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Post by LosingMyBullishness on Jul 10, 2016 17:36:14 GMT -5
What the paper says (I just read the full text) is that insulin levels have a negative effect on lung function. This manifests itself by increased amounts of smooth muscle in the airways, PI3K/AKT mediated up-regulation of the beta catenin signaling pathway, and collagen type 1 deposition, all in an insulin level-dependent manner. That combination of symptoms is profibrotic and procontractile, meaning that the lungs stiffen and become less able to remodel due to the collagen, and asthma like obstructive disease is increased. The work was done in mice and cell culture using standard methods, not in humans, but these are well-studied pathways and similar effects are extremely likely in humans.
The point of the article is that there have been observations in the population that show a pronounced correlation between obesity, insulin resistance, hyperinsulinemia, and lung diseases, but until now nobody could show a cause and effect. This article outlined fairly persuasively a direct cause and effect linkage between hyperinsulinemia and deterioration of lung function due to fibrosis. Once fibrosis is established in any organ (as shown by consolidated collagen type 1 scar) then the organ is permanently impaired. Their conclusion is that nobody (anywhere) should use any insulin product without being aware of the risks, and that inhaled insulin poses an added level of risk that warrants further human studies before it becomes an accepted therapy.
Most of what I do involves regeneration of tissue, especially in fibrotic environments, so I look at this kind of study almost daily. The study was well-designed and controlled, and supports the imposition of a black box warning on Afrezza. The authors would be similarly cautious about careless use of injectable insulins and drugs (like metformin) that affect insulin production. Note again that the effects are seen with ANY insulin that is not properly controlled, not just Afrezza, but the risks are especially high with inhaled formulations. While that does not make for a better investment thesis in Mannkind, the science suggests that some caution is prudent.
For those of you with access to an academic library, the citations are:
PubMed PMID:26919895 DOI: 10.1152/ajplung.00091.2015 Thanks. Great comment. Why do you reckon that inhaled insulin is a higher risk? Inhaled insulin is absorbed rapidly. It just should not make a difference. The time period in the lungs is neglectable compared to the time in the system.
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Post by LosingMyBullishness on Jul 10, 2016 17:48:49 GMT -5
What the paper says (I just read the full text) is that insulin levels have a negative effect on lung function. This manifests itself by increased amounts of smooth muscle in the airways, PI3K/AKT mediated up-regulation of the beta catenin signaling pathway, and collagen type 1 deposition, all in an insulin level-dependent manner. That combination of symptoms is profibrotic and procontractile, meaning that the lungs stiffen and become less able to remodel due to the collagen, and asthma like obstructive disease is increased. The work was done in mice and cell culture using standard methods, not in humans, but these are well-studied pathways and similar effects are extremely likely in humans.
The point of the article is that there have been observations in the population that show a pronounced correlation between obesity, insulin resistance, hyperinsulinemia, and lung diseases, but until now nobody could show a cause and effect. This article outlined fairly persuasively a direct cause and effect linkage between hyperinsulinemia and deterioration of lung function due to fibrosis. Once fibrosis is established in any organ (as shown by consolidated collagen type 1 scar) then the organ is permanently impaired. Their conclusion is that nobody (anywhere) should use any insulin product without being aware of the risks, and that inhaled insulin poses an added level of risk that warrants further human studies before it becomes an accepted therapy.
Most of what I do involves regeneration of tissue, especially in fibrotic environments, so I look at this kind of study almost daily. The study was well-designed and controlled, and supports the imposition of a black box warning on Afrezza. The authors would be similarly cautious about careless use of injectable insulins and drugs (like metformin) that affect insulin production. Note again that the effects are seen with ANY insulin that is not properly controlled, not just Afrezza, but the risks are especially high with inhaled formulations. While that does not make for a better investment thesis in Mannkind, the science suggests that some caution is prudent.
For those of you with access to an academic library, the citations are:
PubMed PMID:26919895 DOI: 10.1152/ajplung.00091.2015 Thanks. Great comment. Why do you reckon that inhaled insulin is a higher risk? Inhaled insulin is absorbed rapidly. It just should not make a difference. The time period in the lungs is neglectable compared to the time in the system. Beside this I find it reasonable to argue that the issue is with long periods of high insulin. This is a situation when people have a lack of control about insulin levels. Afrezza enables a better control. It's insulin is faster out. Again I believe that linking inhaled' and fibrosis in the lung is misleading. At the first glance it sounds as if there is a correlation but that one is very weak. It is about kinetics and duration and both are positive with Afrezza. But sure, it would make great FUD.
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Post by cm5 on Jul 10, 2016 18:09:53 GMT -5
Understand concerns about initiation of fibrosis, specifically asking matt, who consistently posts critical information/assessments ---what is the correlation with duration of insulin (half-life) as an initiator of steps leading to initiation of fibrosis?
