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Post by bobw on Feb 11, 2015 12:15:25 GMT -5
I have been thinking about why titration is not that important when using Afrezza. Feedback or corrections from any doctors, chemists or informed investor on the board would be appreciated. The following is my understanding of the process of insulin’s life in the body.
Insulin is typically degraded, by liver cells, about 71 minutes after its initial release into circulation. Afrezza is quickly released into circulation because it is an insulin monomer and is inhaled into the lungs. Novolog and Humalog are taken subcutaneously as insulin hexamers, so they are slowly released into circulation. This is an important point: the insulin from Novolog and Humalog degrades at about the same rate as the insulin from Afrezza, but because Novolog and Humalog are absorbed slower, there is a much longer tail from Novolog and Humalog.
Now think about how insulin affects glucose absorption. A cell’s insulin receptors, when an insulin molecule binds to it, leads to an increase in the glucose transporter (Glut4) molecules that induce glucose uptake. Once insulin binds to an insulin receptor, additional insulin has no further effect on that receptor.
With Afrezza, insulin is bound to many insulin receptors for about 71 minutes after the insulin has been absorbed through the lungs and into circulation. Since absorption is quick, the final 71 minutes starts soon after inhaling Afrezza. With Humalog and Novolog, the final 71 minutes happens much later because new insulin molecules are continually being absorbed for a much longer period.
While a meal is being digested, there is a steady influx of glucose entering the bloodstream. It takes some time for that glucose to absorb, even if many cells have active insulin receptors. If the rate of glucose is entering circulation is as high as the rate of cellular uptake, then there is no drop in the level of serum glucose. Depending on the glycemic index of the food that was consumed with the meal, glucose will continue to enter circulation for a specific period of time. If the time that glucose is enter the circulation is similar to the time that Afrezza is also still in circulation, then glucose levels will not drop too low.
If the dose of Afrezza was larger than needed, the excess insulin degrades quickly, before the meal is fully digested, without causing a low. With Novolog and Humalog, the excess insulin does not degrade as quickly, the excess insulin is problematic because it is still in circulation after the meal is digested.
My conclusion is that, for these reasons, a higher dose of Afrezza can be taken without causing hypoglycemia. If you need 1-4 units of Novolog, you can take 4 units of Afrezza without a problem; the excess insulin is degraded before it causes a problem.
From Wikipedia: “Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.”
BobW
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Post by robsacher on Feb 11, 2015 14:52:03 GMT -5
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Post by jpg on Feb 11, 2015 15:33:29 GMT -5
I will preface my comment by saying that as a general rule I don't repeatedly reading stuff written by anonymous authors and especially so when I don't trust them. PA happens to fall in my 'double hit' group: anonymous and for various reasons I don't trust him. I haven't read the majority of what PA has recently written. I dislike the asymmetrical advantage that is given to anonymous authors who can spin as they please and just walk away if and when their reputation is toast. I did glance at the link you provided in which PA states (The Pitfalls Of Poster Boys) AU is or might be the 'perfect patient' for Afrezza dosing and that his CGM results shouldn't be extrapolated to others. This to me is simplistic and shows a lack of understanding of basic insulin function. The above poster, using only Wiki it seems, does a far better job explains significant parts of how Aftezza works. Again from his latest article I really doubt PA is very knowledgable about monomeric insulin kinetics and we should be cautious in using his scientific understanding (or lack of) as a basis for evaluating Afrezza. For whatever reason I think he is simply trying to disqualify the poster boy for Afrezza. His statement of 'where are the other users' almost makes me cringe. As an investor I get what he is saying but as an MD I know very few patients who actually like parading publicly wight their disease. In the same section PA equating Afrezza with Exubera leaves me again questioning his understanding of basic insulin PK/ PD. All this to say I really doubt PA is much of a scientific expert on insulin or diabetes. |
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Post by gomnkd on Feb 11, 2015 17:51:29 GMT -5
A simplistic explanation is that it is hard to get hypos when meal time insulin is present only when meal is getting digested. you get into a more unpredictable/uncertain world when meal time insulin continues to work with great force even after 3 hours. After 3 hours you are running on empty and body has to deal with basal + big tail of RAA. to add insult to injury, you take correctional dose, it takes longer to act and you now have basal+ tail of RAA+ fresh correctional. Now think of the situation when you are taking a 2nd correctional. To deal with this inherent uncertainty, you use accurate titration. i also believe that Afrezza users will need less correctional dose. The reason is that PPG excursions are lower for Afrezza. lh4.ggpht.com/_pwLWhRx1CYQ/TFbJxz42hAI/AAAAAAAABF8/-ejbDHsBjC4/s1600-h/ppgbreakfastchallenge3.pngAlso Afrezza shutting off some hepatic secretion also helps. |
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Post by gomnkd on Feb 11, 2015 18:00:18 GMT -5
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Post by mdcenter61 on Feb 11, 2015 19:09:52 GMT -5
Go - not only did you cover it but it looks like you nailed it! I am obviously hoping that more users, given some time, will further support this. I really enjoyed your blog back in the day when I was early into my MNKD journey and am very glad you have joined us here! Cheers. |
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Post by bobw on Feb 11, 2015 22:13:46 GMT -5
Thank you for your thoughtful responses.
