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Post by mango on Aug 22, 2018 13:53:52 GMT -5
The +1 for insulin is that I would like to see it made an option for as early (or late) as the person wants. Personally if I was a Type 2, in order of preference, I would want metformin then anything that lets me treat as seldom as possible, then go to just metformin and MDI. Once I have to take insulin I cannot see the point in any of the other drugs than metformin. I also wouldn't want to go to just basal because by that point I would want better control according to what I am eating so I would want prandial insulin as well. is my understanding correct? Metformin decreases liver glucose neogenisis. Afrezza does that; the first phase. First-phase is regulated by MafA. AMP kinase activation by Metformin induces inhibition of glucose stimulated insulin secretion via down-regulating the key insulin transcription factor MafA (interestingly, MafA is regulated by CaMKII).
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Post by peppy on Aug 22, 2018 14:02:54 GMT -5
is my understanding correct? Metformin decreases liver glucose neogenisis. Afrezza does that; the first phase. First-phase is regulated by MafA. AMP kinase activation by Metformin induces inhibition of glucose stimulated insulin secretion via down-regulating the key insulin transcription factor MafA (interestingly, MafA is regulated by CaMKII).
When I see Ca++, I think thyroid.
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Post by mike0475 on Aug 22, 2018 14:24:02 GMT -5
I don’t understand this thread, perhaps it should be filed somewhere else? I get the intent but this is personally manufactured (based on valid info) but it’s not from mnkd
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Post by agedhippie on Aug 22, 2018 14:55:00 GMT -5
The +1 for insulin is that I would like to see it made an option for as early (or late) as the person wants. Personally if I was a Type 2, in order of preference, I would want metformin then anything that lets me treat as seldom as possible, then go to just metformin and MDI. Once I have to take insulin I cannot see the point in any of the other drugs than metformin. I also wouldn't want to go to just basal because by that point I would want better control according to what I am eating so I would want prandial insulin as well. is my understanding correct? Metformin decreases liver glucose neogenisis. Afrezza does that; the first phase. Afrezza addresses gluconeogenesis at meal times by reducing it via the first phase because the food is going to provide the glucose. Then it is gone and hepatic gluconeogenesis restarts. This is particularly an issue because Type 2 diabetics typically over produce glucose via hepatic gluconeogenesis so that gap is a problem. You can see the effect even more markedly in Type 1 diabetics if they do not take their basal insulin - skyrocketing levels from that hepatic gluconeogenesis. Metformin dramatically reduces that basal hepatic gluconeogenesis - Afrezza cannot do that, it's not designed to.
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Post by mnholdem on Aug 22, 2018 15:07:29 GMT -5
I would agree with both those points. It would be extremely surprising if adding Afrezza to a failed OAD regime would not reduce the A1c, adding RAA would as well. This is largely replicating the 175 trial isn't it? And +1 for using insulin far earlier in the Standard of Care. It's a data point for the use of insulin, but what is really needed is a multi-arm trial for insulin (basal and/or prandial), GLP-1, SGLT-2, and DPP-4. That's a huge trial and it would be expensive to cover the cost. What it would do is provided a strong answer to the what next question. Reviewing trial 175, I have to agree this latest basically just looks like a repeat. I don't quite see the "1+ for using insulin far earlier," however. They say at least six months following standard of care, so all they seem to be doing is following the usual standard of care and just substituting afrezza for a rapid acting insulin at the end of their flowchart. What you just posted is factually incorrect. Insulin therapy is currently the last step on the ADA Standard of Care. The time that elapses between the first and last steps can be 2-3 years. By then the unchecked damage to the pancreas could be permanent. Also, MannKind is not following the SOC by introducing Technosphere Insulin 6 months after Metformin. Have you even read the Standards? There are multiple medications and/or combinations of medications recommended to be prescribed before insulin and the SOC is the primary reason many insurers insist on Prior Authorization or of step therapy requiring the patient has followed the steps recommended in the Standards of Care before they’ll cover insulin. Peppy could you post the Standards of Care chart you keep? Thanks!
