Insulin?

Type 2
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Brian - here is the afrezza label https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf

Page 4 - Insulin Naïve Individuals Start on 4 units of AFREZZA at each meal.

Page 17 - 14.1 Overview of Clinical Studies of AFREZZA for Diabetes Mellitus - AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin. The efficacy of AFREZZA in type 1 diabetes patients was compared to insulin aspart in combination with basal insulin. **AFREZZA has been studied in adults with type 2 diabetes in **combination with oral antidiabetic drugs.

They are referring to metformin. This was only done because the FDA designed the study and the current Step program says metformin first. As Ralph Defronzo has finally realized metformin provides little benefit and we know this because 70%+ of current metformin users are not even meeting an average 154 BG level.

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@George44, why in the world would you suggest that someone should initiate insulin therapy wiih Afrezza. Afrezza is indicated for use in people with T1 and it says you “must use a basal insulin.” And it generally isn’t covered so people will pay through the nose for it. And if Afrezza was approved by the FDA as a standalone insulin treatment it would appear in the prescribing information. The AACE doesn’t recommend any rapid insulin as an appropriate choice for initiating insulin therapy. You can read their T2 treatment guidelines here. So this suggestion is inappropriate. I don’t understand why you are so focused on this. Are you a representative of Mannkind or a shareholder?

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My suggestion would be to stick with a discussion on the medications and uses thereof and avoid jumping into the weeds.

In any event…

Afrezza is FDA approved for Adults with Diabetes.
(ie - without regard to what TYPE of diabetes)

The first bullet point of Afrezza (per FDA currently approved label) is:
“AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus”

The additional mention on the label in regards to long-acting insulin is in regards to Type 1 is a restriction for patients with Type 1 but has no further implication on patients with other forms of diagnosed diabetes.

The FDA approved label for Afrezza DOES have a number of restrictions (which again a doctor can choose to ignore and prescribe off-label although certainly that should be a discussion with both the doctor and the patient being well informed). However a blanket restriction for Type 2 patients is not listed. At least I don’t see it although I am certainly open to correction (as these labels do get long and wordy and easy to miss something).

Certainly there are many discussions on these forums about the use of medications and technology which is outside an FDA approval but for which (hopefully) a Doctor has properly decided it is in the patients best interest and has prescribed something off-label. Although Afrezza is FDA approved for Adults only, we discussed with our Doctor about having this prescribed and used for Pediatric use. Certainly it seemed a reasonable conversation to us and the Doc did not think anything wrong (with the conversation) even though it clearly is not covered per the label. Ultimately we decided not to go with Afrezza for Pediatric usage mostly due to the Doctor having zero experience using this for Pediatrics and simply not having an adequate level of comfort. All in all it was a good conversation.

In my previous post, I had erroneously been looking at an Afrezza FDA approved Label which was not the latest. Here is a link which I believe is the most recent label revised as of September 2017.

https://www.afrezza.com/wp-content/uploads/Prescribinginfo.pdf

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One can go to a state like Arizona and find a doctor who will do all kinds of strange and dangerous things. That doesn’t mean it is recommended. Many doctors will prescribe Afrezza for off-label use, but I suspect there would be very few that would suggest it as a way of initiating insulin therapy. That is just way out of the lane of recommended standards of care and most allopathic doctors would go screaming and running away at the idea of prescribing only a rapid insulin as a way of initiating insulin therapy.

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I’m not sure I understand your motivation in commenting on this? Afrezza is used by T2’s without a basal and it’s not considered off label. Do you have alternative motive? Does your Dr know your treatment better then you? I think your suggestions are way off base, to warn people away from an approved therapy makes no sense to me. What is your experience with it? Why even mention costs? Did you have experience with it that caused such a warning? I think there are some people on this forum need to look at themselves in the mirror.
Yes, don’t try anything different, stay down the same path of failure. Exactly why I’m not impressed by this forum.

