with HbA1c (glycated hemoglobin) in ND and PreD, but these correlations disappeared when T2D subjects were included.
     
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  3. Oldvatr

    Oldvatr Type 2 · Expert

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    Found a clue that supports my theory, which is that fat and calcium easily combine to form soap which is generally insoluble. So the calcium gating that wakes up the beta cell to start the insulin production line could well be snaffled by ectopic fat (lipid fat) in the pancreas thus stopping beta cell function. Note that it is the Ca++ ion that is needed in the beta cell, and this is highly reactive.
    https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/547961

    Note: although the pancreas is classed as adipose tissue, it does not normally get used for storing lipids. Certain conditions such as obesity or a high carb high fat diet can turn the pancreas into a fat store where fat gets stored outside of the normal places (i.e. ectopic fat) leading to stearosis.
     
  4. Oldvatr

    Oldvatr Type 2 · Expert

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    Do we know what they used to measure this? I am presuming it was MRI scan and going by area, which is the normal way it is calculated. Or do they have some mechanism for actually counting the indivdual cells? Post mortem analysis shows that while areas may be different, masses do not, so in pathological samples, there was very little difference in the ratio calculated by mass rather than visual area. Also if betas are changing to alphas, they will not be packing their bags and physically moving to the alpha district, which is quite exclusive of the beta.

    if there is increased glucagon output due to dedifferentiation, then it would be necessary to measure the stimulus and the inputs to the cell as well as its outputs. Or find some other way of decoupling the increase as being due to more alpha's rather than an increase in demand signal or increased nutrients,

    The other thing they do not appear to have decoupled is the size of the cells. Is the change due to actual number of cells, or just the area aoccupied. If the cell sizes are unchnged, the the a/b ratio is valid. They do not seem to have taken cell size into account.
     
  5. Oldvatr

    Oldvatr Type 2 · Expert

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    I notice you omitted their conclusion
    "The islet β to α ratio increased in PreD individuals because of a relative α-cell loss and β-cell compensation and decreased after T2D onset because of both β-cell loss and α-cell reexpansion."

    Are they saying that this is an area or a numeric expansion effect? The number of alphas seems to remain the same in both ND and T2D as confirmed by autopsy analyses. That analysis does agree that T2D leads to beta cell death which appears to be in districts i.e. like there was blood loss to an islet.

    Also they seem to assume that the PreD increase in alphas is as a result of the disease, and not an effect that could be the genetic disposition to T2D i.e. is a cause, not a result.
     
  6. Outlier

    Outlier · Well-Known Member

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    Fascinating discussion - thank you.

    Do we have theories/actual knowledge if/how beta blockers fit into this?
     
  7. Oldvatr

    Oldvatr Type 2 · Expert

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    Not seen anything that suggests beta blockers are connected to this topic.
    https://www.mayoclinic.org/diseases...-pressure/in-depth/beta-blockers/art-20044522
    Beta blockers reduce adrenaline, which will have an effect since adrenaline is the fight/flight hormone that stops fat storage and turns the Krebs cycle (Citric cycle) to use glucose from the stored glycogen. it may have an effect on insulin resistance.

    If beta blockers were directly involved here, then the effect would be quite noticeable and they would be associated with beta cell changes, which has not been reported. The effect we are examining here is the relationship between weight gain/loss on beta cell functionality.
     
  8. Oldvatr

    Oldvatr Type 2 · Expert

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    Note that the ND studies Counterpoint, Counterbalance and DIRECT showed that at best only 46% of the participants achieved remission, meaning that 64% did not. So the weight loss pthway does not apply to the general T2D population.

    Found this research paper that relates to this topic
    https://www.sciencedirect.com/science/article/pii/S2212877819301760
    I provides research independant of the ND studies that confirms adipose fat in the pancreas has a direct effect on insulin secretion
    Edit to add: Having found the full text for that report, I have to warn that it is an endocrine smorgasbord, and will make your eyes water and your head spin. Not for the faint hearted. However, they use keyhole surgery and laser slicing to remove biopsy tissue in vivo for immediate anaylsis, so the meat is indeed fresh. They are able to do microbiological assayes to determine the various enzymes and toxins etc present and they do find crosstalk between the ectopic fat tissue and the beta cells.
    I will include one experimental observation they found
    "Surprisingly, the area of insulin positive cells determined using in situ immunohistological staining was unaltered both in pancreatic tissue with high level of adipocyte infiltration and in tissue from T2DM patients when compared to specimens of non-fatty and non-diabetic humans, respectively. This finding differs from observations made in T1DM pancreata in the islets".
     