I have seen many explanations of what happens, but not why you don't get a low from Afrezza. The simple answer to the what question is that your body is not that sensitive to the precise level of insulin for the amount of carbohydrates ingested as long as the insulin doesn't hang around too long. Consider two different meals, one with a high glycemic index such as a bagel, the other with a low glycemic index such as a bowl of oatmeal, both with the same amount of carbohydrates and calories. The bagel will signal to your pancreas to excrete a large amount of insulin because it detects a rapid and large rise in glucose (fooling it into thinking that a very large meal was consumed), whereas the oatmeal will signal the excretion of a much smaller amount of insulin because the glucose is released much slower (in a manner that evolution has perfected over millions of years). Yet, a non-diabetic will not have a hypoglycemic event from eating the bagel. The bagel may cause a larger glucose spike and a lower post meal low, but the range will not differ enough to cause a significant low. Since the timing of Afrezza is similar to the timing of endogenous insulin, Afrezza works similar to the natural insulin from your pancreas. This all seems to make sense to me for an explanation of what happens.
My post above tried to examine why this happens. The why has taken me much longer to start to understand and I feel less certain that I have everything correct.
Again, thanks for your feedback,
BobW
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Post by ezrasfund on Feb 11, 2015 22:51:38 GMT -5
I have been thinking about why titration is not that important when using Afrezza. Feedback or corrections from any doctors, chemists or informed investor on the board would be appreciated. The following is my understanding of the process of insulin’s life in the body.
Insulin is typically degraded, by liver cells, about 71 minutes after its initial release into circulation. Afrezza is quickly released into circulation because it is an insulin monomer and is inhaled into the lungs. Novolog and Humalog are taken subcutaneously as insulin hexamers, so they are slowly released into circulation. This is an important point: the insulin from Novolog and Humalog degrades at about the same rate as the insulin from Afrezza, but because Novolog and Humalog are absorbed slower, there is a much longer tail from Novolog and Humalog.
Now think about how insulin affects glucose absorption. A cell’s insulin receptors, when an insulin molecule binds to it, leads to an increase in the glucose transporter (Glut4) molecules that induce glucose uptake. Once insulin binds to an insulin receptor, additional insulin has no further effect on that receptor.
With Afrezza, insulin is bound to many insulin receptors for about 71 minutes after the insulin has been absorbed through the lungs and into circulation. Since absorption is quick, the final 71 minutes starts soon after inhaling Afrezza. With Humalog and Novolog, the final 71 minutes happens much later because new insulin molecules are continually being absorbed for a much longer period.
While a meal is being digested, there is a steady influx of glucose entering the bloodstream. It takes some time for that glucose to absorb, even if many cells have active insulin receptors. If the rate of glucose is entering circulation is as high as the rate of cellular uptake, then there is no drop in the level of serum glucose. Depending on the glycemic index of the food that was consumed with the meal, glucose will continue to enter circulation for a specific period of time. If the time that glucose is enter the circulation is similar to the time that Afrezza is also still in circulation, then glucose levels will not drop too low.
If the dose of Afrezza was larger than needed, the excess insulin degrades quickly, before the meal is fully digested, without causing a low. With Novolog and Humalog, the excess insulin does not degrade as quickly, the excess insulin is problematic because it is still in circulation after the meal is digested.