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I’m personally impressed by this forum but I am not impressed by this conversation. If this was the first discussion I had seen on Tudiabetes I would have run screaming in the other direction especially since this organization is supposed to be about supporting diabetics and not down putting other peoples experiences and advice.
People who receive advice from the internet need to make their own decisions, and talk to their own doctors, and take what they read with a grain of salt. Please stop this mean spirited discussion because the person who originally asked the question about insulin has said he will be talking to his Dr. and that is exactly what he should be doing.

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I agree with parts of your post. The attacking was started by a person in power, I think it’s awful.

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Brian - why would you keep saying something which is just wrong? Did you not read the label I posted above?

Now, why would a T2 who still has some beta cell functionality left take a basal? Historically its fear of hypos and to limit the PWDs hypo risk. Before afrezza, insulin was just too damn slow. With afrezza as long as you are not taking a basal you have very little chance of a hypo. As Al Mann said, you really have to try.

T2s first lose post-meal first phase insulin release. The way to treat that is to blunt the spike before its goes 140+. To do that you need an insulin which works like the pancreas and there is only one.

Now why does it work like the pancreas? Two reasons; the delivery methods gets it into the blood immediately like taking it IV or through the pancreatic canal; the second is because it was stabilized as a monomer so speed of action is very consistent.

Now as far as cost, its way too expensive. I would like to see a 90 cartridge box being sold OTC for $29.95. Maybe if more people started understanding what afrezza is and what it can do, more people will start demanding it and more insurance companies will cover it. Once the insurance companies start understanding that in the long run it will be a huge money saver for them they will all cover it.

But if people keep saying things like it must be taken with a basal and keep insisting with authority they are right the average PWD won’t know the truth and will never even ask about it. It will go to the dump heap just like BP would like and never become the paradigm shifting treatment Al Mann envisioned.

Do you realized Al Mann in his studies actually showed T2 beta cell improvement? Now that DeFronzo is showing the same with his TZD/GLP-1 cocktail we have to different approaches achieving the same result both by keeping non-diabetic TIR. The key in stopping T2 progression is non-diabetic TIR.

Now would you rather take the human insulin with minimal chance of hypo or the Actos/Byetta cocktail? Additionally, afrezza is NOT a subq RAA. Its human insulin which is delivered almost immediately into the blood. When the AACE finally catches up in a few years they will get it right and it will be in its own category. Right now the AACE document needs a clean-up. How long did it take the FDA to get the speed right on the afrezza label, 3 years?, and that was a no-brainer.

Here is a video you may want to watch where Al Mann talks pros/cons of current insulins. Al was one of the great minds in diabetes. He invented the insulin pump; the CGM; first implantable pacemaker; solar panel; etc. He starts talking diabetes at 8:30m but it gets interesting at 11:00m and then talks about stopping T2 progression at 15:00M “interesting this lowers insulin resistance… this is even likely to slow and even stop the progression of Type 2 diabetes” Alfred E. Mann Wins 2011 MDEA Lifetime Achievement Award - YouTube

Why does it seem you don’t want people to know about afrezza and what it can do? I know from personal experience it works and stops the progression. I also know from personal experience the dangers of the T2 orals and the deadly consequence some have had like Orinase. Do you think UpJohn did not know the dangers of Orinase? Why was Trulicty rushed to market? What was done, 5 small studies?

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You are missing an important point; insulin is not the only hormone the body uses to control glucose. Insulin’s affect is modified by the bodies use of glucagon to counteract the affect of insulin as needed. That’s why a person with normal pancreas and endo response does not have lows. If the body detects an incipient low it secretes glucagon to counteract the insulin. That’s why development is underway for a pump that delivers both insulin and glucagon.

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Sally and Jerry - you are absolutely correct. I think in my first post to Brian I mentioned afrezza working in conjunction with the liver. By replicating a true first phase insulin release afrezza blocks the alpha cells. They stop producing glucagon which is huge not only in stopping the after meal spike but also in preventing the low.