    #8 Oldvatr, Feb 14, 2022 at 11:51 AM
    Last edited: Feb 14, 2022
  9. Oldvatr

    Oldvatr Type 2 · Expert

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    The takeaway from that last report is of interest (edited to remove external references)
    "
    Effects of adipocytes on β-cell differentiation and function
    The direct crosstalk between pancreatic adipocytes and islets has not yet been studied in depth
    Using the insulin secreting cell line Min6 and 3T3-L1 adipocytes in a co-culture system, a downregulation of glucokinase of the KATP-channel protein Kir6.2, and of insulin has been observed . In vitro exposure of human islets to preadipocytes and adipocytes in a co-culture system revealed that mRNA levels of islet differentiation markers (islet specific hormones, PDX-1 and GLUT-2) did not change [1]. The theory that fat cells do not affect β-cell differentiation is further corroborated by the unaltered in situ immunostaining for insulin,glucagon and somatostatin of islets in the neighborhood of fat cells. Of note, this method may not be sensitive enough to detect changes of hormone storage until the reduction is already well advanced. Hormone content, moreover, may not correlate with the ability to secrete insulin in response to glucose. "
    In simple terms, they did not find any evidence that fat cell secretome altered cell differentiation in alpha, beta or delta pancreatic cells. No change. No deprogramming At the same time they noted downregulation of function in the samples ie reduced c-peptide and reduced insulin output. This is not to be read as proof, because they probably only examined a small portion of the sample. Only that it was not seen. important that they confirmed this finding from the mRNA itself
     
  10. Oldvatr

    Oldvatr Type 2 · Expert

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  11. Ronancastled

    Ronancastled Type 2 · Well-Known Member

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    Interesting that you mention Counterpoint/balance, can never remember.
    Anyway, buried in the data is the 12 week follow up OGTT he administered to the "successful" candidates.
    https://link.springer.com/article/10.1007/s00125-011-2204-7

    [​IMG]

    So basically they were still very very prediabetic.
    Obviously prone to higher than normal spikes & further beta cell damage due to glucoxiticity.

    The real breakthrough in my mind came in the 2 year follow up to Direct where they saw the slow return to normal 2nd phase secretion rates across 12 months, then maintaining at 24.
    https://diabetesjournals.org/diabet...OR-Remission-of-Type-2-Diabetes-for-Two-Years
    In other words the 2011 Counter[?] cohort were given an OGTT far too early at 12 weeks.
    Funnily enough though he never repeated the OGTT on the larger Direct group.
     
  12. Oldvatr

    Oldvatr Type 2 · Expert

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    Indeed, The remission objective declared for all his studies was meeting fasting levels of below 48 mmol/l.

    The Springer paper you linked is one I have studied, and it is actually an IGTT, i.e. intravenous not oral. It has some errors in it that I have raised with Prof Taylor, and he has declared that the error although systemic, is not significant. I discussed this in another thread last year,

    The one I have not discussed with him is that others doing the same type of test have shown that their results are nowhere near as spectacular because the IGTT process has less effect when compared to the tradiitional OGTT, Some have found that the IGTT may be missing some of the enzyme triggers associated woth the First Stage insulin response that is triggered by amylase secreted in the saliva, which of course is missing in the intravenous technique. There may be other enzymes and incretins that the gut secretes that are also going to be missing.

    The beta cell output technique he adopted uses an arginine bolus to block the output channel thus damming up the normal secretion in the local granules. When the clamp is removed, then there is a sudden flood from the stored insulin, Unfortunately, the output capacity test followed a normal GTT cycle, and the timing is such that the second test was overlapping the residue from the first test. The two tests were not uncoupled sufficiently and is not representative of normal activity. Therefore his conclusions regarding first and second phase respnses are not reliable IMO.

    What he has in my opinion achieved is to show that the capacity in tems of storing and releasing a full 'bladder' is probably demonstrated, and the improvement from the weight loss can be claimed, but the mechanism cannot. I.e. the removal of ectopic fat in the pancreas will be of benefit in clearing signalling pathways, emptying cells and capilliaries blocked or chocked by the fat. The actual beta cell capacity may not be changing at all, just the delivery system. in other words he is measuring the contents of the storage warehouse, not the ability of the production line to produce in response to a step demand change.

