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Post by peppy on Jan 11, 2018 9:47:44 GMT -5
vdexdiabetesoh.com/Coming soon (Early 2018) “Take care of the patient and the business will take care of itself.” That was Alfred Mann’s philosophy. And it was his perspective that inspired the creation of Vdex. Al Mann started with the simple premise that the best way to manage blood sugar was the way the body did naturally…with insulin. But existing, synthetic insulins were dangerous, and it was not possible to make insulin that was chemically identical to that produced by the pancreas. For that reason, the pharmaceutical industry developed a host of medications to circumvent the use of insulin. Al Mann set his sights on the development of a natural, and safe, insulin. With a couple of decades of effort and more than a billion dollars, he gave us Afrezza, a bio-identical insulin, chemically identical to what the pancreas makes. ... Where do they think the insulin used in Afrezza comes from? It's the most widely sold insulin in the world, Regular insulin, and chemically identical. That highlighted sentence is flat out wrong. To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that?
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Post by victoria on Jan 11, 2018 11:51:28 GMT -5
Where do they think the insulin used in Afrezza comes from? It's the most widely sold insulin in the world, Regular insulin, and chemically identical. That highlighted sentence is flat out wrong. To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that? Isnt injected insulin an acidified hexamer insulin, to slow breakdown in the blood which would be too quick, ie its not the same chemical as the active form of insulin in the body whereas Afrezza is monomeric insulin contained within the Technosphere coating ie same type of insulin as the active form in the body? By contrast I think the body does produce a type of hexamer insulin but that is as part of storage and synthesis, not active use. So one can I suppose say hexamer insulin is 'natural' but its just not the right stuff if you want active sugar response, rather it is a chemical precursor of active insulin. With afrezza one directly uses the active natural version of insulin without the middleman. But Im no biochemist. Im not much of an investor either, now I think about it... I expect someone here can say it better. I think Im making similar point to Peppy.
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Post by agedhippie on Jan 11, 2018 13:38:27 GMT -5
Where do they think the insulin used in Afrezza comes from? It's the most widely sold insulin in the world, Regular insulin, and chemically identical. That highlighted sentence is flat out wrong. To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that? The performance of the insulin was identical, the delivery mechanism isn't. Subcutaneous insulin doesn't have a long tail (basals apart) because of the insulin, it has it because of the delivery mechanism - it takes time for the insulin to percolate into the bloodstream from the fatty tissue. This is why IV delivered insulin and Afrezza behaves so fast, because there is no slow draining from the fatty tissue. The long and short of it is that Afrezza does not act like a pancreas any more than I act like a musician because I can play the opening note of Beethoven's 5th. Afrezza delivers an arbitrary lump of insulin into the pulmonary veins unaccompanied by all the other hormones and similar that a human pancreas produces. The pancreas delivers a cocktail of hormones, insulin amongst them, in the exact size required and in pulses for maximum effect through the portal vein. The focus should be on outcomes - Afrezza gives a better outcome. The pancreas/natural insulin/whatever statement is a feature, while a better outcome is a benefit. Doctors will buy into patient benefits, not so much into features. This is the reason I keep beating the drum for superiority trials.
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Post by dreamboatcruise on Jan 11, 2018 13:45:41 GMT -5
To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that? Isnt injected insulin an acidified hexamer insulin, to slow breakdown in the blood which would be too quick, ie its not the same chemical as the active form of insulin in the body whereas Afrezza is monomeric insulin contained within the Technosphere coating ie same type of insulin as the active form in the body? By contrast I think the body does produce a type of hexamer insulin but that is as part of storage and synthesis, not active use. So one can I suppose say hexamer insulin is 'natural' but its just not the right stuff if you want active sugar response, rather it is a chemical precursor of active insulin. With afrezza one directly uses the active natural version of insulin without the middleman. But Im no biochemist. Im not much of an investor either, now I think about it... I expect someone here can say it better. I think Im making similar point to Peppy. I wrote a very long response getting into details, hit send and got an error... and the post was lost Short answer. There are different types of injected insulin, for the most part they are engineered to shift the balance of monomers vs hexamers vs even larger groups of multiple hexamers. The larger they are the longer it takes to migrate through fat and cross capillary walls. It isn't an issue of what happens once in the bloodstream. The pancreas does release insulin into blood in hexamer form and it disassociates rapidly into monomers, so the time differences are about how long it takes to get the insulin into the blood. Capillaries in pancreas are more permeable to the large hex insulin than capillaries elsewhere in body. Taking insulin solutions meant to be used subq and injecting them into muscle or intravenous will result in faster kinetics... with IV basically behaving similar to Afrezza. I believe that would even be true of long and ultra-long acting insulins though I'm not 100% positive on that. agedhippie ... agree that Afrezza is far from replicating the complex and reactive behavior of Pancreas (and the fact of where in circulatory system it releases insulin). Doctors who presumably know the physiology would be less impressed by the claim of "Pancreas like" behavior, but it appears that association does have some resonance with many patients even if the truth is the more complicated "replacing the first phase insulin response in a way closer to the pancreas' own response better than any other insulin other than when injected IV". Didn't see your post until I had already created mine. Yours is even more succinct.