Once in a resting state when the BG starts to go low they too have a first phase release and stop the low by signalling the liver. This is why it is very difficult to get hypos with a healthy pancreas and with afrezza. Just don’t use metformin as it will affect this release and so will a basal btw. Here is what Dr. Alan Marcus who helped develop the insulin pump at Minimed said about it starting at the 2:55Mark https://youtu.be/LO886BKhGek

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Hi, I am Ken. I have HNF1-alpha (monogenic) diabetes, and it is mild. I first diagnosed myself in 2010, and I use human insulin (Regular and NPH) alone.
I would recommend switching to insulin, with emphasis upon the bolus for meals, in conjunction with a very low carbohydrate diet.
The fundamental defect in diabetes is an insulin deficiency, but this causes hyperglucagonemia because islet insulin (counter-)regulates the alpha cell(s), and hence glucagon. It is excessive portal glucagon that causes diabetic hyperglycemia, especially in response to meals, via excessive hepatic glucose production.
In a diabetic a predictable bolus of injected insulin can shunt the excess hepatic glucose production (HGP) stimulated by amino acids into the peripheral tissues, but cannot predictably do the same for HGP stimulated by glucose. The normal negative feedback in a non-diabetic is converted to positive feedback in a diabetic, at the level of the islets, for GSIS and GSGS (glucose-stimulated insulin/glucagon secretion). This is simply unstable, fundamentally. Hence, meal boluses must be dietary protein dominated.
The dominant cause of diabetic complications (i.e. cell death) is (post)prandial hyperglycemia. Only peripheral insulin and proper diet can control this to any significant degree. Using any other regimen will guarantee neurological and microvascular tissue loss, admittedly over many years or decades.
I use ~16U of Novolin R daily for (2) meal boluses, and 3U doses (one in morning, one at bedtime) of Novolin N for basal doses. The evening dose controls dawn phenomenon well, since the NPH peaks roughly at time of awakening. These each cost ~$25 per 1000U vial at Walmart in Massachusetts, sold over-the-counter.
For controlling prandial hyperglycemia, which is the name of the game, any other regimen than peripheral insulin is grossly inadequate IMO.

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I got sick from each drug the Dr prescribed me and my sugars were getting worse. I had stopped each drug because of the side effects. The last hold out was metformin, but I was hugely nauseated every time I took it. I stopped it and I asked my Doctor for insulin and she prescribed Lantus which made a huge difference. I wouldn’t go back to the endocrinologist who also just kept wanting to put me back on drugs. I had been labeled not compliant by the way. I switched Doctors to an internist, who then also added Humalog and I did much better.
It was a game changer, however I was still in the high 7’s A1C. She sent me to a new Endo the group had gotten who tested me for type 1 which it turned I was. I would skip insulin before thinking my body could deal with it when I was active and eating right. Once I knew I was a type 1 I knew my body couldn’t deal no matter how well I was eating. I changed to always taking insulin I am now in the low 7’s or high 6’s and seem to be doing well, luckily with no problems from being diagnosed wrong for years.
For me insulin was much better, but I ended up being type 1. A slow acting insulin to start on to get used to insulin is going to be easier to adjust to than a fast acting.
I have never tried an inhaled insulin but I think the person that was against it, it was because it’s a fast acting insulin and that is harder to learn than to learn a once a day insulin.
But I am a type 1, so my experience is different. But I do understand not wanting the drugs because of the issues I had with them too. Insulin didn’t make me feel bad per se, unless I am/was taking the wrong dose. Then you can have a drop and it can be dangerous

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Thanks Ken, interesting read. Lots of information which honestly I am not familiar with. But I will learn. I thank you sir!

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Do you know if this is true for all types of diabetes including T1 and T2? I am a long-term T1D and have read many T2D posts over the years about their liver messing up post-meal control. This, however, has not been my experience.

Here is my continuous glucose monitor trace from last Monday, a particularly good day for me.

03 AM
03 AM781×152 7.73 KB

I ate two meals that day, one at noon and another at 7:00 p.m. While I use an automated insulin dosing system now, I’ve been able to do this in a manual mode, too. I’m not using large amounts of insulin, either. My total daily dose that day was just under 27 units, about 0.35 units/kg of body weight.

I don’t understand the complete role of the liver in glucose metabolism but I suggest it is more complicated when considering the full spectrum of diabetes.

