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Post by sayhey24 on Feb 22, 2018 21:09:41 GMT -5
What the data is actually starting to show is ALL beta cell loss is initially caused by an underlying attack on the beta cells. As we test more and more T2s and earlier we have been seeing and will continue to see more who test positive for the current anti body tests. As testing gets better additional ones will probably also be found.
We know insulin resistance is not the cause because you can take that same early stage T2 put then on insulin, keep non-diabetic TIR and see not only progression stopped but beta cell regeneration. The insulin resistance requires a greater demand on the pancreas but a healthy pancreas will adapt and generate large clumps of beta cells. We see this when you autopsy an obese insulin resistant non-diabetic. If you sprain your ankle running a marathon is not a good idea. If you have lost some beta cell function and are now asking the remaining beta cells to work harder and that obese person needs a lot of insulin things are not going to work out too well unless you can allow the pancreas to rest. Get the PWD to a fasting state asap, allow the pancreas to rest and good things will happen.
Genetics fits into the equation as it opens up certain groups to a greater risk of infection and it can also effects how fast a person's beta cells can regeneration. Its like hair, some people have good hair and others don't and some people's hair grows faster. My hair is not so great. However, the Qatar study is showing with pretty much certainty almost all will regenerate beta cells to some degree. We also know its not just genetics because identical twins will not always both get diabetes. If it was simply genetics they both would always get it.
As far as Al's assertion about basal vs prandial there is no question he is right. Prandial in T2s should be first line treatment. That is a main pillar in the Al Mann Dogma. It is the medically correct way to treat T2s. It also seems to be the direction David Kendall is taking. It seems finally, someone has read Al's 50+ studies.
We have clinical studies from the 1950's on early insulin intervention. However the key with afrezza is its ability to restore hepatic function and achieve greater time in range. To see beta cell regeneration you need to keep the time in range near non-diabetic. DeFronzo is doing this in Qatar with his Actos/Byetta cocktail. I don't recommend this approach but he is achieving near non-diabetic TIR by removing the after meal spike and increasing insulin sensitivity. You can not so this with a basal. After meal the T2 will spike 200, 250, 300+ then take the next 4 hours to bring it down with the on board basal only to see it spike again after lunch and diner. At the same time the liver is dumping glucose adding to the mess and the pancreas never ever gets to a fasting state.
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Post by dreamboatcruise on Feb 22, 2018 22:00:22 GMT -5
What the data is actually starting to show is ALL beta cell loss is initially caused by an underlying attack on the beta cells. As we test more and more T2s and earlier we have been seeing and will continue to see more who test positive for the current anti body tests. As testing gets better additional ones will probably also be found. We know insulin resistance is not the cause because you can take that same early stage T2 put then on insulin, keep non-diabetic TIR and see not only progression stopped but beta cell regeneration. The insulin resistance requires a greater demand on the pancreas but a healthy pancreas will adapt and generate large clumps of beta cells. We see this when you autopsy an obese insulin resistant non-diabetic. If you sprain your ankle running a marathon is not a good idea. If you have lost some beta cell function and are now asking the remaining beta cells to work harder and that obese person needs a lot of insulin things are not going to work out too well unless you can allow the pancreas to rest. Get the PWD to a fasting state asap, allow the pancreas to rest and good things will happen. Genetics fits into the equation as it opens up certain groups to a greater risk of infection and it can also effects how fast a person's beta cells can regeneration. Its like hair, some people have good hair and others don't and some people's hair grows faster. My hair is not so great. However, the Qatar study is showing with pretty much certainty almost all will regenerate beta cells to some degree. We also know its not just genetics because identical twins will not always both get diabetes. If it was simply genetics they both would always get it. As far as Al's assertion about basal vs prandial there is no question he is right. Prandial in T2s should be first line treatment. That is a main pillar in the Al Mann Dogma. It is the medically correct way to treat T2s. It also seems to be the direction David Kendall is taking. It seems finally, someone has read Al's 50+ studies. We have clinical studies from the 1950's on early insulin intervention. However the key with afrezza is its ability to restore hepatic function and achieve greater time in range. To see beta cell regeneration