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Post by carefulinvestor on Nov 22, 2023 0:40:23 GMT -5
Great job Doctor! Really appreciate your peronal patience and description of your patient's experiences. Well done iny opinion!
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Post by prcgorman2 on Nov 22, 2023 8:31:52 GMT -5
And THIS is why I like stevil, agedhippie, and sayhey24 debating. Such good information that comports with the information we have in the form of Symphony-reported sales. Based on stevil’s remarks around MannKind marketing literature and Afrezza study investments what I would like to know, @sportsrancho and stevil, is VDEX collaborating with MannKind on study development to corroborate VDEX experiences (sports) and are the pump/switch, pediatric, and India (where’s the read-out on this!??!?!?!?!) the right good studies to begin establishing the superiority and SAFETY (SAFETY, SAFETY) of Afrezza (stevil)? And now I must apologize to our dear moderators for making Yet Another Off-Topic Post (YAOTP). |
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Post by sportsrancho on Nov 22, 2023 9:11:02 GMT -5
And THIS is why I like stevil, agedhippie, and sayhey24 debating. Such good information that comports with the information we have in the form of Symphony-reported sales. Based on stevil’s remarks around MannKind marketing literature and Afrezza study investments what I would like to know, @sportsrancho and stevil, is VDEX collaborating with MannKind on study development to corroborate VDEX experiences (sports) and are the pump/switch, pediatric, and India (where’s the read-out on this!??!?!?!?!) the right good studies to begin establishing the superiority and SAFETY (SAFETY, SAFETY) of Afrezza (stevil)? And now I must apologize to our dear moderators for making Yet Another Off-Topic Post (YAOTP). I am sending this for Bill to read, but it’s gonna be a while because he’s extremely busy. From what I have had time to read, which is not all of it, stevil is right about patients and Afrezza, at least in our experience. The difference is we have the time to work with them on the CGM’s, on the dosing, on their attitudes about fitness and nutrition. We’ve partnered with Endo’s that can’t wait to handover their diabetic patients to us so they can just concentrate on the other diseases they treat because the diabetics take too much time. You could argue since they’re coming to a diabetic specialty clinic. They’re not so apt to take the path of least resistance they really want that control. |
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Post by BD on Nov 22, 2023 9:33:44 GMT -5
And now I must apologize to our dear moderators for making Yet Another Off-Topic Post (YAOTP). NP, we see much worse  |
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Post by hellodolly on Nov 22, 2023 9:54:27 GMT -5
And THIS is why I like stevil, agedhippie, and sayhey24 debating. Such good information that comports with the information we have in the form of Symphony-reported sales. Based on stevil’s remarks around MannKind marketing literature and Afrezza study investments what I would like to know, @sportsrancho and stevil , is VDEX collaborating with MannKind on study development to corroborate VDEX experiences (sports) and are the pump/switch, pediatric, and India (where’s the read-out on this!??!?!?!?!) the right good studies to begin establishing the superiority and SAFETY (SAFETY, SAFETY) of Afrezza (stevil)? And now I must apologize to our dear moderators for making Yet Another Off-Topic Post (YAOTP). I am sending this for Bill to read, but it’s gonna be a while because he’s extremely busy. From what I have had time to read, which is not all of it, stevil is right about patients and Afrezza, at least in our experience. The difference is we have the time to work with them on the CGM’s, on the dosing, on their attitudes about fitness and nutrition. You could argue since they’re coming to a diabetic specialty clinic. They’re not so apt to take the path of least resistance they really want that control. I like that, "We’ve partnered with Endo’s that can’t wait to handover their diabetic patients to us so they can just concentrate on the other diseases they treat because the diabetics take too much time." Target the endo so they can hand them off to you. That takes a special kind of relationship building, trust and partnerships for an endo to hand off their patients. Is it reciprocal in some way? |
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Post by sayhey24 on Nov 22, 2023 11:20:42 GMT -5
Stevil - Wow! I don't know where to start but lets try here - "The other problem is information is nowadays too accessible". If thats a problem its only a problem for those trying to hide something. What happened to the info Josil use to have on the web about diabetes and viral infections? I haven't looked in a while but the last time I could not find it. It got scrubbed. For years Aged said over and over the reason he/she would not try afrezza is his/her endos said it would cause serious lung damage. It was just the other week I heard they stopped saying that 5 years ago. Really?. Here is what he/she just said "The fact that he/she for years said afrezza would cause serious lung damage?" No he did not, he just gave up correcting you because you refuse to listen. I have just debunked this statement literally days ago and yet here you are repeating the same stuff yet again." - Are you kidding me! Yes I was born but it was not yesterday. You ask - I don’t know why you feel pressured or responsible to find the root cause to fix the problem. The answer is that is what I do. Things to me have to make sense. I am the kind of guy when I drive down "Church Road" I ask where is the church. I was one of those guys