Good for you for advocating for yourself and using insulin in an intelligent and appropriate way. You’re living with such a rare form of diabetes. What methods did you use to teach yourself about it? Are there any online fora dedicated to monogenic diabetes?

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Hi Terry4,

I would have to say that yes, I feel sure that the hyperglycemia of almost all forms of diabetes, certainly including T1DM and T2DM and most of the monogenic forms, is dominantly caused by a deficit in acute GSIS (glucose-stimulated insulin secretion), which in turn generates hypersecretion of glucagon and excess HGP. Here is a good primer reference:

Roger Unger et al really demonstrated this definitively in the early through mid 1970’s, and all research since has been in agreement. It is simply not widely known of (clinically).
MODY2 (glucokinase monogenic diabetes) is the only exception that I know of, wherein there is NO insulin secretion deficit, and ONLY BASAL hyperglycemia. Those with MODY2 NEVER suffer any diabetic complications and are not treated with any medication. This alone well illustrates the phenomenon of hyperglycemia-induced apoptosis due to glycemic transients (see Michael Brownlee’s research).
For yourself, there is the additional complication of “loss of intraislet insulin decrement” to be concerned with. In any diabetic who produces little to no endogenous insulin for three to five years or so (typically), the alpha cells thereafter become less responsive to absolute hypoglycemia. I personally believe this is due to the loss of intraislet insulin signaling and subsequent epigenetic transformation in the alpha cells. In any case, there is a massive literature on this – it is a long-observed phenomenon in T1Ds and very advanced T2Ds.
If one does a simple set of BG area-under-the-curve calculations based upon a small or moderate sized glucose bolus in a diabetic, one can easily see that the bolus itself cannot begin to explain the increase in peripheral (i.e. systemic) glucose flux. This applies to a T1D or T2D or one such as myself.
Here is a Youtube video by Alan Cherrington explaining how portal hormone and nutrient fluxes are actually measured, and showing real-life results in diabetic and non-diabetic models:

A key thing to note in the video above is the “inversion” of response to dietary (i.e. portal) glucose in the diabetic. This converts regulation (i.e. negative feedback) into instability (i.e. positive feedback). This is the fundamental reason that diabetics cannot predictably compensate for significant dietary carbohydrate. Cherrington and others refer to this inversion as a “perverse” response.
Your BG data is not inconsistent with the model of diabetic hyperglucagonemia, unless you are claiming that you accomplish this with a high-carbohydrate diet.
Since you are LADA (right?), if you are still in early years since diagnosis you may still have substantial endogenous insulin production as well. Exogenous insulin ONLY acts peripherally – NONE gets to the liver. It is not at all the equivalent of endogenous (portal) insulin at all, and can only drive down BG by increasing flux into the peripheral tissues (mainly muscle).
This TuDiabetes-produced interview with Robert Geho discusses this role of portal hormones and liver in diabetes vs. non-diabetes:

It is also important to understand that, while absorbing a meal, portal hormone levels of islet hormones (e.g. glucagon, insulin) can be 40x or more higher than peripheral blood levels. This is why exogenous insulin cannot act on the liver, without a technological intervention such as Geho is working on.
My form of diabetes is very similar to T1DM – both forms phenotypically exhibit normal or supranormal whole-body insulin sensitivity, unlike T2DM. In T2DM, and especially in the earlier years, there is a “compensatory” period of heavy endogenous insulin secretion, initially even in the acute or 1st-phase response. Unger and many others have proposed that an alpha-cell defect is actually the initiator of T2DM. Unger proposes this takes place via induced insulin resistance in the alpha cell itself, which then produces hyperglucagonemia even before the beta-cell decline starts. There is a LOT of experimental evidence for something like this – G. Shulman et al, R. Unger et al, and many, many more.
This phenomenon of apparent alpha-cell initial defect, followed by beta-cell decline is UNIQUE to T2DM. And there is no question of why many insulin-controlled T2Ds use HUGE doses of insulin – this is due to the fact that a T2D (unlike a T1D) eating a high-carb diet (as the ADA advocates) produces massive hyperglucagonemia because of the “perverse” islet-hormone response and the T2D’s characteristic whole-body IR. I personally believe that there IS some type of alpha-cell IR unique to T2DM.
However, it is also true of T2DM that (at least in early years) the beta cells and alpha cells still respond NORMALLY to amino acids! That is why an early T2D can maintain perfect BG homeostasis purely with a very-low-carb diet and no medication. Whereas in HNF1-alpha and T1DM there is an insulin-secretion deficit in response to dietary protein, and this produces excess glucagon secretion, and hence requires bolus insulin to compensate. That is why I use insulin.