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Post by peppy on Jan 11, 2018 14:11:33 GMT -5
To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that? The performance of the insulin was identical, the delivery mechanism isn't. Subcutaneous insulin doesn't have a long tail (basals apart) because of the insulin, it has it because of the delivery mechanism - it takes time for the insulin to percolate into the bloodstream from the fatty tissue. This is why IV delivered insulin and Afrezza behaves so fast, because there is no slow draining from the fatty tissue.The long and short of it is that Afrezza does not act like a pancreas any more than I act like a musician because I can play the opening note of Beethoven's 5th. Afrezza delivers an arbitrary lump of insulin into the pulmonary veins unaccompanied by all the other hormones and similar that a human pancreas produces. The pancreas delivers a cocktail of hormones, insulin amongst them, in the exact size required and in pulses for maximum effect through the portal vein. The focus should be on outcomes - Afrezza gives a better outcome. The pancreas/natural insulin/whatever statement is a feature, while a better outcome is a benefit. Doctors will buy into patient benefits, not so much into features. This is the reason I keep beating the drum for superiority trials. quote; unaccompanied by all the other hormones and similar that a human pancreas produces. Aged, as a type one diabetic, does the pancreas still push out the pancreatic enzymes? (I know I should look it up) Normally, a healthy Pancreas will secrete about 8 cups of this pancreatic juice each day. This juice contains both pancreatic enzymes for digestion and bicarbonate to help neutralize stomach acid. pancreatitisfacts.com/pancreatic-enzymes/
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Post by agedhippie on Jan 11, 2018 14:45:53 GMT -5
To your point. it was not possible to make insulin that performed identically to that produced by the pancreas, because the delivery was subcuteneous rather than into the blood stream. How's that? Isnt injected insulin an acidified hexamer insulin, to slow breakdown in the blood which would be too quick, ie its not the same chemical as the active form of insulin in the body whereas Afrezza is monomeric insulin contained within the Technosphere coating ie same type of insulin as the active form in the body? By contrast I think the body does produce a type of hexamer insulin but that is as part of storage and synthesis, not active use. So one can I suppose say hexamer insulin is 'natural' but its just not the right stuff if you want active sugar response, rather it is a chemical precursor of active insulin. With afrezza one directly uses the active natural version of insulin without the middleman. But Im no biochemist. Im not much of an investor either, now I think about it... I expect someone here can say it better. I think Im making similar point to Peppy. Sort of Lantus and maybe other basals behave like that because you want to form crystals which the body's pH then slowly dissolve (also apparently why Lantus occasionally stings). Hexamers are a hugely overstated problem. As soon as a hexamer hits the blood stream the lower pH and low zinc environment mean the hexamer can nolonger hold together and the hexamer falls apart into monomers. You are absolutely correct though that hexamer form insulin cannot be used to store glucose, only monomeric form insulin can do that. From the useless facts section... The body keeps hexamers stable by keeping them in a high zinc environment with the zinc ions holding the hexamers together. NPH insulin uses zinc for the same purpose.