you need to keep the time in range near non-diabetic. DeFronzo is doing this in Qatar with his Actos/Byetta cocktail. I don't recommend this approach but he is achieving near non-diabetic TIR by removing the after meal spike and increasing insulin sensitivity. You can not so this with a basal. After meal the T2 will spike 200, 250, 300+ then take the next 4 hours to bring it down with the on board basal only to see it spike again after lunch and diner. At the same time the liver is dumping glucose adding to the mess and the pancreas never ever gets to a fasting state. That actually isn't what the bulk of literature says, such as the paper that I provided link, which itself was looking at a lot of literature. Not saying there couldn't be some paper that says that, but I'd be interested in their methodology and how many subjects were involved. A bulk of diabetics do not test positive for antibodies. And immune disorders don't work where you can have undetectable levels of antibodies and yet have a clinically significant immune response. It's actually quite the opposite, where modern tests for antibodies can pick up levels well below when there is any meaningful immune response... such as the cases in Afrezza trials where insulin antibodies were detected in the lungs, but no immune response effects. The notion that all diabetes is an auto-immune disease is way, way off from what the medical profession believes. I'm curious if you know of a single scientist that has stated that all diabetes is immunological. As for Al Mann dogma... part of Albert Einstein's dogma was that quantum mechanics had to be bogus. Scientists rightly realize that accepting dogma from smart men isn't part of the scientific process. I personally believe Al Mann, but the scientific method requires evidence in the form of clinical trials. As for your statement about beta cell growth from insulin resistance that is totally consistent with what the mainstream lit says. Here is a paragraph from the paper I provided a link for on T2 progression. "Thus, in type 2 adipogenic diabetes, excessive carbohydrate and fat intake causes hyperinsulinemia in association with increased hepatic lipoprotein secretion, adipose tissue growth, and increased free fatty acid levels in genetically susceptible individuals. Together with episodes of postprandial hyperglycemia, elevated free fatty acid levels cause muscle and liver insulin resistance and increase hepatic glucose production. The same stimuli also facilitate β-cell compensation by promoting insulin secretion and biosynthesis as well as β-cell growth. In late stages, however, the progressive rise in insulin resistance, combined with alterations in β-cell gene expression and signaling induced by rising levels of free fatty acids, cause β-cell failure. Overt diabetes occurs as a result of this β-cell decompensation, with altered insulin secretion and apoptosis as possible contributing factors." It is recognized that insulin resistance first causes beta cell growth... but in many it will then progress to beta cell failure. As I stated in my prior post, it is also recognized that some have genetics that seem to have burn out proof beta cells, so they can have significant insulin resistance and their pancreas successfully adjusts. Other phenotype pancreases have limits to how much they can adjust.
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Post by agedhippie on Feb 22, 2018 22:08:40 GMT -5
We know insulin resistance is not the cause because you can take that same early stage T2 put then on insulin, keep non-diabetic TIR and see not only progression stopped but beta cell regeneration. The insulin resistance requires a greater demand on the pancreas but a healthy pancreas will adapt and generate large clumps of beta cells. We see this when you autopsy an obese insulin resistant non-diabetic. If you sprain your ankle running a marathon is not a good idea. If you have lost some beta cell function and are now asking the remaining beta cells to work harder and that obese person needs a lot of insulin things are not going to work out too well unless you can allow the pancreas to rest. Get the PWD to a fasting state asap, allow the pancreas to rest and good things will happen. I think your analogies are wrong. This paper is the best explanation for how beta cells work in Type 2 ( β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes). It's the paper that is usually cited by (3,732) academic papers talking about this topic, including the AACE consensus statement on Type 2 management where it is given as the mechanism by which Type 2 occurs. Anything by Butler or Bonner-Weir is worth reading in my opinion. For those who don't want to read the whole thing; this is the paper that documented the mechanism by which Type 2 diabetics lose beta cells, and why they don't get replaced. Basically there is a genetic flaw that means the body miscalculates and thinks it has built more beta cells than it has, and because beta cells are naturally continually dying and being replaced this error accumulates until the body has a lot less beta cells than it thinks it does. You cannot regenerate beta cells because the body thinks it has the right number.