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Post by tomtabb on Aug 22, 2018 15:44:27 GMT -5
Reviewing trial 175, I have to agree this latest basically just looks like a repeat. I don't quite see the "1+ for using insulin far earlier," however. They say at least six months following standard of care, so all they seem to be doing is following the usual standard of care and just substituting afrezza for a rapid acting insulin at the end of their flowchart. What you just posted is factually incorrect. Insulin therapy is currently the last step on the ADA Standard of Care. The time that elapses between the first and last steps can be 2-3 years. By then the unchecked damage to the pancreas could be permanent. Also, MannKind is not following the SOC by introducing Technosphere Insulin 6 months after Metformin. Have you even read the Standards? There are multiple medications and/or combinations of medications recommended to be prescribed before insulin and the SOC is the primary reason many insurers insist on Prior Authorization or of step therapy requiring the patient has followed the steps recommended in the Standards of Care before they’ll cover insulin. Peppy could you post the Standards of Care chart you keep? Thanks! Yes, I looked up the standard of care and saw where the rapid insulins were used. The point I was trying to make is that the trial doesn't specify a time other than at least 6 months on other medications. In other words, it appears to me that the trial can enroll candidates who have gone through the entire SOC routine for 2-3 years.
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Post by thekindaguyiyam on Aug 22, 2018 15:49:29 GMT -5
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Post by sayhey24 on Aug 22, 2018 19:02:09 GMT -5
is my understanding correct? Metformin decreases liver glucose neogenisis. Afrezza does that; the first phase. Afrezza addresses gluconeogenesis at meal times by reducing it via the first phase because the food is going to provide the glucose. Then it is gone and hepatic gluconeogenesis restarts. This is particularly an issue because Type 2 diabetics typically over produce glucose via hepatic gluconeogenesis so that gap is a problem. You can see the effect even more markedly in Type 1 diabetics if they do not take their basal insulin - skyrocketing levels from that hepatic gluconeogenesis. Metformin dramatically reduces that basal hepatic gluconeogenesis - Afrezza cannot do that, it's not designed to. According to the 118 study analysis afrezza stops gluconeogenesis by signalling the alpha cells which in turn signal the liver. This is the way a health body works. This is what afrezza brings back to the PWD.
Aged - "Then it is gone and hepatic gluconeogenesis restarts" Are you saying a healthy body is not properly designed?
T2s lose first phase release. Because of this their liver is out of wack and continues to produce glucose when it should not be. This is not the case with afrezza. In the use of afrezza metformin is more of a problem than a help. An in sync liver is what allows the afrezza user to over dose and not worry about a severe hypo. Look at the CGM charts in the VDex paper
You want gluconeogenesis to restart and not metformin getting in the way.
The problem we have today is T2s are not using afrezza yet as step 1. If they were most would never progress to ever needing a basal. However, even in the case of late stage T2s currently using a basal, after the 2 hour period, after a meal, the job of afrezza is done. The job of the basal is to regulate fasting BG. As was demonstrated in the STAT study and through the Affinty-1 analysis, remember Dr. Kendall's comment A1c 8 to 6.8 with no additional hypos. How? Increasing the basal for fasting period control of liver glucose production.
As Ralph DeFronzo said “The most waste in type 2 diabetes is to continuously put people on metformin and sulfonylureas (glyburide, glimepiride, etc.). These drugs have no protective effect on the beta cell, and by the time you figure out what you’re doing, there are no beta cells left to save.” – Dr. Ralph DeFronzo (University of Texas Health Science Center) diatribe.org/the-diatribe-foundation-and-tcoyd-11th-annual-forum
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Post by agedhippie on Aug 22, 2018 22:05:23 GMT -5
Afrezza addresses gluconeogenesis at meal times by reducing it via the first phase because the food is going to provide the glucose. Then it is gone and hepatic gluconeogenesis restarts. This is particularly an issue because Type 2 diabetics typically over produce glucose via hepatic gluconeogenesis so that gap is a problem. You can see the effect even more markedly in Type 1 diabetics if they do not take their basal insulin - skyrocketing levels from that hepatic gluconeogenesis. Metformin dramatically reduces that basal hepatic gluconeogenesis - Afrezza cannot do that, it's not designed to. According to the 118 study analysis afrezza stops gluconeogenesis by signalling the alpha cells which in turn signal the liver. This is the way a health body works. This is what afrezza brings back to the PWD.
Aged - "Then it is gone and hepatic gluconeogenesis restarts" Are you saying a healthy body is not properly designed? No, I am saying you are incorrect in how the body works. If what you say was true Type 1 diabetics on Afrezza would not need basal insulin - patently that is not true. Also diabetics would not suffer from the Dawn Phenomenon.
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Post by mnkdfann on Aug 22, 2018 23:29:58 GMT -5
"Are you saying a healthy body is not properly designed?" Actually, so far as that goes, the human body (healthy or not) IS in many ways poorly / not properly designed. www.wsj.com/articles/the-botch-of-the-human-body-1523630069(If you don't believe in evolution, substitute 'our creator' or words to that effect in the appropriate places.) There are better articles (and books) that discuss the poor design of the human body, but the link above was the most convenient to post.