My conclusion is that, for these reasons, a higher dose of Afrezza can be taken without causing hypoglycemia. If you need 1-4 units of Novolog, you can take 4 units of Afrezza without a problem; the excess insulin is degraded before it causes a problem.
From Wikipedia: “Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.”
BobW
I think that this is the key to understanding why additional insulin does not mean additional glucose uptake. The limiting factor is the number of insulin receptors. If insulin binds to them all then additional insulin has no effect on the rate of glucose uptake. But while the rate of glucose uptake is not effected by additional insulin, the total amount of glucose uptake is still effected by the total time that elevated levels of prandial insulin remain in the system. Because Afrezza leaves the body quickly and the rate of glucose metabolism is capped, the total glucose metabolized is similarly capped. With subcutaneous insulins the rate also may be capped, but the time can be hours and so the total glucose metabolized can be too much and cause a hypo. (It may be that the body's fail-safe mechanism is that insulin is degraded after about 71 minutes in the blood stream, but subcutaneous insulin subverts this mechanism by continuing to add insulin to the blood over a prolonged period of time.) [forgive me, but I do not even pretend to understand biochemistry] |
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Post by EveningOfTheDay on Feb 12, 2015 0:31:37 GMT -5
I have been thinking about why titration is not that important when using Afrezza. Feedback or corrections from any doctors, chemists or informed investor on the board would be appreciated. The following is my understanding of the process of insulin’s life in the body.
Insulin is typically degraded, by liver cells, about 71 minutes after its initial release into circulation. Afrezza is quickly released into circulation because it is an insulin monomer and is inhaled into the lungs. Novolog and Humalog are taken subcutaneously as insulin hexamers, so they are slowly released into circulation. This is an important point: the insulin from Novolog and Humalog degrades at about the same rate as the insulin from Afrezza, but because Novolog and Humalog are absorbed slower, there is a much longer tail from Novolog and Humalog.
Now think about how insulin affects glucose absorption. A cell’s insulin receptors, when an insulin molecule binds to it, leads to an increase in the glucose transporter (Glut4) molecules that induce glucose uptake. Once insulin binds to an insulin receptor, additional insulin has no further effect on that receptor.
With Afrezza, insulin is bound to many insulin receptors for about 71 minutes after the insulin has been absorbed through the lungs and into circulation. Since absorption is quick, the final 71 minutes starts soon after inhaling Afrezza. With Humalog and Novolog, the final 71 minutes happens much later because new insulin molecules are continually being absorbed for a much longer period.
While a meal is being digested, there is a steady influx of glucose entering the bloodstream. It takes some time for that glucose to absorb, even if many cells have active insulin receptors. If the rate of glucose is entering circulation is as high as the rate of cellular uptake, then there is no drop in the level of serum glucose. Depending on the glycemic index of the food that was consumed with the meal, glucose will continue to enter circulation for a specific period of time. If the time that glucose is enter the circulation is similar to the time that Afrezza is also still in circulation, then glucose levels will not drop too low.
If the dose of Afrezza was larger than needed, the excess insulin degrades quickly, before the meal is fully digested, without causing a low. With Novolog and Humalog, the excess insulin does not degrade as quickly, the excess insulin is problematic because it is still in circulation after the meal is digested.
My conclusion is that, for these reasons, a higher dose of Afrezza can be taken without causing hypoglycemia. If you need 1-4 units of Novolog, you can take 4 units of Afrezza without a problem; the excess insulin is degraded before it causes a problem.
From Wikipedia: “Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.”
BobW
Bob, thank you very much for your post. I also have been trying to find the exact same thing, so I could explain it to a very good friend that is Type 1. Your explanation makes total sense and is concise and easy to understand. I hope you do not mind but I probably will copy it and send it to my friend after editing the parts about Homolog and Novolog and change them for other rapid acting insulins. Once again thank you very much for your post. |
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Post by gomnkd on Feb 12, 2015 8:58:51 GMT -5
To me, the single most important piece of info that increases the value of MNKD is that Afrezza users can achieve better results by tweaking compared to trial results.
I want to echo jpg sentiments about psychoanalyst. He doesn't seem to get Afrezza. PA writes so much and has so little to say.
Analyze PA's comment about better trial design to show A1C superiority. A trial entails following a same protocol for all patients. You follow a simple instruction like "take Afrezza before X minutes ". Finta has shown how this can be tweaked based on initial bg level to achieve better results.