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Post by agedhippie on Jan 11, 2018 14:51:31 GMT -5
The performance of the insulin was identical, the delivery mechanism isn't. Subcutaneous insulin doesn't have a long tail (basals apart) because of the insulin, it has it because of the delivery mechanism - it takes time for the insulin to percolate into the bloodstream from the fatty tissue. This is why IV delivered insulin and Afrezza behaves so fast, because there is no slow draining from the fatty tissue.The long and short of it is that Afrezza does not act like a pancreas any more than I act like a musician because I can play the opening note of Beethoven's 5th. Afrezza delivers an arbitrary lump of insulin into the pulmonary veins unaccompanied by all the other hormones and similar that a human pancreas produces. The pancreas delivers a cocktail of hormones, insulin amongst them, in the exact size required and in pulses for maximum effect through the portal vein. The focus should be on outcomes - Afrezza gives a better outcome. The pancreas/natural insulin/whatever statement is a feature, while a better outcome is a benefit. Doctors will buy into patient benefits, not so much into features. This is the reason I keep beating the drum for superiority trials. quote; unaccompanied by all the other hormones and similar that a human pancreas produces. Aged, as a type one diabetic, does the pancreas still push out the pancreatic enzymes? (I know I should look it up) Normally, a healthy Pancreas will secrete about 8 cups of this pancreatic juice each day. This juice contains both pancreatic enzymes for digestion and bicarbonate to help neutralize stomach acid. pancreatitisfacts.com/pancreatic-enzymes/Gulp. I never thought about that, but I suspect it does or I would have bigger problems. There are other things that don't happen or are blunted with Type 1 c-peptide, amylin, and glucagon to an extent (glucagon response is blunted). I am not sure about some of the peptides, typically they seem to be blunted.
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Post by dreamboatcruise on Jan 11, 2018 15:17:26 GMT -5
quote; unaccompanied by all the other hormones and similar that a human pancreas produces. Aged, as a type one diabetic, does the pancreas still push out the pancreatic enzymes? (I know I should look it up) Normally, a healthy Pancreas will secrete about 8 cups of this pancreatic juice each day. This juice contains both pancreatic enzymes for digestion and bicarbonate to help neutralize stomach acid. pancreatitisfacts.com/pancreatic-enzymes/Gulp. I never thought about that, but I suspect it does or I would have bigger problems. There are other things that don't happen or are blunted with Type 1 c-peptide, amylin, and glucagon to an extent (glucagon response is blunted). I am not sure about some of the peptides, typically they seem to be blunted. Typically you hear that beta cells are the ones being attacked by immune system in T1. Those are responsible for insulin including the c-peptide which is a fragment byproduct of insulin production. Glucagon is produced by alpha cells so if that is also blunted it would imply either immune system is also killing them off or there is some dependency of their action on proper action of beta cells. The endocrine functions of the pancreas are carried out by the islets of Langerhans cell clusters (alpha, beta, gamma and delta cells). The non-endocrine functions, such as enzyme production, are from other cells within pancreas, which I'm pretty certain are not being attacked by immune system in T1. I wonder if there are rarer forms of autoimmune where the other pancreatic cells are attacked... it seems there is hardly any type of cell in the body where there isn't possibility for auto-immune attack. It is curious why some cells are much more susceptible to having autoimmune response develop. I don't think they've really figured that out conclusively though I think the answer is being pursued by many. I have one of the autoimmune diseases, so always been interested in following new research in the field.
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Post by mango on Jan 11, 2018 15:54:04 GMT -5
Injectable insulins, especially RAAs, are unstable, contain numerous additives, and have erratic and slow absorption—all of which consequently allows for it to easily degrade/misfold. This is why injectable insulins can cause a serious condition known as localized insulin-derived amyloidosis.
With Afrezza, there is none of those issues. Afrezza is a stable monomeric insulin whose kinetics mimic intra-arterial administration. There has been zero incidence and/or evidence to date regarding insulin amyloids within the pulmonary tract from use of Afrezza. Put simply—Afrezza is the safest insulin, as well as, the best prandial insulin in the world.
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Post by peppy on Jan 11, 2018 16:13:48 GMT -5
Gulp. I never thought about that, but I suspect it does or I would have bigger problems. There are other things that don't happen or are blunted with Type 1 c-peptide, amylin, and glucagon to an extent (glucagon response is blunted). I am not sure about some of the peptides, typically they seem to be blunted. Typically you hear that beta cells are the ones being attacked by immune system in T1. Those are responsible for insulin including the c-peptide which is a fragment byproduct of insulin production. Glucagon is produced by alpha cells so if that is also blunted it would imply either immune system is also killing them off or there is some dependency of their action on proper action of beta cells. The endocrine functions of the pancreas are carried out by the islets of Langerhans cell clusters (alpha, beta, gamma and delta cells). The non-endocrine functions, such as enzyme production, are from other cells within pancreas, which I'm pretty certain are not being attacked by immune system in T1. I wonder if there are rarer forms of autoimmune where the other pancreatic cells are attacked... it seems there is hardly any type of cell in the body where there isn't possibility for auto-immune attack. It is curious why some cells are much more susceptible to having autoimmune response develop. I don't think they've really figured that out conclusively though I think the answer is being pursued by many. I have one of the autoimmune diseases, so always been interested in following new research in the field. quote: I wonder if there are rarer forms of autoimmune where the other pancreatic cells are attacked... reply: as an aside dreamboat, cyctic fibrous requires pancreatic enzymes as part of trx.