In other words, referring back to another post: Increased Intrinsic Disorder Propensity in Some Insulin Analogues as a Marker of their Increased MitogenicityPlus, untreated DM Type II are clinically notorious for multiple fibrotic changes, including cataracts, small vessel disease, poor healing, hard blood draws from thick, stiff, waxy integument----
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Post by cm5 on Jul 10, 2016 18:27:39 GMT -5
And, specifically asking matt, in studying fibrosis, what consideration is given to the role of matrix metalloproteinases (MMPs) activity? For explanation, MMP's involved in pathogenesis of glomerular fibrosis (renal fibrosis) and idiopathic pulmonary fibrosis--- Also, from Wikepedia---The MMPs play an important role in tissue remodeling associated with various physiological or pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and metastasis.
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Post by agedhippie on Jul 10, 2016 18:36:19 GMT -5
This is interesting. My endos's position is that he will not prescribe Afrezza until after the lung safety trials. Not because of a cancer risk (he doesn't expect there to be any cancer risk) but because of fibrosis. He believes that they were starting to see fibrosis in Exubera users. From this paper the chances are that it problem is far more widespread but they never had reason to look at the lungs of non-inhaled insulin users. I guess your endo needs to understand how Exubera works and Afrezza works so as to make that assumption. I meant the technology behind both. I am sure he is considering them same as they both are inhaled ? I feel sorry for his patients He knows how they work, I talked it over with him. His position is that they are both inhaled insulin so if there is an issue with one there may (not will) be an issue with the other. Diabetes is a long haul disease and a couple of years of OK treatment (a sub 7 A1c) makes little difference in the end so it is better to wait in his opinion. Even with a 'normal' A1c diabetics are prone to complications as insulin is only part of the problem. There is an immediate pay off in physically feeling better for being in range though.
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Post by cm5 on Jul 10, 2016 18:42:16 GMT -5
And, still considering MMP's in pathway to fibrosis-----for those interested, here is a good overview of MMP's and effects Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006 May 1;11:1696-701.www.ncbi.nlm.nih.gov/pubmed/16368548Diverse functions of matrix metalloproteinases during fibrosisMatthew Giannandrea, William C. Parks Disease Models and Mechanisms 2014 7: 193-203; doi: 10.1242/dmm.012062 dmm.biologists.org/content/7/2/193
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Post by cm5 on Jul 10, 2016 19:18:18 GMT -5
And, considering influence of insulin and promotion of fibrosis, prolongation of insulin association with elevated MMP's--- And, considering the it is a fact of physiology that the entire blood volume is pumped through the body approximately three times/minute, and that the lungs receive 100% of cardiac output, (for comparison, of course 100% of blood volume flows through heart; Brain, 14%; Heart, 4%; Liver and digestive system, 27%;Kidneys, 20%; Skeletal muscle, 21%; Skin, 5%; Bone and other tissues, 9%) Would not prolonged elevation/persistence of insulin (of any form) be relatively more significant than inhalation, especially given the close necessary proximity of alveolar blood vessels and air space to enable oxygen exchange?And, would not the longer lasting insulins continuing to circulate for many hours rather than the very short half life of Afrezza be a specific concern?Insulin augments matrix metalloproteinase-9 expression in monocytes. (just one study about this issue--) Cardiovasc Res. 2007 Mar 1;73(4):841-8. Epub 2006 Dec 12.www.ncbi.nlm.nih.gov/pubmed/17234168
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Post by peppy on Jul 10, 2016 19:37:27 GMT -5
What the paper says (I just read the full text) is that insulin levels have a negative effect on lung function. This manifests itself by increased amounts of smooth muscle in the airways, PI3K/AKT mediated up-regulation of the beta catenin signaling pathway, and collagen type 1 deposition, all in an insulin level-dependent manner. That combination of symptoms is profibrotic and procontractile, meaning that the lungs stiffen and become less able to remodel due to the collagen, and asthma like obstructive disease is increased. The work was done in mice and cell culture using standard methods, not in humans, but these are well-studied pathways and similar effects are extremely likely in humans.
This is interesting. My endos's position is that he will not prescribe Afrezza until after the lung safety trials. Not because of a cancer risk (he doesn't expect there to be any cancer risk) but because of fibrosis. He believes that they were starting to see fibrosis in Exubera users. From this paper the chances are that it problem is far more widespread but they never had reason to look at the lungs of non-inhaled insulin users. I have seen endo's stiffen up when asked about Afrezza. I see what your endo decided to tell patents.
My words, every picture tells a story don't it. If I was an endo and I didn't want to prescribe something, I could come up with a good reason. your endo was spewing it out.
