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Post by mango on Jun 10, 2022 11:25:43 GMT -5
Aged, it’s medically incorrect to put a T2D on basal insulin. T2Ds have a diminished, ineffective first phase response, also known as an eating-induced insulin secretion response. All the “other problems” are because of dysregulation of post prandial glucose homeostasis. Afrezza fixes this. In fact, it’s the only insulin currently on the market that is capable of fixing the underlying defect in T2D which is the loss of the eating-induced insulin response. Afrezza mimics physiologic prandial insulin secretion. No other mealtime insulin has the pharmacokinetics to achieve this. This where we differ. You seem to see Type 2 as a result of and insulin deficiency and all the associated issues like high BP, lipid disfunction, insulin resistance, alpha cell disfunction, etc. as a result of that. The medical world sees those as a broken metabolism usually referred to as Metabolic Syndrome. I am in that latter camp, I think hyperglycemia is just one aspect of Metabolic Syndrome. Sorting out post prandial meal spikes does not fix all the other issues and those continue to drive hyperglycemia (alpha cells, excessive basal output, increasing insulin resistance in muscles). You can restore glucose homostasis for a while via diet and/or weight loss since both reduce the demand on the pancreas and allow you to live within your insulin budget. Depending on how aggressive the Metabolic Syndrome is (which genes are involved) that can result in almost indefinite remission, or buy you a few years. Aged, do the people with Type 2 who use Afrezza have those problems? I don’t think they do. It’s because not only do they have their post meal spike fixed, they have their eating-induced insulin secretion problem fixed, which is a vital player in glucose homeostasis. None of the orals or injectables (including RAAs) addresses the underlying defect, which is the diminished eating-induced insulin secretion response that is responsible for the post meal spike. Without addressing the underlying defect you’re just putting a bandaid on the problem. That’s why Afrezza is special, it solves the underlying issue. Remember, it’s the first phase kinetics of the eating induced insulin response (the very response that Afrezza kinetics mimics) that is responsible for all the wonderful things we see like the signaling to stop hepatic glucose production. When the first phase is defective, post prandial glucose homeostasis is dysregulated and we get the post meal spike. |
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Post by sayhey24 on Jun 10, 2022 11:27:04 GMT -5
Aged - you say "Sorting out post prandial meal spikes does not fix all the other issues" how do we know? The thing is until afrezza we could not stop the post meal spike. We really have as a community very very little experience "stopping the spike". In a non-diabetic they don't usually have all these other Metabolic Syndrome issues do they?
I am a simple guy. We know we can fix the post meal spike so lets start there. Maybe after the beta cells start regenerating we will also see improvement with "insulin resistance" and the other issues. Maybe having that screwed up glucose level and no first phase release is making most of the mess? We do know that big pop of afrezza gets the liver back in sync.
BTW - there is nothing wrong with a good walk and some weight loss but adding afrezza on top of that is even better and the earlier the better to restore PPG control. The walk and weight just don't help a lot with the first phase release as we see on the CGMs we are still seeing the spikes not coming down soon enough.
I also love that line - "it’s medically incorrect to put a T2D on basal insulin" That was Al's line if I remember correctly and I will second what Al said.