who called bull on Covid coming from the under cooked bat burger when that was accepted truth. I am the kind of guy who asks why are we not giving people insulin when their bodies are no longer producing enough for their needs? Now, we can slap a CGM on them and watch their BG spike after meals so we give them metformin or better yet Ozempic so they don't eat as much - now that's brilliant. Lets mask the underlying problem. As you said too much information is a problem. We can also see we had a spike in diabetes when everyone was watching the numbers during Covid. We can again ignore that and pretend it did not happen. We can also ignore that we got a bunch of research money which allowed some good work including the autopsy of some pancreas and some fine pictures of three deferent types of beta cell clumps as a result. We can ignore that too as that may be too much info. Now for me this is a show stopper - "Lack of compelling information/data that Afrezza is superior to existing medications". Which medication - an RAA, an antiglycemic, which exactly? Afrezza crushes RAA's. We can measure those results with a CGM. There is not one antiglycemic which address the underlying problem - the body not making enough insulin for the body's need. Whether the body is "insulin resistant" or not we can slap a CGM on someone and see they have lost post prandial control. Again maybe we have to much information these days. We have Richard Bernstein as a living example of what happens when we do have great BG numbers. Is Bernstein an outlier at 89? I say no and Bernstein says no. We also have a ton of studies which have shown time and again, early insulin intervention has huge benefits. The goal regardless of the medication is blood glucose control. Can we do it with the Bernstein diet, yep. Can we do it with other insulins, yep. Does anything mimic first phase release like afrezza - nope. Afrezza makes the job much easier. Can you do it with metformin - nope nor the GLP1s if the people start eating again. On this one - At least half but probably closer to 75% of the patients I have started on Afrezza have made the decision to stop using it on their own. Thats not surprising. If you have not pointed them to afrezza direct at $99 they are paying too much. Is $99 too much, maybe for some. What are they paying for Ozempic? 80%+ stop using in 2 years. Now the big question - if you start the early T2 on afrezza do they even need it after 1 year? Should afrezza be available for $35 on Medicare with out pre auths - yep but the powers to be are doing all they can to stop it. Answering one question leads to 2 more. I would like to address your questions, if I can. Josil probably got scrubbed because they realized it wasn't accurate information. I don't live in a conspiracy theory world. I do think there are dark forces and absolute power corrupts absolutely, however, I'm not connecting the conspiracy theory dots that you are. I really don't understand why you're so fixated on this. It has no relevance to Afrezza. I am far from an expert on immunology- that's it's own beast. Do we know viruses cause disease? Absolutely. I think a better explanation for any increase in diabetes during covid would be better explained by people getting some nice stimi checks, eating a ton of fast food, not working or leaving their houses, being sedentary, being stressed, actually going to their doctors when they're sick because they don't do preventive checkups and now that they need medical care, it reveals all sorts of new things, etc. The vast majority of people I knew said they gained weight during the pandemic. Unhealth leads to diabetes. I think that's a way more plausible cause than covid, when again, we're injecting the very protein into people's bodies that causes all the harmful effects of covid, some up to 5 times now and they're still not getting diabetes. To be honest with you, though, it's not really an argument that I care to entertain because it doesn't interest me and I don't see any relevance to Afrezza. Not a hill I'm willing to die on and I'm probably the wrong person to engage/entertain the argument because I'd be just as content if covid did cause diabetes. For a while, yes, aged said there was concern about lung issues. I don't see him saying that anymore and actually see the opposite? I don't see conflict here. Do you just need him to admit his endo was wrong to move on? This is another one that confuses me... If finding the root cause of something is what you do, great! My follow up question for you would be- what has this done for you? Where have you gotten? Are you any closer to getting to that root cause than you were, say 7 years ago? Even if you find that elusive root cause, what will you do with it when you find it? What influence or ability do you have to then effect any change with the newfound information? I don't want to rob you of your joy, but unless you're more than "just an engineer" (which is not a slight, by the way)... good luck, I guess? We have had this argument so many times on this board I'm not even sure if it's worth addressing. In a perfect world where I could have my patients do exactly what I wanted them to do and cost were no issue, I would probably choose Afrezza for the vast majority, if not all, of my patients. I didn't say that Afrezza wasn't better than all other diabetes treatments- I simply said that MNKD has failed to prove that it is. Everything you state after my quote has not come from evidence you've gotten from MNKD. That's a problem, or a "root cause", if you will, for the lack of Afrezza's success. What literature are you citing when you say using Afrezza early in their disease will halt the progression of diabetes? Sure, we have literature on early, intensive insulin treatment. It's been a