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You are very welcome, Jamey. By the way, I should probably have emphasized that it is ESSENTIAL for a T2D to maintain a very strict low-carb diet if using insulin. Otherwise a roller-coaster BG response will result.
Unless you are pretty advanced the required basal and bolus doses should be small – otherwise something is wrong. See my response to Terry4 below. Early T2Ds can maintain normal BG without any medication at all – see Gannon and Nuttall lo-BAG (i.e. low-carb) clinical studies, etc. It has been recognized since the 1970s that AASIS (amino-acid stimulated insulin secretion) is preserved in early T2DM. Since that time noone seems to have bothered to further study this.
The “hepatic transcription factor” forms of monogenic diabetes (HNF1a, HNF1b, HNF4a) comprise over 1% of all diabetes. These are not all THAT rare. These forms are virtually NEVER correctly diagnosed – almost always diabetics of these types are (mis)diagnosed either T1D or T2D.
If you are naturally lean and insulin-sensitive, you might consider either LADA or monogenic diabetes. Being on this forum you (and/or MD) have likely considered LADA already. Hyperglycemia in response to a pure-meat meal may indicate non-T2DM.
In any case, you should be using one of the Abbott Labs meters with the Freestyle Lite strips for adequate accuracy in the normal (~80mg/dL) range (assuming no CGM).
Start with insulin very gradually and carefully. Read Richard Bernstein’s book Diabetes Solution – he outlines some formulaic procedures for working up an insulin regimen on your own. Viewing RKB’s Youtube series Diabetes University is also recommended.
Apologies if I am repeating some advice you have been given by others already.

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One thing worth considering is that an approach combining oral meds and insulin may be most effective for some. I say this as a T1 diabetic who uses insulin but has also had improved results when adding metformin to my regimen, which T1s are doing more and more. If you have insulin resistance, you can keep injecting more and more insulin, but you will likely need high doses, gain weight in unhealthy patterns, and may still have difficulty maintaining good control. Using something that decreases insulin resistance and liver output can help the exogenous insulin work more effectively and can counter things like the dawn phenomenon effectively for some, which can otherwise be hard to manage without a pump. Not to mention that every time I look, it seems like there’s more evidence for potential other beneficial effects of metformin. So while I agree with wondering why people don’t go on insulin earlier, I also tend to think the same thing is true of metformin—if you can tolerate it (and while not everyone can, many people do ok with the ER formulation), it’s probably to your benefit to go on it at the earliest signs of insulin resistance. I wouldn’t be surprised if people with strong family histories of T2 start being advised to use it preventatively in the near future.

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P.S. Jamey – a corollary to the excessive HGP of (most) diabetes is that a diabetic has substantially more gluconeogenic production (each day) than a non-diabetic. This is required in order to replace the extra (hepatic) glycogen lost to the extra HGP. And this has been confirmed repeatedly by lab measurement in vivo on diabetics compared with non-diabetics.
The substrate for gluconeogenesis are certain of the amino acids (especially branched-chain AAs, aka BCAAs).
Hence, it is crucial for any diabetic (excepting MODY2) to get adequate high-quality (i.e. animal-sourced) protein to prevent sarcopenia and many other health problems, and the diabetic must get MORE than the non-diabetic to keep pace with excessive HGP, even with perfect BG control.
If BG is poorly controlled, the need for dietary protein gets still larger, but there are myriad reasons to make sure of good BG control.
The need for more dietary protein is another clinically little-recognized problem of diabetes, but it is intrinsic.