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Post by agedhippie on Jun 10, 2022 12:13:02 GMT -5
This is what happens when work makes you stop editing part way through the reply  Pretty much anything that relieves stress on the beta cells will restore first phase insulin secretion. There was even a study that showed GLP-1 will do it: |
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Post by agedhippie on Jun 10, 2022 12:36:00 GMT -5
Aged - you say "Sorting out post prandial meal spikes does not fix all the other issues" how do we know? The thing is until afrezza we could not stop the post meal spike. We really have as a community very very little experience "stopping the spike". In a non-diabetic they don't usually have all these other Metabolic Syndrome issues do they? You can see the remaining issues in people who are on Low Carb High Fat diets where they have no meal time spikes because essentially they eat so few carbs the digestion is slowed enough for any spike to be manageable with your own insulin. I don't discount anything, but I need to see evidence. I do discount beta cell regeneration beyond what regular apoptosis supports - that remains one of those grail items and is a topic particularly close to my heart for obvious reasons! This is distinct from beta cells recovering from stress which definitely happens (as earlier; the honeymoon period it Type 1 is the poster child for this). At the moment this is all theoretically, and until it is proven in trials there will not be traction in mindshare which is what we need. Exercise works and so does weight loss. The amount to which it helps is a matter of degree - losing a pound or two is not significant whereas losing more is significant and does restore first phase response (the Newcastle protocol shows this). If either the exercise or diet is insufficient then Afrezza will definitely help. |
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Post by mango on Jun 10, 2022 12:36:18 GMT -5
This is what happens when work makes you stop editing part way through the reply  Pretty much anything that relieves stress on the beta cells will restore first phase insulin secretion. There was even a study that showed GLP-1 will do it: The participants were administered IV Exenatide. I believe in the real world Exenatide is given via subcutaneous injection. Do you have a study demonstrating it restores the first phase by administering Exenatide via subcutaneous injection like it is prescribed? The effects will be different. It’s interesting to note also all the side effects and potentially serious adverse events associated with GLP-1s, compared to the incredible safety profile of Afrezza. Appears one is disrupting metabolic pathways and the other is working harmoniously with them. |
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Post by agedhippie on Jun 10, 2022 12:43:33 GMT -5
This is what happens when work makes you stop editing part way through the reply Pretty much anything that relieves stress on the beta cells will restore first phase insulin secretion. There was even a study that showed GLP-1 will do it: The participants were administered IV Exenatide. I believe in the real world Exenatide is given via subcutaneous injection. It’s interesting to note also all the side effects and potentially serious adverse events associated with GLP-1s, compared to the incredible safety profile of Afrezza. Appears one is disrupting metabolic pathways and the other is working harmoniously with them. Personally I would take Afrezza over GLP-1 as well, but my point was that Afrezza is not the only way to restore first phase response and that GLP-1 can do it as well. |
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Post by mango on Jun 10, 2022 12:49:24 GMT -5
The participants were administered IV Exenatide. I believe in the real world Exenatide is given via subcutaneous injection. It’s interesting to note also all the side effects and potentially serious adverse events associated with GLP-1s, compared to the incredible safety profile of Afrezza. Appears one is disrupting metabolic pathways and the other is working harmoniously with them. Personally I would take Afrezza over GLP-1 as well, but my point was that Afrezza is not the only way to restore first phase response and that GLP-1 can do it as well. That study was done via IV. That is not how it is prescribed. Given subcutaneously it will have a different effect. Is there a study demonstrating the same results but from subcutaneous administration like it is prescribed in the real world? |
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Post by sayhey24 on Jun 10, 2022 14:13:35 GMT -5
Aged - like a lot of things there are different approaches people take in trying to solve a problem. I have read Ralph's one study where they juiced GLP1. I forget what he combined it with maybe glipizide, not sure. But they claimed beta cell restoration.
I do think it was not long after this study he and Al got into it as Al told him it was medically incorrect now that we have monomer human insulin which hits the blood immediately not to give them afrezza as afrezza is the medically correct approach for PPG control. Of course this was coming from a guy who was not an MD to a world leading MD diabetes "thought leader".
Don't you agree that the medically correct approach for a deficiency in first phase release is to give them monomer human insulin which near mimics the pancreas release? I know I agree with Al and Mango on this.