while since I checked, but I have never seen Afrezza listed in those studies. If you're going to change a paradigm in a long-established disease and its treatment, theoretical arguments aren't going to influence opinions. Doctors want to see evidence and data. I don't know what to tell you other than it doesn't exist outside of what VDEX has published, which, unfortunately, doesn't fit criteria for a reputable source in the medical community. A white paper has never been authoritative but is an idea that will hopefully sprout into a new study that confirms its findings. This just hasn't been done yet. I really don't know what there is to argue about. Nothing matters until this happens... It's just the way it is and denying it or saying it shouldn't be that way is just going to leave you banging your head against the wall for all of us to keep seeing. For the showstopper- Yes, I have several patients on Afrezza. A couple I have started early, and they have increased their dose since they started on it. I have 100s of patients at this point on GLP-1s. I think I have maybe 2, that I can think of, that have stopped treatment due to side effects. I have had several quit because their diabetes went into remission and they didn't want to take it anymore if they weren't diabetic. But I'm not quite at the 2 year mark yet at my practice, so maybe I need to give them more time... And, yes, I live in a high cost of living area with very good insurance coverage. Surprisingly, only about 15% of my patients were on medicaid and about 65% were commercially insured the last time I ran a report. $99 is too much for many of them. People just don't care about Afrezza the same way you do. They want the path of least resistance. Not to shame my patients, but in general, we're not talking about weekend warriors. While there are some unfortunate type 2s that do everything right when it comes to diet and exercise, the majority of people that get the disease didn't get it from making healthy choices. Half of my patients quit Afrezza on their own. The biggest issue was it was too much work to babysit their CGM with Afrezza. They got excellent results- they admitted as much. They just got tired of having to dose so many times a day when they could get 0.4-0.5% higher A1c with less than half the effort. Cost wasn't the issue for most of them. I think I only have 1 person right now that is using the cash program. MNKD covers all commercially covered Afrezza at $35/month with their coupon card. BTW, Mounjaro has a $25 coupon card for 3 months, which is much cheaper than what Afrezza would cost. These things don't matter to me, though. What matters to me is finding a plan that works for my patient. If I make them use Afrezza and they refuse to do it, you end up with an uncontrolled diabetic. I try to meet them where they are and give them the tools they're willing to use. The biggest problem I see you having is that people with diabetes don't always care about getting "the best" treatment. They care about good enough with the least amount of effort. I have said this many times in the past and I've been argued with probably every one of those times. I don't really see the point in arguing it. It just is what it is. Sometimes you have to accept things for what they are. Hopefully I have addressed everything you wanted me to. Stevil - are you breaking major news here? Did you just say your patients were seeing a 0.4-0.5% lower A1c when using afrezza than using what - Mounjaro? I am not sure what you are comparing afrezza to but if its GLP1s that is HUGE news. Can you clarify, please. Mike mentioned awhile back that the India trial could show results on par to GLP1s but 1/2% more is very significant if a head to head trial was done between afrezza and Ozempic/Mounjarno. |
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Post by sportsrancho on Nov 22, 2023 11:35:02 GMT -5
From Bill…
“ I’ll confine my comments to Stevil’s recent post and our experience with Afrezza. In overview, I can confirm much of his experience with Afrezza. We at VDex have had many patients drop but it was almost always over the cost. Given Afrezza’s tier placement on most plans (if it’s even on formulary at all) it’s just not affordable for most people. Aside from the cost there is a learning curve with the use of Afrezza. As I may have said before we use the analogy of riding a bike. You don’t just give a kid a bike and tell him to go learn to ride. He’ll never do it. A parent puts the kid on the bike holds on to the bike to steady it till the child gains enough confidence to ride off on his own. Same with Afrezza. You’ve got to hold patients’ hand in the early stage and that is the reason for CGM. I don’t want to misinterpret Stevil but it sounds like many of his patients drop because of the hassle factor with CGM and multiple dosing per day. I’m not surprised by that. To enjoy wide acceptance among Type 2s (93% of the market) a therapy has to be cheap, easy, convenient, safe and MUST NOT make the patient feel lousy. Afrezza checks all those boxes AFTER getting past the learning curve, EXCEPT cheap. The multiple dosing and hassles with CGM really is part of the learning curve. We at VDex used to do multiple dosing, especially post-prandially. We don’t anymore because again, it’s a hassle. The better strategy we’ve found is to dose higher at the mealtime (because you really don’t need to worry about lows) and not worry about follow up dosing. There’s such a wide safety margin with the drug that If one doses 24 units instead of say 18, the patient won’t have a problem. The key is to dose the meal aggressively then forget it. You won’t need follow up doses. Less hassle. The only real problem with this approach is that it involves inhaling more powder and can cause a cough.