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Mac - I read all your information and it was interesting. It is also contrary to what Al Mann showed in his testing with afrezza. What it basically comes down to was aside from IV insulin, the absorption of all other exogenous insulin is too slow to replicate first phase release. ALL T2s first lose the robust first phase release which affects glucogen blocking. Once this is lost everything becomes a mess which no oral or subq insulin can address.

What Dr. Alan Marcus and Al Mann found out was if you can replicate the first phase robust release it will actually block the glucogen production which stops the liver’s glucose.

Now, this is more than theory. Since afrezza replicates the first phase release it will blunt the post meal spike as shown consistently through CGM monitoring. Without stopping liver glucose release getting these results are improbable.

Now, if Dr. Alan Marcus and Al Mann were both wrong then the livers roll in BG control is less important than we think and that I doubt.

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Hi George,
I don’t know too much about Afrezza – have read mixed reviews. I understand that rapidity of entry into the peripheral blood is its forte and goal.
It would not be possible for it to influence the liver because portal insulin/glucagon hormone levels are much too high in the portal vein. Only direct injection into the portal vein, and nowhere else, can accomplish this. That is what the islets do.
However, high peripheral insulin levels can compensate for excess HGP by driving the BG into tissues. The problem is one of consistency and control – avoiding both hypoglycemia and hyperglycemia – with any peripheral compensation. This would apply to Afrezza too – rapidity has nothing to do with point of entry into the circulation.
All of the hormonal imbalance in most diabetes is generated in the ISLETS, where prandial hormone levels are as high as 400x (yes, that is four hundred times) those in peripheral blood. Islet hormone regulation is PARACRINE, meaning that the alpha cells are regulated by the beta cells, acting as a portal nutrient (especially glucose) sensor, via local islet insulin. When insulin is deficient glucagon will be excessive – both prandially and basally. That is how it works – this has been established for well over four decades without any valid challenge.
Rapidity of action does not solve the problem at all. Afrezza will be tested in the marketplace – I myself would not consider using it. But it does not address the fundamental paracrine defect of diabetes in any fundamental way. This is entirely within the islets. The liver just gets an imbalanced hormonal signal as a result.
Also, it is questionable whether T2Ds first lose acute GSIS. There is a rapidly increasing amount of evidence from many investigators that the initial defect is in the alpha cells, first inducing hyperglucagonemia even while the beta cells (via expansion of cell population) are still hypersecreting insulin successfully. Here is just one of the most fascinating examples of this type of research, for anyone curious:

It is the earlier phases of the decades-long progression of T2DM, including pre-diabetic (by ADA definition) phases especially, that are difficult or impossible to explain without an alpha-cell origination. The experiment above is a plausible mammal model of excessive carbohydrate in human diet as the initial insult, first leading to hyperglucagonemia despite concurrent hyperinsulinemia. What causes this change within the alpha cells is not known. But it has been established that this occurs in many experiments by many different research groups.
I would also opine, based upon extensive poring over the research literature, that beta-cell recovery is possible in T2DM. However, it takes years and years, just as the decline does. It REQUIRES insulin therapy, apparently. Also, it requires early intervention with a few years of diagnosis. And it probably requires periodic prolonged fasting. The Roy Taylor / Newcastle Univ. experiment with human cohorts is just one of the more recent pieces of evidence, but similar human trials and many individual cases have shown similar results over many decades.
The constantly excessive HGP of T2DM probably induces both the excessive apoptosis and the dismorphia of beta cells due to persistent, excessive ROS (free-radical) damage and signaling for which cellular repair cannot keep pace. Insulin granulation is lost when beta-cell function (measured as disposition index) declines to ~20% (true in all forms of diabetes) – this is when initial diagnosis occurs due to acute and sudden loss of BG regulation, with polyuria and polydipsia also first appearing.
Crossing back over this threshold has definitely been accomplished in T1DM, and also in T2DM. But it takes a lot of discipline and patience, and a very strict dietary and BG-control regimen. Getting all the way back to normalcy (i.e. a normal OGTT response) has never been documented, to my knowledge. But I think it can be done, in theory.

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