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Post by dreamboatcruise on Feb 23, 2018 1:11:15 GMT -5
We know insulin resistance is not the cause because you can take that same early stage T2 put then on insulin, keep non-diabetic TIR and see not only progression stopped but beta cell regeneration. The insulin resistance requires a greater demand on the pancreas but a healthy pancreas will adapt and generate large clumps of beta cells. We see this when you autopsy an obese insulin resistant non-diabetic. If you sprain your ankle running a marathon is not a good idea. If you have lost some beta cell function and are now asking the remaining beta cells to work harder and that obese person needs a lot of insulin things are not going to work out too well unless you can allow the pancreas to rest. Get the PWD to a fasting state asap, allow the pancreas to rest and good things will happen. I think your analogies are wrong. This paper is the best explanation for how beta cells work in Type 2 ( β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes). It's the paper that is usually cited by (3,732) academic papers talking about this topic, including the AACE consensus statement on Type 2 management where it is given as the mechanism by which Type 2 occurs. Anything by Butler or Bonner-Weir is worth reading in my opinion. For those who don't want to read the whole thing; this is the paper that documented the mechanism by which Type 2 diabetics lose beta cells, and why they don't get replaced. Basically there is a genetic flaw that means the body miscalculates and thinks it has built more beta cells than it has, and because beta cells are naturally continually dying and being replaced this error accumulates until the body has a lot less beta cells than it thinks it does. You cannot regenerate beta cells because the body thinks it has the right number. Don't have time to read right now. At the risk of being a plot spoiler... is it a single gene... what percent of the population has the flaw? [Edit] Actually I just quickly read through the discussion at the end. Are you sure this is the paper you were intending to provide a link to. It doesn't seem to suggest what you are saying in the second paragraph. Such as... "One very positive implication from the present studies is that the rate of new islet formation is sustained in patients with longstanding diabetes. In fact, there was no difference in the rate of new islet formation versus age in patients with or without type 2 diabetes. These data imply that if the increased rate of apoptosis present in type 2 diabetes (vida infra) could be inhibited, it should be possible to restore β-cell mass in these patients." This seems to be saying that if cell death were halted the pancreas would happily produce enough beta cells to rebuild itself. Or am I misreading something... I could be, as it's late and that is fairly dense reading.
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Post by sayhey24 on Feb 23, 2018 6:36:06 GMT -5
We know insulin resistance is not the cause because you can take that same early stage T2 put then on insulin, keep non-diabetic TIR and see not only progression stopped but beta cell regeneration. The insulin resistance requires a greater demand on the pancreas but a healthy pancreas will adapt and generate large clumps of beta cells. We see this when you autopsy an obese insulin resistant non-diabetic. If you sprain your ankle running a marathon is not a good idea. If you have lost some beta cell function and are now asking the remaining beta cells to work harder and that obese person needs a lot of insulin things are not going to work out too well unless you can allow the pancreas to rest. Get the PWD to a fasting state asap, allow the pancreas to rest and good things will happen. I think your analogies are wrong. This paper is the best explanation for how beta cells work in Type 2 ( β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes). It's the paper that is usually cited by (3,732) academic papers talking about this topic, including the AACE consensus statement on Type 2 management where it is given as the mechanism by which Type 2 occurs. Anything by Butler or Bonner-Weir is worth reading in my opinion. For those who don't want to read the whole thing; this is the paper that documented the mechanism by which Type 2 diabetics lose beta cells, and why they don't get replaced. Basically there is a genetic flaw that means the body miscalculates and thinks it has built more beta cells than it has, and because beta cells are naturally continually dying and being replaced this error accumulates until the body has a lot less beta cells than it thinks it does. You cannot regenerate beta cells because the body thinks it has the right number. Yes, I understand that is what the traditional research said " You cannot regenerate beta cells" but that is not what they are seeing in the Qatar study and not what Al Mann saw. None of the prior studies were able to keep non-diabetic time in range. At this point its really just a matter of doing it in the general population now thats its easily done and see what happens. If only stopping progression is achieved thats much better than we have today but if TIR is the key and it appears to be thats even better.
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Post by agedhippie on Feb 23, 2018 10:25:01 GMT -5
I think your analogies are wrong. This paper is the best explanation for how beta cells work in Type 2 ( β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes). It's the paper that is usually cited by (3,732) academic papers talking about this topic, including the AACE consensus statement on Type 2 management where it is given as the mechanism by which Type 2 occurs. Anything by Butler or Bonner-Weir is worth reading in my opinion. For those who don't want to read the whole thing; this is the paper that documented the mechanism by which Type 2 diabetics lose beta cells, and why they don't get replaced. Basically there is a genetic flaw that means the body miscalculates and thinks it has built more beta cells than it has, and because beta cells are naturally continually dying and being replaced this error accumulates until the body has a lot less beta cells than it thinks it does. You cannot regenerate beta cells because the body thinks it has the right number. Don't have time to read right now. At the risk of being a plot spoiler... is it a single gene... what percent of the population has the flaw? [Edit] Actually I just quickly read through the discussion at the end. Are you sure this is the paper you were intending to provide a link to. It doesn't seem to suggest what you are saying in the second paragraph. Such as... "One very positive implication from the present studies is that the rate of new islet formation is sustained in patients with longstanding diabetes. In fact, there was no difference in the rate of new islet formation versus age in patients with or without type 2 diabetes. These data imply that if the increased rate of apoptosis present in type 2 diabetes (vida infra) could be inhibited, it should be possible to restore β-cell mass in these patients." This seems to be saying that if cell death were halted the pancreas would happily produce enough beta cells to rebuild itself. Or am I misreading something... I could be, as it's late and that is fairly dense reading. Your reading is correct. The rate of creation is the same so you are not seeing an error there, the quantity though is not the same. The rate is important it tells you that the problem is not in creating cells so if you can correct the genetic flaw then the body will correctly count the beta cells, realize there is a shortfall, and replace them - all will be well. The other option is to inhibit cell death so the body thinks it has killed the cell but it really hasn't however that carries a high cancer risk. In both cases you would end up with more beta cells, but neither of them is beyond the lab stage yet.