Regarding CGM, we don’t use it continuously again because of hassle. The therapy needs to be easy. So CGM is used during learning phase (learning to ride the bike). Then forget it until perhaps annual assessment of patients’ BG profile. Once patients learn that they have three inhalations per day at mealtimes and NOTHING ELSE, they’re happy and compliance goes up.
Last point, despite the popularity of Ozempic and similar drugs, they can’t compare to Afrezza. Not even close. It’s just that use of Afrezza is different and one has to learn. But then wasn’t bike-riding the same? And didn’t we all learn?”
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Post by mayday on Nov 22, 2023 11:36:05 GMT -5
And now I must apologize to our dear moderators for making Yet Another Off-Topic Post (YAOTP). NP, we see much worse Hey! I'm sitting right here! |
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Post by mango on Nov 22, 2023 12:11:31 GMT -5
When Bill and Stevil mention cost being a major factor in discontinuation of Afrezza, I am just curious if these people did not qualify for the Afrezza Savings Card copay can be as low as $15-$35. Or Eagle Pharmacy savings program that is $99 for 1 month of 90 carts or $199 for 1 months of 180 carts. Did both VDex and Stevil use these services? If not, why not? If so, what went wrong? stevil sportsrancho |
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Post by prcgorman2 on Nov 22, 2023 12:34:25 GMT -5
From Bill… “ I’ll confine my comments to Stevil’s recent post and our experience with Afrezza. In overview, I can confirm much of his experience with Afrezza. We at VDex have had many patients drop but it was almost always over the cost. Given Afrezza’s tier placement on most plans (if it’s even on formulary at all) it’s just not affordable for most people. Aside from the cost there is a learning curve with the use of Afrezza. As I may have said before we use the analogy of riding a bike. You don’t just give a kid a bike and tell him to go learn to ride. He’ll never do it. A parent puts the kid on the bike holds on to the bike to steady it till the child gains enough confidence to ride off on his own. Same with Afrezza. You’ve got to hold patients’ hand in the early stage and that is the reason for CGM. I don’t want to misinterpret Stevil but it sounds like many of his patients drop because of the hassle factor with CGM and multiple dosing per day. I’m not surprised by that. To enjoy wide acceptance among Type 2s (93% of the market) a therapy has to be cheap, easy, convenient, safe and MUST NOT make the patient feel lousy. Afrezza checks all those boxes AFTER getting past the learning curve, EXCEPT cheap. The multiple dosing and hassles with CGM really is part of the learning curve. We at VDex used to do multiple dosing, especially post-prandially. We don’t anymore because again, it’s a hassle. The better strategy we’ve found is to dose higher at the mealtime (because you really don’t need to worry about lows) and not worry about follow up dosing. There’s such a wide safety margin with the drug that If one doses 24 units instead of say 18, the patient won’t have a problem. The key is to dose the meal aggressively then forget it. You won’t need follow up doses. Less hassle. The only real problem with this approach is that it involves inhaling more powder and can cause a cough. Regarding CGM, we don’t use it continuously again because of hassle. The therapy needs to be easy. So CGM is used during learning phase (learning to ride the bike). Then forget it until perhaps annual assessment of patients’ BG profile. Once patients learn that they have three inhalations per day at mealtimes and NOTHING ELSE, they’re happy and compliance goes up. Last point, despite the popularity of Ozempic and similar drugs, they can’t compare to Afrezza. Not even close. It’s just that use of Afrezza is different and one has to learn. But then wasn’t bike-riding the same? And didn’t we all learn?” I LOVE that Bill emphasized the SAFETY (SAFETY, SAFETY) of mealtime dosing with more than enough units of Afrezza. This feels 100% analogous to what a pancreas does. There's no micrometer-precise BG measurement followed by some equally precise ratio of units of insulin to deal with mealtime blood glucose increase. The pancreas senses (or is signaled) blood glucose increase and then squirts a glob of insulin and allows the body to uptake/store blood glucose as needed business-as-usual. A certain amount of heuristic "slop" in a self-regulating system is perfectly acceptable.