We have turned over our medical treatments and knowledge bases to third parties that have been taught to medicate and care about.... ? The story being sold, I will not put you on afrezza, I care about your lungs too much. screencast.com/t/O4E1NxGdWKvt
The life cycle, we are born, we live, we die. Try to escape part three of life.
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Post by cm5 on Jul 10, 2016 19:54:40 GMT -5
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Post by agedhippie on Jul 10, 2016 20:25:40 GMT -5
Those patients all have high HbA1c numbers, that's not what I (or he) was talking about. I said 'a sub 7 A1c' and their lowest endpoint is 8. Since complications are exponential in that region it's a huge difference.
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Post by agedhippie on Jul 10, 2016 20:33:31 GMT -5
This is interesting. My endos's position is that he will not prescribe Afrezza until after the lung safety trials. Not because of a cancer risk (he doesn't expect there to be any cancer risk) but because of fibrosis. He believes that they were starting to see fibrosis in Exubera users. From this paper the chances are that it problem is far more widespread but they never had reason to look at the lungs of non-inhaled insulin users. I have seen endo's stiffen up when asked about Afrezza. I see what your endo decided to tell patents.
My words, every picture tells a story don't it. If I was an endo and I didn't want to prescribe something, I could come up with a good reason. your endo was spewing it out. For a lot of my doctors I would agree with you. However I went through a lot of endos to end up with this one and I chose him specifically because he would try most things, would go off label, and did a lot of research work. He very seldom says no (the last time was when I suggested using alcohol to suppress basal glucose )
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Post by tayl5 on Jul 10, 2016 22:20:04 GMT -5
I also read the paper and had the unexpected pleasure of meeting Anurag Agurwal at an event in Silicon Valley. He was highly knowledgeable about pulmonary function and very committed to the idea that inhaled insulin is bad. He was not particularly open to the idea that the mechanism of delivery is very different between inhaled Afrezza in Technosphere particles vs naked insulin protein shot up a rat's nose and would significantly affect the residence time in the airway epithelium. He also has a lung function device that he says is more sensitive than spirometry and detects effects that spirometry does not.
It will be good to get the safety study done to nail down and address any ongoing concerns.
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Post by mannmade on Jul 10, 2016 23:52:22 GMT -5
Forgive my ignorance on the subject, but if the issue is sustained high levels of insulin in the body doesn't the fast in/fast out profile of AFREZZA make it a better alternative than the current RAA's in which PWD often stack their insulin after meals?
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Post by Deleted on Jul 11, 2016 5:27:58 GMT -5
I guess your endo needs to understand how Exubera works and Afrezza works so as to make that assumption. I meant the technology behind both. I am sure he is considering them same as they both are inhaled ? I feel sorry for his patients He knows how they work, I talked it over with him. His position is that they are both inhaled insulin so if there is an issue with one there may (not will) be an issue with the other. Diabetes is a long haul disease and a couple of years of OK treatment (a sub 7 A1c) makes little difference in the end so it is better to wait in his opinion. Even with a 'normal' A1c diabetics are prone to complications as insulin is only part of the problem. There is an immediate pay off in physically feeling better for being in range though. thats why I feel sorry for your endo and you to assume since both are inhaled, there may be an issue with one since they was issue with one . Thats just an un educated way. You dont have to be an endo to make that assumption. Unfortunately he did. And when i say how they work, does he know exubera does also have sodium citrate,mannitol ,glycine ,sodium hydroxide ? they work the same lol...
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Post by agedhippie on Jul 11, 2016 7:28:43 GMT -5
He knows how they work, I talked it over with him. His position is that they are both inhaled insulin so if there is an issue with one there may (not will) be an issue with the other. Diabetes is a long haul disease and a couple of years of OK treatment (a sub 7 A1c) makes little difference in the end so it is better to wait in his opinion. Even with a 'normal' A1c diabetics are prone to complications as insulin is only part of the problem. There is an immediate pay off in physically feeling better for being in range though. thats why I feel sorry for your endo and you to assume since both are inhaled, there may be an issue with one since they was issue with one . Thats just an un educated way. You dont have to be an endo to make that assumption. Unfortunately he did. And when i say how they work, does he know exubera does also have sodium citrate,mannitol ,glycine ,sodium hydroxide ? they work the same lol... It's a valid approach - he says it may be an issue, you say it may not. At this point nobody knows because it hasn't been in the field long enough or widely enough. If there will be minimal progression while you wait and find out the result that is a perfect reasonable. We both think the probability of fibrosis is low but why take the risk? As to how it works - I said was that they were both inhaled not that they both worked the same (Exubera, Afrezza, and Dance all deliver inhaled insulin differently).
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