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Post by mytakeonit on Aug 23, 2018 0:48:35 GMT -5
Ooooh ... now they are messing with GOD !!! I wouldn't want to associate with these idiots ... just in case someone is watching from above. My guess is that we will win this battle whether we want to or not. Shucks! I didn't even break a sweat yet.
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Post by sayhey24 on Aug 23, 2018 7:30:40 GMT -5
I think your take on it is correct. I am not messing with GOD either. Unfortunately that is exactly what we do with PWDs and the oral meds. We affect one thing which then lowers BG to some degree only to make a bigger mess some where else.
The body is not making enough insulin for its needs, just give it the human insulin it needs.
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Post by sayhey24 on Aug 23, 2018 7:45:30 GMT -5
According to the 118 study analysis afrezza stops gluconeogenesis by signalling the alpha cells which in turn signal the liver. This is the way a health body works. This is what afrezza brings back to the PWD.
Aged - "Then it is gone and hepatic gluconeogenesis restarts" Are you saying a healthy body is not properly designed? No, I am saying you are incorrect in how the body works. If what you say was true Type 1 diabetics on Afrezza would not need basal insulin - patently that is not true. Also diabetics would not suffer from the Dawn Phenomenon.
Aged -sometimes I think there are multiple Ageds, just saying. You said " Type 1 diabetics on Afrezza would not need basal insulin"?
If a T1's pancreas was making enough insulin during fasting to handle gluconeogenesis and they were using afrezza, it is correct they would not need a basal. Thats what we call a T2. The problem is a T1 is not making enough insulin.
Since we don't have AGP's on most T2s we don't even know for sure their pancreas's are making enough insulin during fasting. Today we assume so. Then we put commerical's on TV for Trulicity saying how it gets the body to use the insulin it still has left instead of giving the body the extra human insulin it needs. How bad is that? Its hard fixing stupid.
There was another thread where Aged mentioned about a trial of afrezza against the GLP1s and SGLT2s. Now thats the study I would like to see. Since the job of a prandial is during meals and up to 2 hours after the meal, those would be interesting CGM charts. Since the issue T2s have is post prandial BG spikes, I sure hope Dr. Kendall gives us that study soon; 30 people; 10 per group; 2 weeks with a CGM.
Lets see some charts like in the VDex paper.
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Post by peppy on Aug 23, 2018 8:04:54 GMT -5
I think your take on it is correct. I am not messing with GOD either. Unfortunately that is exactly what we do with PWDs and the oral meds. We affect one thing which then lowers BG to some degree only to make a bigger mess some where else.
The body is not making enough insulin for its needs, just give it the human insulin it needs.
I so agree with this statement. SGLT2 - have the glucose go out your bladder through the kidney. (It will take H20 with it.) GLP-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. www.ncbi.nlm.nih.gov/pmc/articles/PMC1934514/DPP-4 -Dipeptidyl-peptidase IV (DPP-4) inhibitors inhibit the degradation of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). ETC, ETC: there is no end to it. I will stop, www.screencast.com/t/rd6BfbsqLwww.screencast.com/t/Pq0UbjiZAM9All because rapid acting insulin is to dangerous. Then came afrezza. Insulin you can take. In my opinion the medical system will contort our bodies to death to make a buck.
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Post by agedhippie on Aug 23, 2018 8:56:32 GMT -5
No, I am saying you are incorrect in how the body works. If what you say was true Type 1 diabetics on Afrezza would not need basal insulin - patently that is not true. Also diabetics would not suffer from the Dawn Phenomenon. Aged -sometimes I think there are multiple Ageds, just saying. You said " Type 1 diabetics on Afrezza would not need basal insulin"?
If a T1's pancreas was making enough insulin during fasting to handle gluconeogenesis and they were using afrezza, it is correct they would not need a basal. Thats what we call a T2. The problem is a T1 is not making enough insulin.
Since we don't have AGP's on most T2s we don't even know for sure their pancreas's are making enough insulin during fasting. Today we assume so. Then we put commerical's on TV for Trulicity saying how it gets the body to use the insulin it still has left instead of giving the body the extra human insulin it needs. How bad is that? You want more of me? I am touched There is just the one. In Type 2 (and in the honeymoon phase in Type 1 sometimes) you can initially produce enough insulin to cover your basal glucose output. However that does not change the my original point that Afrezza only reduces the basal glucose for meals, as does a healthy pancreas, and not continuously as metformin does.
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