I've convinced myself the key to marketing Afrezza (i.e., increasing prescription counts) is proving how much safer Afrezza is as compared to RAAs. My slogan would be, "Afrezza, the SAFE choice."
Remember the saying "Nobody ever got fired for buying Big Blue?". Convince doctors (with well-designed studies) that "Nobody ever got sued for prescribing Afrezza" or "Nobody ever died of an accidental hypoglycemic event because of using Afrezza" and address the price per prescription issue and Bob's your uncle.
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Post by mango on Nov 22, 2023 13:33:47 GMT -5
Side Note (This is fun)
Pancreatic Beta Cell Memory
—Pancreatic beta cells obtain, store, and retrieve metabolic information contained in calcium signals
—Pancreatic beta cell memory regulates insulin secretion and is mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII)
—Beta cell memory is dependent on the activation of CaMKII
—CaMKII is activated via an influx in Ca2+
—CaMKII is a Ca2+ sensor
—CaMKII regulates Ca2+ homeostasis, insulin secretion, glycogen metabolism, neurotransmitter release, and the epigenetic and gene expressions
—Calmodulin is a calcium binding protein involved in the transmission and amplification of calcium signals
—CaMKII also plays a key role in beta cell circadian rhythm oscillations and clock gene expression
—CaMKII regulates the transcription factors MafA and CREB
—The metabolic memory of pancreatic beta cells is demonstrably reflected in expression changes of CaMKII regulated proteins involved in insulin secretion:
1. Glucokinase (glucose sensor, facilitates phosphorylation of glucose to glucose-6-phosphate)
2. Voltage-dependent Ca2+ channels
3. Synaptosomal-associated protein 25
4. Transcription factor MafA
Transcription Factor MafA
—MafA is expressed in human pancreatic beta and alpha cells and is key transcription factor of the insulin gene
—C-box 2 is the regulatory sequence for the insulin gene that binds to MafA
—MafA is a master regulator of genes involved in maintaining proper beta cell function: Glucokinase, Glut2, Pdx-1, Nkx6.1, GLP-1 receptor and GLP-1 signaling, prohormone convertase-1/3 and pyruvate carboxylase metabolism secretion coupling
—MafA also plays a key role in regulating the first-phase insulin secretion, insulin granule density, and docked insulin granules
Ca2+ and the Endocannabinoid System
—A fully functional endocannabinoid system is expressed in pancreatic beta cells
—The ECS in pancreatic beta cells regulates Ca2+ signaling and insulin secretion. The ECS can both stimulate and inhibit insulin secretion
—Endogenous cannabinoids, Anandamide and 2-AG, can both affect the amplitude of Ca2+ signals and the patterns of Ca2+ oscillations
—Anandamide and 2-AG bind to the CB1 receptor and induce focal adhesion kinase phosphorylation, a prerequisite of insulin secretion
Metabolic Memory of Beta Cells and Circadian Rhythm
—CaMKII is essential for maintaining normal oscillation of cellular clocks
—Pancreatic islets express their own circadian clocks
—CaMKII regulates circadian oscillation functions
—CaMKII activation is essential for cell-autonomous circadian oscillations and synchronization of circadian oscillators of both the suprachiasmatic nucleus and peripheral cells
—In the brain, CaMKII is highly expressed and is enriched in the postsynaptic density of glutamatergic synapses
—In the beta cell, glucose metabolism causes an increase in the ATP/ADP ratio, which in turn closes KATP channels. This leads to membrane depolarization > opening of VDCC > influx of Ca2+ > and a rise in cytosolic free Ca2+ concentration. This elevation directly triggers insulin exocytosis
Glutamate and GABA
—Pancreatic beta cells co-secrete insulin and GABA
—Pancreatic alpha cells co-secrete glucagon and glutamate
—Several transduction pathways are involved in glutamate and GABA mediated modulation of insulin secretion
—Aside from the co-secretion of GABA and insulin, the pancreatic beta cells will also produce and secrete GABA independently of insulin in response to certain conditions and exposures. An example would be beta cells secreting GABA in response to high levels of extracellular glucose. GABA would then bind to the GABAA receptor located on the pancreatic alpha cell, which then would induce plasma membrane hyperpolarization and inhibit the release of glucagon
—Additionally, GABA released by beta cells can bind to the GABAB receptor located on the beta cell. Here, it modulates insulin secretion, functioning as a negative feedback loop. Such a scenario would be during an episode of hyperglycemia whereby the GABAB receptor stimulates G-protein inhibition of VDCC, hindering increased intracellular calcium concentration
The Cephalic Phase plays a key role in glucose homeostasis.