I expect some crowd sourced intelligence to help diabetics come up with thumb rules to extract the best out of Afrezza and beat the living crap out of Novolog & Humalog.
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Post by bobw on Feb 12, 2015 9:14:26 GMT -5
EveningOfTheDay, feel free to use as you see fit and thanks for your appreciation. gomnkd, jpg and ezrasfund I couldn't agree more with your comments.
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Post by ezrasfund on Feb 12, 2015 10:35:13 GMT -5
Still more simply...Remember that insulin does not act directly on glucose in the bloodstream.
Insulin enables the cells to metabolize glucose. It is easy to think that the amount glucose metabolized is proportional to the amount of insulin in the blood. This is an oversimplification. It is true only to the extent there are cells to metabolize glucose. So at a certain point more insulin does not mean more glucose metabolized.
But there is another source of misunderstanding. More insulin over a longer period of time (like subcutaneous) does mean more glucose metabolized. This is why Afrezza's "fast out" property is so important.
"[Insulin] regulates the metabolism of carbohydrates and fats by promoting the absorption of glucose from the blood to skeletal muscles and fat tissue and by causing fat to be stored rather than used for energy. Insulin also inhibits the production of glucose by the liver"
-Wikipedia
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Post by gomnkd on Feb 12, 2015 11:44:32 GMT -5
Still more simply...Remember that insulin does not act directly on glucose in the bloodstream. Insulin enables the cells to metabolize glucose. It is easy to think that the amount glucose metabolized is proportional to the amount of insulin in the blood. This is an oversimplification. It is true only to the extent there are cells to metabolize glucose. So at a certain point more insulin does not mean more glucose metabolized. But there is another source of misunderstanding. More insulin over a longer period of time (like subcutaneous) does mean more glucose metabolized. This is why Afrezza's "fast out" property is so important. "[Insulin] regulates the metabolism of carbohydrates and fats by promoting the absorption of glucose from the blood to skeletal muscles and fat tissue and by causing fat to be stored rather than used for energy. Insulin also inhibits the production of glucose by the liver" -Wikipedia First, researchers are still working on to get a better understanding. 2nd: Nature, using millions of years of evolution comes up with a process that works. The process is high spike during ingestion followed by rapid drop. Guess what, Afrezza is mimicking it better than others. 3: See last but two para in www.medbio.info/horn/time%203-4/insulin%27s%20mechanism%20of%20action.htm"Insulin's regulation of hepatic metabolism is a major element in control of blood glucose levels. Inappropriate gluconeogenesis in postprandial periods is a key to the hyperglycemia seen in type 2 diabetes. "  Afrezza curve is better For type 1's like Finta, the dosage of basal + timing of meal time insulin controls the hypos. 4. Another key to understanding Afrezza is the GIR curve. I had posted this in OPC board under thread "faster fast"  I drew a vertical line to highlight the difference. Look at how at 30 mins, Afrezza acts very strong and then tapers off rapidly. You need this rapid tapering off to reduce hypos. GIR in simple terms is the amount of glucose you need to infuse in the body (for given amount of insulin already injected) to maintain normal bg levels. In graph above, after 150, Afrezza doesn't need much glucose but lispro is acting strong and needs tons of glucose. If you dont provide the extra, you get into hypos. |
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Post by bobw on Feb 12, 2015 13:30:00 GMT -5
gomnkd, I think your point 2 is the crux of why Afrezza works so well. I have always heard that Afrezza regulates hepatic glucose production better than the RAAs, but have not seen the graph before, so thatnk for posting it. I am assuming that the y-axis, EGP is endogenous glucose production.
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Post by silentbob on Feb 12, 2015 18:30:57 GMT -5
Gomnkd is correct, differentiating factor is all about how afrezza affects gluconeogenesis/endogenous glucose production.
Bobw, your theory about insulin receptors and glucose transporters is not wrong by itself, but this effect mostly just influences the conversion rate we need to use for technosphere insulin vs injected insulin. If cells were able to take up more glucose in the short timespan that Afrezza is active, then we would just need a different conversion factor (now it is 10:4 for afrezza:injected).
I will write a more thorough post on this over the weekend if there is sufficient interest...
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