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Post by mango on Jan 11, 2018 16:27:03 GMT -5
Isnt injected insulin an acidified hexamer insulin, to slow breakdown in the blood which would be too quick, ie its not the same chemical as the active form of insulin in the body whereas Afrezza is monomeric insulin contained within the Technosphere coating ie same type of insulin as the active form in the body? By contrast I think the body does produce a type of hexamer insulin but that is as part of storage and synthesis, not active use. So one can I suppose say hexamer insulin is 'natural' but its just not the right stuff if you want active sugar response, rather it is a chemical precursor of active insulin. With afrezza one directly uses the active natural version of insulin without the middleman. But Im no biochemist. Im not much of an investor either, now I think about it... I expect someone here can say it better. I think Im making similar point to Peppy. Sort of Lantus and maybe other basals behave like that because you want to form crystals which the body's pH then slowly dissolve (also apparently why Lantus occasionally stings). Hexamers are a hugely overstated problem. As soon as a hexamer hits the blood stream the lower pH and low zinc environment mean the hexamer can nolonger hold together and the hexamer falls apart into monomers. You are absolutely correct though that hexamer form insulin cannot be used to store glucose, only monomeric form insulin can do that. From the useless facts section... The body keeps hexamers stable by keeping them in a high zinc environment with the zinc ions holding the hexamers together. NPH insulin uses zinc for the same purpose. Once in the bloodstream, it is glutamate 13 that promotes the dissociation of the insulin hexamer into an insulin monomer. Glutamate 13 is on the b chain located at the center of an insulin hexamer. The lower zinc concentration in the bloodstream simply allows for the dissocation. Also, the pH in the bloodstream is higher, not lower, than the storage vesicles.
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Post by dreamboatcruise on Jan 11, 2018 16:31:18 GMT -5
Injectable insulins, especially RAAs, are unstable, contain numerous additives, and have erratic and slow absorption—all of which consequently allows for it to easily degrade/misfold. This is why injectable insulins can cause a serious condition known as localized insulin-derived amyloidosis. With Afrezza, there is none of those issues. Afrezza is a stable monomeric insulin whose kinetics mimic intra-arterial administration. There has been zero incidence and/or evidence to date regarding insulin amyloids within the pulmonary tract from use of Afrezza. Put simply—Afrezza is the safest insulin, as well as, the best prandial insulin in the world. I think you're getting ahead of what the literature says about "why" insulin amyloids form at injection site. It could be that taking insulin directly from someone's pancreas (if feasible) and injecting it subq would cause the same. Insulin amyloids occur in the pancreas itself for people with diabetes regardless of insulin treatment (according to at least one source I've read)... so it certainly is possible for insulin amyloids that have nothing to do with small differences in RAA vs what the body produces. Who knows, perhaps if TS Insulin were injected subq it might also illicit that response in some. You are correct that no evidence of amyloids in lungs has yet to be reported with Afrezza. That may simply be that it is transported so quickly into blood stream it doesn't stick around in high concentrations in the lung long enough to invoke whatever process results in amyloids. Lack of amyloid possibility may thus be benefit of route of delivery. On the flip side the theoretical issue with lung deliver is insulin antibody development, though this was looked at extensively with Afrezza and so far seems to not be clinically relevant... though some chance long term studies would have this pop up as a quite rare issue of concern. At least that is the only outstanding safety issue I personally believe is a credible one. I would also perhaps question use of "serious" with regard to insulin amyloidosis. It is considered rare (though perhaps under reported), and most seem to believe that more frequent rotation of injection sites would prevent it for the vast majority. Additionally, the main complication is that it can mess with insulin absorption if one continues to use an injection site where it has formed. But obviously "serious" is in the eye of the beholder. [Edit: Between the three of us, I think we could write a good tutorial on insulins. Though I suspect the three of us would be the only ones interested in the final product.]