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Post by agedhippie on Jun 10, 2022 14:18:02 GMT -5
Personally I would take Afrezza over GLP-1 as well, but my point was that Afrezza is not the only way to restore first phase response and that GLP-1 can do it as well. That study was done via IV. That is not how it is prescribed. Given subcutaneously it will have a different effect. Is there a study demonstrating the same results but from subcutaneous administration like it is prescribed in the real world? I would suggest the LIBRA trial which addressed the use of GLP-1 and showed improved OGTT consistent with de-stressing beta cells as with Afrezza. Is there an Afrezza trial showing the recovery of beta cells and first phase recovery? I don't see why it shouldn't work, I just wondered if there were studies - I feel Affinity may cover this. |
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Post by agedhippie on Jun 10, 2022 14:30:28 GMT -5
Aged - like a lot of things there are different approaches people take in trying to solve a problem. I have read Ralph's one study where they juiced GLP1. I forget what he combined it with maybe glipizide, not sure. But they claimed beta cell restoration. I do think it was not long after this study he and Al got into it as Al told him it was medically incorrect now that we have monomer human insulin which hits the blood immediately not to give them afrezza as afrezza is the medically correct approach for PPG control. Of course this was coming from a guy who was not an MD to a world leading MD diabetes "thought leader". Don't you agree that the medically correct approach for a deficiency in first phase release is to give them monomer human insulin which near mimics the pancreas release? I know I agree with Al and Mango on this. As I said earlier, personally I would rather take Afrezza than GLP-1 that doesn't mean it is better for everyone (the traditional diabetes YMMV disclaimer goes here). I suspect Ralph DeFronzo's objection to Afrezza is the same as his objection to metformin - it doesn't address a broad enough scope of the aspects of Type 2. He likes GLP-1 because per the earlier diagram it simultaneously addresses multiple causes of hyperglycemia (alpha cells, insulin resistance, and so on). Do you have any sort of link to that conversation or record as I would love to see it? |
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Post by sayhey24 on Jun 10, 2022 18:25:42 GMT -5
That study was done via IV. That is not how it is prescribed. Given subcutaneously it will have a different effect. Is there a study demonstrating the same results but from subcutaneous administration like it is prescribed in the real world? I would suggest the LIBRA trial which addressed the use of GLP-1 and showed improved OGTT consistent with de-stressing beta cells as with Afrezza. Is there an Afrezza trial showing the recovery of beta cells and first phase recovery? I don't see why it shouldn't work, I just wondered if there were studies - I feel Affinity may cover this. Aged - got a link to the study you are referring to? I would like to read it. I see this but no results were posted. clinicaltrials.gov/ct2/show/NCT01270789I also see this from the ADA which has results and basically says 1. 6 PWDS had to be put on metformin rescue. Was this so bad that metformin was better? 2. While taking liraglutide the beta cells produced more insulin and within 2 weeks of stopping they lost the improvement. The conclusion I would draw as a casual observer is it acted like a TZD. The really odd part is they never posted the official results at the government site but the ADA has something which makes me think hmmm.... diabetesjournals.org/care/article/37/12/3270/29432/Liraglutide-and-the-Preservation-of-Pancreatic I very much doubt any GLP-1 can do what afrezza can. I would fully expect with afrezza we would see as good or better results of the boat load of subq early insulin intervention studies done over the years. It just seems if the GLP1 did work as good as insulin the body would have developed over time to generate GLP1 and not insulin for BG control. Al's medically correct approach of replacing the body's lost mealtime insulin with the same human insulin just seems to make the most sense. Since thats what the body needs and wants and now we have a way in which we can reproduce first phase release, this seems like a no-brainer, right? |
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Post by agedhippie on Jun 11, 2022 12:24:27 GMT -5
Aged - got a link to the study you are referring to? I would like to read it. I see this but no results were posted. clinicaltrials.gov/ct2/show/NCT01270789I also see this from the ADA which has results and basically says 1. 6 PWDS had to be put on metformin rescue. Was this so bad that metformin was better? 2. While taking liraglutide the beta cells produced more insulin and within 2 weeks of stopping they lost the improvement. The conclusion I would draw as a casual observer is it acted like a TZD. The really odd part is they never posted the official results at the government site but the ADA has something which makes me think hmmm.... diabetesjournals.org/care/article/37/12/3270/29432/Liraglutide-and-the-Preservation-of-Pancreatic I very much doubt any GLP-1 can do what afrezza can. I would fully expect with afrezza we would see as good or better results of the boat load of subq early insulin intervention studies done over the years. It just seems if the GLP1 did work as good as insulin the body would have developed over time to generate GLP1 and not insulin for BG control. Al's medically correct approach of replacing the body's lost mealtime insulin with the same human insulin just seems to make the most sense. Since thats what the body needs and wants and now we have a way in which we can reproduce first phase release, this seems like a no-brainer, right? ZDs are another point solution. They address