Take mGlur5 for example. This metabotropic glutamate receptor is found in the tongue, brain, and pancreatic beta cells. In the tongue, it is a sensory receptor where it is involved in taste memory. Several metabotropic glutamate receptors are found on the pancreatic beta cell. Also, inotropic glutamate receptor is found on beta cells and stimulates insulin secretion. So, mGlur5 as a taste receptor, and would be involved in the Cephalic Phase. This makes sense considering it is also located on pancreatic beta cells. This is a memory response.
If we rememeber from our science lesson from earlier, Pancreatic beta cell memory is dependent on CaMKII activation. Loss of the FPIR means CaMKII activation is impaired. Also, CaMKII activation is not dependent on glucose-stimulated Ca2+ influx, but can also be activated by cell membrane depolarization.
CaMKII is a Ca2+ sensor. The triggering Ca2+ signals is necessary in GSIS. Amplification of the second-phase insulin response is dependent on the magnitude and time-course generated during the triggering of first-phase insulin response
In the brain, CaMKII is essential for long-term potentiation, memory formation and learning. CaMKII in the pancreatic beta cell is part of a homeostatic memory network.
When there is a loss of the first-phase insulin response, there is also a gradual loss of the second-phase insulin response. I believe the function of the second-phase is entirely dependent on the function of the first-phase. When there is diminished first-phase insulin secretion there is a decrease in the amplitude of calcium signals. The second-phase is affected by the amplification of the first-phase that is generated during the triggering of Ca2+ that initiates the first-phase response. Calmodulin plays a role in Ca2+ transmission and amplification. CaMKII is a Ca2+ sensor.
The amplitude generated from the Triggering of Ca2+ modulates the first and second phases.So if CaMKII inhibited, beta cells cannot properly sense calcium signaling and so the the first-phase insulin response would be deficient.
Impaired beta cell memory makes sense, and I suspect it plays a crucial and detrimental role in beta cell function, and especially in the regulation of insulin release in response to extracellular glucose concentrations. This could explain how and why metabolic memory plays vital role in beta cell function and survival. CaMKII misregulation can cause a loss of the first-phase insulin response, which results in dysregulation of glucose homeostasis. It would make sense that CaMKII becomes a critical factor involved in this process of first-phase insulin deficiency. We have to ask ourselves, what happened? Beta cell function is bound by memory function. When CaMKII activation is inhibited, there is significant impaired in the first-phase insulin response.
This is because when CaMKII is activated, key proteins involved in insulin secretion have increased expressions: Glucokinase, VDCC, SNAP25, and MafA. CaMKII also regulates the transcription factor CREB. If CaMKII activation becomes inhibited, MafA expression becomes decreased. MafA is essential for maintaining insulin secreting beta cell function. So obviously, beta cell memory plays a vital role in insulin secretion, and beta cell function.
Proper first-phase insulin release relies on the amplitude generated during the triggering of Ca2+ signals. CaMKII is a calcium sensor and calmodulin plays a role in calcium signal transmission and amplitude.
The endocannabinoids, Anandamide and 2-AG, along with both cannabinoid receptors, can directly regulate Ca2+ signals and insulin secretion as well. Anandamide and 2-AG can both actually regulate Ca2+ oscillation patterns also. Both the CB1 and CB2 receptors are found in beta cells and in the brain and sensor organs. They are found everywhere in the body in fact, and are homeostatic regulators of bodily function.
Beta cells have a GABAb receptor that functions as a regulator of insulin secretion, and beta cells co-secrete GABA with insulin, and also secrete GABA in a non-dependent routine manner.