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Post by sayhey24 on Jan 11, 2018 19:55:38 GMT -5
vdexdiabetesoh.com/Coming soon (Early 2018) “Take care of the patient and the business will take care of itself.” That was Alfred Mann’s philosophy. And it was his perspective that inspired the creation of Vdex. Al Mann started with the simple premise that the best way to manage blood sugar was the way the body did naturally…with insulin. But existing, synthetic insulins were dangerous, and it was not possible to make insulin that was chemically identical to that produced by the pancreas. For that reason, the pharmaceutical industry developed a host of medications to circumvent the use of insulin. Al Mann set his sights on the development of a natural, and safe, insulin. With a couple of decades of effort and more than a billion dollars, he gave us Afrezza, a bio-identical insulin, chemically identical to what the pancreas makes. ... Where do they think the insulin used in Afrezza comes from? It's the most widely sold insulin in the world, Regular insulin, and chemically identical. That highlighted sentence is flat out wrong. "Flat out wrong" - Now that's a little harsh. I think most of us know what they meant but maybe did not say it correctly. Maybe something like "Al Mann started with the simple premise that the best way to manage blood sugar was the way the body did naturally…with insulin. However, traditional insulin treatment is viewed as dangerous because exogenous insulin prior to afrezza has not been able to mimic the speed of naturally released pancreatic insulin. This is the result of a number of factors but primarily is due to the absorption rate of the insulin into the blood when injected in a subcutaneous manner. The absorption rate varies due to many factors including the amount of insulin injected, the molecular makeup of the insulin analog and other factors such as a persons hydration at that point in time. This unpredictable absorption rate raises the risk of hypoglycemia which can cause a serious medical condition including death. To avoid the risk of hypoglycemia the pharmaceutical industry developed a host of medications to circumvent the use of insulin..." As Al Mann said "In early Type 2, a variety of alternative antiglycemic drugs are used today and these products are viable largely because of the deficiencies of current insulin products. But it is insulin that the body needs for glucose metabolism. Even with the limitations of current insulin products, there is increasing pressure to move patients much sooner to exogenous insulin. The alternative antiglycemic products are intended simply to supplement endogenous pancreatic insulin more effectively. Some of them are directed to increasing pancreatic output, likely contributing to early-year beta cell burnout. Other products have tested lower resistance to insulin to inhibit hepatic glucose release or to slow digestion, but all of these drugs have limited efficacy and side effects that can be significant in some patients and the long-term safety for many of them may still be in doubt. Moreover, none of these antiglycemics, I believe, does slow progression of the disease so that, after 8 to 12 years, patients using those drugs typically move on to insulins.” Al Mann set his sights on the development of a natural, and safe, insulin. After several decades of effort and more than a billion dollars, the result was "afrezza", a bio-identical insulin, which is molecularity identical to the monomer human insulin naturally used by the body and made by the pancreas." Please help crowd-source to better wordsmith the above and we can help VDex make their website better.
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Post by dreamboatcruise on Jan 11, 2018 20:38:56 GMT -5
I think Al may have been too generous in his view of the medical community when stating that "there is increasing pressure to move patients much sooner to exogenous insulin" when in reality it seems the focus is as much as ever on creating new non-insulin drugs to postpone insulin initiation. But if that is a quote from Al, you can't edit it.
Only thing I'd take exception to outside of Al's quote, is the second to last paragraph. The way that is worded makes it seem as if MNKD invented Recombinant Human Insulin. Would suggest...
"Al Mann set his sights on the development of an insulin that could better mimic the rapid onset and clearance of endogenous pancreatic insulin and thus provide greater time within target range for blood glucose. After decades and more than a billion dollars, the result was "Afrezza", a mechanism of stabilizing recombinant human insulin in a form that can be delivered into the deep lung through inhalation and rapidly pass into the bloodstream."
If it were me, I'd want to see some reference to Al stating that "natural" was something he considered Afrezza before using that term. Mimicking the pancreas in first phase release, yes... but from what I know of Al, he wouldn't have claimed Afrezza was "natural" or had that as a goal in the first place. I suspect he viewed it as a marvel of engineering, rather than natural. Open to correction if he really ever said something about Afrezza being a more "natural" form of exogenous insulin. Might be picking nits, but "if it walks like a duck and quakes like a duck, it is a natural duck" isn't going to hold true once we have android ducks.
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Post by rockstarrick on Jan 12, 2018 1:47:29 GMT -5
What Al did was what every Pharmaceutical Company with a Diabetes profile was trying to do. Al figured out how to stabilize and deliver Human Insulin in the form of a monomer. Not only did he stabilize monmeric Human Insulin, he also developed a delivery device that allows the Insulin to be delivered without getting destroyed in the stomach. Isn’t that why most Insulin is injected, because it can’t survive ingestion ??
I’m way out of my league on this subject, but this is how I understood it. Proteins and peptides are not stable enough to ingest, that’s why they are injected, Right ?? BP tried and failed, Al Mann got it right. Afrezza isn’t going anywhere,,, Inhaled Insulin is now a reality. Take a Bow Al 🎬
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