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Post by agedhippie on Feb 23, 2018 10:40:13 GMT -5
I think your analogies are wrong. This paper is the best explanation for how beta cells work in Type 2 ( β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes). It's the paper that is usually cited by (3,732) academic papers talking about this topic, including the AACE consensus statement on Type 2 management where it is given as the mechanism by which Type 2 occurs. Anything by Butler or Bonner-Weir is worth reading in my opinion. For those who don't want to read the whole thing; this is the paper that documented the mechanism by which Type 2 diabetics lose beta cells, and why they don't get replaced. Basically there is a genetic flaw that means the body miscalculates and thinks it has built more beta cells than it has, and because beta cells are naturally continually dying and being replaced this error accumulates until the body has a lot less beta cells than it thinks it does. You cannot regenerate beta cells because the body thinks it has the right number. Yes, I understand that is what the traditional research said " You cannot regenerate beta cells" but that is not what they are seeing in the Qatar study and not what Al Mann saw. None of the prior studies were able to keep non-diabetic time in range. At this point its really just a matter of doing it in the general population now thats its easily done and see what happens. If only stopping progression is achieved thats much better than we have today but if TIR is the key and it appears to be thats even better. Traditional is in the eye of the beholder The thing with diabetes research is that it's continually evolving. Occasionally there are big jumps like the paper I cited earlier, but mostly it's baby steps. Even then it takes time, I think it took six years to reach a point where this paper was mainstream, and there was probably at least four years before that. There are other theories sitting out there and my favorite is the Accelerator Hypothesis but it's still got a way to go.
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Post by sayhey24 on Feb 23, 2018 19:47:26 GMT -5
DBC - I finally had time to review the paper you supplied and which you found useful: www.ncbi.nlm.nih.gov/pmc/articles/PMC2811457/I thought it was pretty spot on with the exception of the first sentence which states "Type 2 diabetes is a progressive disease". It should better read Type 2 diabetes is a progressive disease the way we treat it today but it does not have to be if we treated early with afrezza. After reading the paper and a number of the underlying reference which are also pretty good I am struggling to understand your statement "T2 in many people is caused by insulin resistance that develops from lifestyle, though with some having better genetic resistance to poor lifestyles than others * AND T2 in some can be caused by genetic predisposition The paper does not say that. What it says is "Normal glucose tolerance was maintained by a compensatory increase in insulin secretion, whereas failure to increase insulin secretion led to impaired glucose tolerance, and a decrease in insulin secretion led to overt diabetes" It also says "Thus, the progressive decrease in β-cell insulin secretion, particularly the first-phase insulin secretion that occurs acutely after an increase in glycemia, is likely the most critical functional β-cell defect in the development of type 2 diabetes A hallmark of type 2 diabetes is a decline in β-cell function, which begins as early as 12 years before diagnosis and continues throughout the disease process. Pancreatic β-cells normally respond to insulin resistance by increasing their output of insulin to meet the needs of tissues." I think this was what I was trying to say. The paper also talked about loss of beta cell mass loss and how the obese will generate large clumps of beta-cells but in T2 they are missing. Now the $64,000 question is what causes the beta cell loss which starts the progressive decline which can be stopped if the PWD is keep in range for a period of time usually less than 6 months. If you can have a temporary suspension of disbelief and bare with me. What some of the best guesses are now is about 15% of T2s will test positive for LADA. One of the references in your paper said current testing is only finding those anit-bodies we know about and current testing is not 100%. So lets say 20% are LADA but that still leaves 80% and that 80% is the big target for afrezza. While genes and insulin resistance are traits it appears there is something which triggers the "recursive plunge" of the beta cells. Once triggered we then see all the symptoms including beta mass loss. Now, some are referring to this trigger as an "environmental factor" others are calling it an "outside agent" but I will simply call it the pancreatic flu. Between not yet knowing how to detect this "outside agent" and the fact that little T2 testing is done in time no one yet knows what the trigger or triggers are. Do we have multiple strains of this "flu"? Well its all together possible and we do know Influenza A viruses commonly cause pancreatitis. It is all together possible the "outside agent" theory is wrong but we do know for a fact that most fat people don't get diabetes and neither do all identical twins. Additionally we have plenty of thin active T2s. The bottom line is know one really yet knows the trigger(s). But, we do know that if we treat it early with afrezza we can stop beta cell loss and in some cases see some restoration.