Pancreatic alpha cells have a GABAA receptor and glutamate is co-secreted with glucagon release. Glutamate has numerous beta cell receptors that cab influence insulin secreton and beta cell function. MGlur receptors and iGlur receptors as well as the cannabinoid receptors and the endogenous cannabinoids, can all can affect insulin secretion and Ca2+ signaling. TRPV1 is a cannabinoid receptor and is a ion-channel receptor. It co-localizes with CB1 and CB2 receptors in sensory and brain neurons.
Anadamide and 2-AG can directly alter Ca2+ oscillation patterns in beta cells and can affect the amplitude of Ca2+ signals. So here we have the endocannabinoid system playing a key role in regulating Ca2+ signaling and insulin secretion.
CaMKII regulates Ca2+ homeostasis and CaMKII is required for maintaining proper cardiac function. Why is there such a prevelance of heart disease with diabetes? Could it be linked to Memory Homeostasis and CaMKII?
When I think about sight, I think about the collapse of a wave. Photons are measured within the retina and sensed by sensory cells and receptors and the photon wave is collapsed, which is how visual perception can be made and information exchanged via electrolyte interaction. Memory is the trigger for sensory perception and initiates the Cephalic Phase Insulin Response.
The heart is an electromagnetic force that relies on calcium. Interestingly, it has been demonstrated and proven that the heart can "sense" something before a person ever "sees" it. The heart responds to the environment before we are able to process outside stimuli and information and become aware.
How is this possible? Because the heart is an electromagnetic force, and not only that, outside currents/forces interact with the body on a molecular, subatomic level. The electromagnetic field produced by the human heart is able to sense and respond to the surrounding environment by generating an oscillating wave pulse that extends outside the body.
It has been well known that a person's (genotype) environment directly affects their physical development and adaptation (phenotype).
So let's go back to the insulin gene transcription factor MafA. When DNA is stressed, gene expression becomes hindered. Human DNA can become stressed by thoughts and emotions, our internal energy responses. Stress directly affects memory, both in the pancreatic beta cells and in the brain.
Perhaps one example comes from the environmental contaminant Metformin.
—AMP kinase activation by Metformin induces inhibition of glucose stimulated insulin secretion by causing down-regulation of insulin transcription factor MafA.
—This mean that Metformin consumption inhibits CaMKII activation and insulin gene expression in pancreatic beta cells, causing beta cell failure.
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Post by sayhey24 on Nov 22, 2023 13:42:36 GMT -5
I think this thread should be renamed Tyvaso DPI vs. Yutrepia PLUS much much more Stevil - you asked - That's a problem, or a "root cause", if you will, for the lack of Afrezza's success. What literature are you citing when you say using Afrezza early in their disease will halt the progression of diabetes? Sure, we have literature on early, intensive insulin treatment. It's been a while since I checked, but I have never seen Afrezza listed in those studies. To answer your question I was not citing literature. I was citing root source - Al Mann. This was posted here many years ago based on an interview Al did. When Al mentions "thought leaders" Jay Skyler was one of Al's go to guys. If you want to talk with him he is teaching at the University of Miami. As Al mentioned they did over 50 trials. Once Dave Kendall was pointed to them he referred to them as "Veins of Gold". Of course right as Dave was just starting to make progress his old employer was getting ready to introduce Mounjaro and I would think did not want Dave and afrezza messing things up. Al 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. Another issue is that many of the newer, more advanced antiglycemic agents are very expensive. If only there were a physiologic ultra-fast-acting insulin that would reduce postprandial hyperglycemia to within normal guidelines without the risk of hypoglycemia or weight gain and without the complexity of titration or the need for multiple daily measurements of glucose. Such a prandial insulin would far better deal with postprandial excursions throughout the entire spectrum of diabetes. Moreover, key opinion leaders assert that, by reducing pancreatic and hepatic stress, such an insulin would slow and perhaps even stop progression of Type 2 diabetes and prediabetes. Surely, that would seem to offer a far better solution than those alternative drugs. Moreover, a therapy that does not require the inconvenience and discomfort of multiple daily injections, would certainly be more patient-friendly. AFREZZA has been shown in over 50 clinical trials to mimic endogenous insulin kinetics and this should enable this insulin to more effectively and more safely address the objectives of providing improved glycemic control. A product such as AFREZZA would be especially appealing to children and should ease the issues about treatment in the classroom. Because of the FDA's aversion about risk in this young population, the initial label for AFREZZA will be restricted to patients 18 years and older. The age -- asked us [ph] to submit a post-approval Phase IV protocol for a trial in children. We responded with a proposed study in children ages 12 to 18. Interestingly, FDA directed us to include children down to age 4." Read more: mnkd.proboards.com/thread/8725/remember-al-said#ixzz4v3r43fKP |