the glucose uptake in the muscles and liver so there is overlap with GLP-1, but GLP-1 covers other aspects as well. The action on the muscles was the USP as it enhances the muscles response to glucose. You can pull glucose from the bloodstream by muscular movement and this is independent of insulin - it's one of the reasons exercise can make you go low. Metformin was the fallback so if you couldn't tolerate GLP-1 then you reverted to metformin, hence metformin rescue. The patients recovered beta cell function, but once the GLP-1 was withdrawn the pre-treatment stress was reasserted and the beta cells shut down again. That article was the one I would have pointed you at The body does generate GLP-1, and GIP, but the role of GLP-1 is not to pull glucose out of the blood but rather to help regulate that function. People fixate on insulin, but the glucose metabolism is far more complicated than that. For a long time insulin was all we had so this fixation is understandable, but with the arrival of these other hormone treatment like GLP-1, and amylin the ability to straighten out the glucose metabolism at it's core rather than just treat the symptoms improves. We are a long way off completely cracking this though. By looking at the reduced insulin output you are looking at the symptom - what caused that? Beta cell stress. And what caused that? Now we are back to Ralph DeFronzo's diagram. Insulin is a great bandaid and for decades it was all we had, but it doesn't treat the wound (to mangle an analogy). You will find people in the Type 2 community who are positively anti-insulin because part of insulin resistance is down-regulation of the receptors due to the amount of insulin your body is putting out and their view is that treating with insulin is trying to put out the fire with gasoline. They believe a LCHF diet alone will do it, and in fairness they have some good results despite medical disapproval of this approach. |
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Post by sayhey24 on Jun 13, 2022 7:17:43 GMT -5
Aged - Wow - you say "Insulin is a great bandaid and for decades it was all we had, but it doesn't treat the wound" If I am not mistaken what the body wants and needs is monomer human insulin. Without it we will die. Now we have monomer human insulin which can replicate first phase release. If someone is dehydrated we are going to give them water. We are not going to give them a tomato. If someone needs monomer human insulin why are we going to give them a GLP1? How is that "medically correct"? Because BP can make $$$Bs selling GLP1s? Because they say the body is already making insulin? That's Ralph's line. The guy who gave us metformin. If someone is losing a lot of blood you give them a transfusion. Maybe they got shot, maybe they got slashed but it doesn't really matter. We don't care at that point why they have lost so much blood we just get them the blood. Thats what the body wants and needs. We don't give them water. With blood loss figuring out the root cause is usually easy. With diabetes we don't know for sure what root cause is of pancreas dysfunction. We do have some strong theories and we know with covid we have more PWDs. What we do know is they have lost first phase insulin release and they need insulin. We can see their CGM and watch the spike. The root cause of the uncontrolled post meal spike is lack of insulin. At this point we really don't care about why the pancreas is screwed up. Just get them the insulin. You say "By looking at the reduced insulin output you are looking at the symptom - what caused that? Beta cell stress" Its not stress its b-cell loss and dysfunction. With CGMs what we are seeing is loss of first phase release to be the first thing happening before Ralph's "resistance". However what we have know for years is we lose b-cell mass and the b-cells are different. Something is screwing them up and killing them off. Josil said its different viruses but with covid others are also developing similar theories. Here is one write-up on screwed up b-cells which was done in 2011. Thats before wide spread availability of CGMs. They do try to justify "insulin resistance" so I will give them a pass on that. Its a pretty good study and has real facts. I do love their line "harmful environmental influences" - who knows may a virus or two or three? Joslin identified four until they were defunded. www.ncbi.nlm.nih.gov/pmc/articles/PMC4008010/#:~:text=The%20average%20%CE%B2%E2%80%90cell%20size,in%20type%202%20diabetic%20subjects. I have to say I am with Bernstein on his position that that high blood sugars are the cause of all diabetic complications. Your statement "You will find people in the Type 2 community who are positively anti-insulin because part of insulin resistance is down-regulation of the receptors due to the amount of insulin your body is putting out and their view is that treating with insulin is trying to put out the fire with gasoline " was the flash point between Al and DeFronzo and what we see is as we get the post meal spike under control we see an easing in blocked receptors. BTW - this is a great talking point for BP and GLP1 sales and with CGMs we can see it is not correct. Lets just fix the post meal spike and then lets see if Bernstein is right. |
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Post by sayhey24 on Jun 13, 2022 7:32:38 GMT -5
Aged - BTW - I see Bernstein's Wiki page was updated "This page was last edited on 12 June 2022, at 18:59 (UTC)". Was that you who added "The rationale behind the approach is what Bernstein calls "the law of small numbers"
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Post by uvula on Jun 13, 2022 7:59:42 GMT -5
If someone is bleeding heavily you give them a transfusion AND you stop the bleeding. You don't just give them transfusions continuously and tell them their problem is they don't have enough blood.
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