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Post by dreamboatcruise on Feb 23, 2018 20:40:55 GMT -5
sayhey24... I believe that paper came out before Afrezza, so they aren't going to mention it. Hopefully MNKD can eventually do trials to show Afrezza can slow or even stop progression. As for what causes the loss of beta cells, that is the paragraph I quoted. It describes a sequence of events that occur. This would not apply to whatever portion of people simply were not diagnosed as having an auto-immune disease (whether you wish to call all auto-immune T1s or call some LADA because they were not recognized as having auto-immune disease until later in life). Here is the cascade that applies to most T2s (non auto-immune) and why obesity is a main predictor of T2 diabetes. You'll notice the beginning of this chain of events is "excessive carbohydrate and fat intake causes..." As for Afrezza, the question would be where in this chain should it be inserted if the goal is to halt or reverse (if possible). Can beta cell gene expression changes be reversed, etc.? If those questions were looked at in all the unpublished MNKD clinical trials, hopefully they will some day come out... or there will be new ones that do look at it. "Thus, in type 2 adipogenic diabetes, excessive carbohydrate and fat intake causes hyperinsulinemia in association with increased hepatic lipoprotein secretion, adipose tissue growth, and increased free fatty acid levels in genetically susceptible individuals. Together with episodes of postprandial hyperglycemia, elevated free fatty acid levels cause muscle and liver insulin resistance and increase hepatic glucose production. The same stimuli also facilitate β-cell compensation by promoting insulin secretion and biosynthesis as well as β-cell growth. In late stages, however, the progressive rise in insulin resistance, combined with alterations in β-cell gene expression and signaling induced by rising levels of free fatty acids, cause β-cell failure. Overt diabetes occurs as a result of this β-cell decompensation, with altered insulin secretion and apoptosis as possible contributing factors."
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Post by sayhey24 on Feb 24, 2018 9:21:55 GMT -5
You see this statement is in conflict with other parts of the paper "excessive carbohydrate and fat intake causes hyperinsulinemia" because under normal conditions the beta cells will adapt and release more insulin. And we know through autopsy non-diabetic insulin resistant people will have grown large clumps as the paper mentions.
I also agree with the last sentences but the key phrase is "In late stages" which is well after the initial attack and loss of beta cell functionality.
The bottom line is no one yet knows. We do know if you are fit you have less chance of diabetes. Is that because a fit person is much more insulin sensitive and needed much less insulin prior to the beta cell attack which allowed the pancreas to easily recover after the attack because the demand on it was less? Concerning genes, is it because some people based on a certain gene set can rapidly replace there beta cells and after the attack the body was able to quickly regenerate. Maybe.
We also know most obese insulin resistant people do not get diabetes. We also know both identical twins will not always get diabetes, sometimes one will and the other won't. We also know there are a number of thin, fit T2s.
We also know if we reduce the demand on the pancreas after diagnosis the progression can be stopped and if soon enough before much beta cell loss some beta cell regeneration. Is afrezza the only way to do this? No. DeFronzo is doing it with Actos and Byetta. I have been working with two indian brothers and one started using afrezza and the other a keto diet. Both were showing great results until the keto diet caused kidney issues. As soon as he came off the diet a few days ago his BG zoomed. If he was able to stay on it longer he probably would have had better long term results.
The cause of T2 IMO is a really interesting problem and clearly one we will not solve on a message board but thanks for the engagement and info. As you know I am a big believer in what Al Mann said that the medically correct way to treat all diabetics is with prandial insulin and nothing is better than afrezza. To me its a no-brainer and its sad to me that after all this time afrezza has yet to become the standard of care. Hopefully Dr. Kendall can make a huge impact and change that for the sake of all diabetics. I just wish they would cut the price of a box to $29.95 so everyone can afford it.
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