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Post by porkini on Nov 22, 2023 13:44:58 GMT -5
Side Note (This is fun) Pancreatic Beta Cell Memory —Pancreatic beta cells obtain, store, and retrieve metabolic information contained in calcium signals —Pancreatic beta cell memory regulates insulin secretion and is mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) —Beta cell memory is dependent on the activation of CaMKII . . . Perhaps one example comes from the environmental contaminant Metformin. —AMP kinase activation by Metformin induces inhibition of glucose stimulated insulin secretion by causing down-regulation of insulin transcription factor MafA. —This mean that Metformin consumption inhibits CaMKII activation and insulin gene expression in pancreatic beta cells, causing beta cell failure. Source, reference? Thank you. |
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Post by mango on Nov 22, 2023 14:05:41 GMT -5
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Post by sayhey24 on Nov 22, 2023 14:15:40 GMT -5
Mango - here is an oldlie but goodie with the original name AFRESA and I still have my T-shirt. Its from the 3Q2009 Quarterly call where Al mentions AFRESA restores more physiologic hepatic function. Stevil - for you I highlighted a couple of lines. I think you called my bad insulin theory "goop insulin" with regard to hyperinsulinemia and insulin resistance. BTW - I talked with Al about afrezza stopping progression and he really believed this. I also think he was basing a lot of his comments from the 118 trial clinicaltrials.gov/ct2/show/NCT00570687 Per the 3Q2009 Quarterly call Al Mann said - I have long argued that AFRESA does not require complex meal titration. Certainly there is no need for carb counting and so forth. The basis of my view was derived from the dose escalation study with meal challenges in which better glucose control was achieved with ever greater doses of AFRESA, yet without any hypos. Yet based on decades of battling these challenges of conventional insulin therapy, some physicians have questioned my suggestion. Therefore, I proposed a meal escalation study in which patients would take a fixed dose of AFRESA and then a series of meal challenges. Our clinical team designed a protocol to set a standard meal with 50 g of carbohydrates. That was the 100% challenge. This was followed by challenges at 200%, 50% and zero percent. When I heard of zero I was shocked. Surely there would be severe hypo. The remarkable thing was that with the regular prescribed dose of AFRESA regardless of carbohydrate intake between zero and 100 grams the range of excursion is only plus or minus 30-35 mg [reduction] from baseline for all of the Type II patients in the study. At the ASDA meeting I described to Dr. [Jay Skyler] the finding that in Type II diabetes with a fixed dose of AFRESA and even with no food there is excellent control without hypo risk. I asked him how that was possible. "Obvious," he responded. He was basing his comments on our recently reported 118 trial in which we showed rapid and virtually complete sensation of [hepatic] glucose relief with AFRESA and the common inability of the remaining endogenous insulin to maintain control, as is the case for a healthy person without diabetes. Indeed, I mentioned this result to a number of KOL's who agree with Jay. So I say to you that AFRESA is what no other insulin has ever done for Type II diabetes. AFRESA restores more physiologic hepatic function, takes a load off the pancreas and avoids the hyperinsulinemia resulting from resistance of other insulins. It better mimics the normal pancreas response. So what does all this mean? First let me say that we will need to follow these findings with much larger trials. If the results of the larger trials support the earlier findings then I state to you that AFRESA should be used very early, certainly after failure with Metformin and as a first sign therapy for a significant portion of patients who are not candidates for Metformin or who do not do well with Metformin. It should be used well before fasting glucose is out of control and as we have seen, AFRESA even leads to lower fasting levels by eliminating the excessive gluconeogenesis. Of course, we will have to repeat some of these findings with specific trials but we have already seen the possibilities for AFRESA as we evaluate the timing of hypos in our already completed trials to date. From what we have seen in our extensive clinical program, AFRESA should benefit the entire progression spectrum of Type II diabetes with a very simple therapy and the experts tell us that it could even stop the progression of the disease.Read more: mnkd.proboards.com/thread/9453/jdrf-partners-eoflow-develop-wearable#ixzz563IqzdqJ |
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