    Lastly, which I noted the other day, he has a typo that is most unfortunate in a final report. He refers to the insulin responses in terms of T1D not T2D A minor mishap.

    I think overall there is much to commend this work, its just the conclusions and explanations following it that i have a quibble with.
     
  13. Dr Snoddy

    Dr Snoddy Type 2 · Well-Known Member

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    I wasn't aware that the pancreas could be classified as adipose tissue given that 95% of the tissue has an exocrine function.
     
  14. Oldvatr

    Oldvatr Type 2 · Expert

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    It is , but does not normally store lipids. It has the capability to do so. But the pancreatic fat that causes the stearosis is ectopic . i.e. not in the authorised parking bay.
    https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6600604/
     
  15. Ronancastled

    Ronancastled Type 2 · Well-Known Member

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    I do remember one of the editorials of his Direct follow up questioned whether it was beta cells restoring normal function or just the remaining beta cells working harder.

    You have bear in mind that pathology has shown that the amount of beta cells in the healthy population can vary widely I can remember one report quoting between 250 million and 1 billion in normoglycemic individuals.

    There's also cases of patients achieving normal glucose control after partial pancreas removal.
     
  16. Oldvatr

    Oldvatr Type 2 · Expert

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    The paper I linked in Post#10 discusses the numeric and physical properties of the alpha cells. I believe alphas outnumber beta's by a factor of at least 50:1 in ND samples. Not the sort of number a guy with a microscope and exceedingly good eyesight can omfortably count in a lifetime. I believe that scannng electon microscopes (SEM) are used with a dye that makes the stained cells of interest fluoresce and a scintillator counts them automatically. I believe pixel size is a limting factor according to one paper I read recently. The other problem is that a SEM is a 2-D scan, but the pancreas is 3-D object.

    The beta cell recovery after surgery is discussed in this paper
    https://pubmed.ncbi.nlm.nih.gov/22079939/

    The pancreas is made from precursor stem cells, but apparently the pancreas also has spare precursor cells that are differentiated with their correct mRNA but do not activate and remain dormant. The pancreatic surgery leaves many of these behind, and they become switched on to perform their beta cell function post surgery..
     
  17. Oldvatr

    Oldvatr Type 2 · Expert

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    My research so far has allowed me to accept the term de-differentiation as being the corruption, removal or replacement of the mRNA code in the Beta cell which stops the cell from performing its original programmed function. I have found no evidence that the function changes to the Alpha Cell function. The experimental evidence from the ND study shows that simple dietary intervention can reverse the deprogramming and restore normal beta cell operation, so the corruption or change that occurred is not permanent. Most interventions such as toxins, radiation, virus etc that damage cells is permanent and the cell must be renewed / replaced through the normal autophhage process. Beta cells do not have this mechanism.

    In vivo observations of T2D progression shows that beta cells do not get replaced under normal operations of the body. The body does not repair damaged ,RNA code, which requires gene splicing in vitro outside the body. Therefore the theory that de-differentiation in T2D leads to Beta cells changing to perform Alpha Cell operation is incorrect. The claim that the ND diet causes recovery back to beta cell operation by reversing that theorised process is also incorrect.

    One thing I discovered in my research which i did not know is that recent studies have shown that beta cells not only respond to the GLUT enzymes for operation, but also have a GLP-1 receptor that also triggers an insulin excretion cycle. Other research has also demonstrated that Alpha cells secrete not just glucagon, but also GLP-1 under certain circumstances. GLP-1 has a half life of 2 minutes, so there is srong coupling between the alpha and beta cells in this respect. The conditions for this to happen appear to be very high glucose levels even when the alpha cell is still producing glucagon. This appears to be an emergency stop correction factor since normally GLP-1 is produced by the gut in the presence of protein and fat metabolism and normally is triggering insulin for adipose storage to occur in the absence of a carb intake (i.e. carnivore and the fed state)
    https://www.sciencedirect.com/science/article/pii/S2212877820300880
    http://www.glucagon.com/GLP-1 and the Alpha Cell.html

    I think this mechanism may explain the sleep post meal syndrome that has been reported elsewhere in the Forum, and may be a mechanism involved in RH diadetes.
     
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