Insulin?

Type 2
42

What Al Mann showed is it the glucogen insulin ratio. I am not sure about the “free radicals” we think it viral and the more we test the more “LADAs” we see.

What he believed and demonstrates with current afrezza users is by directly getting the insulin into the blood through the lungs he was able to replicate release into the portal vein or at least close enough. The magic of afrezza is it does work in conjunction with the liver.

When you say “I don’t know too much about Afrezza” all afrezza is is human insulin in a monomer form. I am not sure what the mixed reviews are you are reading. I would like to read them. Its looks like and is at the molecule level the exact same insulin released through the pancreatic canal. Pretty simply, anyone saying afrezza does not work is arguing a healthy pancreas also does not work.

I would suggest you give it a try while measuring with a CGM. Interesting is how well it works with the liver. A non-diabetic taking the 4u with no food is an interesting graph.

43

Hi George,

Here is a typical excerpt from a description of Afrezza:

A major benefit of Afrezza is its ability to quickly raise blood insulin levels. In Type 2 diabetes a major defect is the loss of first phase insulin release that gets quickly released from the pancreas after a meal and then reaches high levels in the portal vein that goes directly to the liver. Afrezza obviously does not mimic this pathway when delivered through the lungs to the peripheral circulation, but blood levels of insulin may rise faster and further with inhaled insulin.

This is consistent with my understanding. I do not see how Afrezza can possibly accomplish a significant rebalancing of portal glucagon/insulin. It enters the bloodstream peripherally.
Portal blood is upstream of peripheral blood, and liver consumes the vast majority of islet hormones. Peripheral blood only “sees” the remainder of islet hormones that exit liver via hepatic artery.
This sets up the basic problem that any dose of peripheral insulin that can significantly alter the “upstream” higher-concentration portal blood hormones balance will absolutely swamp the peripheral tissues with excessive insulin, and generate massive hypoglycemia. I would encourage you to review the extensive literature describing this fundamental issue.
And beyond just this huge problem, the islets themselves are upstream of the portal vein, with still higher concentrations of hormones. And this is where the imbalance is generated via a defect of the normal INTRAISLET paracrine endocrinology.
Thanks for your enthusiastic suggestion, but I just don’t believe the claims you are citing. They are anatomically not possible, and furthermore everything that I have read about Afrezza, including some of the trials data, does not seem to reflect any magical properties.
Richard K. Bernstein has weighed in on Afrezza, and not positively. He does not prescribe it at all, I believe. If I recollect correctly, his problem with it is the unreliability of dosing and effect. This seems more than plausible to me.
Moreover, for myself, Afrezza is trying to solve the wrong “problem”. A diabetologist had me on Novolog to cover meals for a while – inappropriately. Absorption of a dominantly protein meal takes 4+ hours. Insulin Regular best matches this time profile, and the results show it. My prandial BG control is much better with the Regular than it was with the Novolog.
All of these attempts at “fast-acting” peripheral insulin are really trying to solve the problem of compensating for dietary carb’s, which themselves are fast-acting. I tried to explain, using a control-loop analogy, why this is impossible. All of empirical experience of human diabetes confirms that it is impossible, because positive feedback creates an unstable regulatory system. In other words, the correct dose and time profile of insulin will be different for every identical carbohydrate meal consumed. The islets secrete hormones in an oscillatory manner – it is unstable and unpredictable, when deficient islet insulin amplifies, rather than attenuates, glucagon secretion in response to portal glucose. This is what is going on in the diabetic.
The portal vein is extremely isolated, for good reason, anatomically. That is why very few human experiments requiring mere measurement access to the portal vein have been attempted. In rodent models it is physically impossible to get access as well. Canine model is one of the most favored, but even in the dog catheterization into portal vein is difficult and elaborate to accomplish.
The portal blood has to be well isolated from peripheral blood in order for the endocrinology of meal absorption to work properly. The liver must “see” the islet hormones first, and exclusively.
Al Mann is telling a story, trying to sell his drug. It looks like the early marketplace verdict is in as well – Afrezza and Mannkind have not been successful, from what I read.
There are far more people out there who have no clue about the basics of islet endocrinology than who do – maybe 1 in a 1000 diabetes pro’s know anything about it. I suspect that Mann is one of the 999, or that he just didn’t care to tackle the real problems which noone else has solved either. Geho and his company are actually trying, and have a partial solution. But even their idea only enhances hepatic buffering of glycogen/glucose/carb. I myself am happy to avoid carb’s, and so their solution would offer me nothing. The Geho “hepatic directed vesicle” insulin would theoretically allow a typical T1D to eat some carb’s without massive loss of BG control. But it does nothing at all to reduce excessive HGP which is strongly stimulated (at the level of the islets, upstream of liver) by dietary carb’s. If I were a T1D with no insulin production I would not use the Geho product either, for this reason.
Being a diabetic myself, I have spent eight years reading the basic research in the field. I was driven to isolate the significant material partly because most of it I recognized had to be incorrect, because it was inconsistent with the behavior of my own case as well as those of other diabetics. The vast majority of the literature is totally insulinocentric, and it is hopeless to understand diabetes by ignoring the role of glucagon, which is really the master hormone of whole-body fuel regulation. Insulin acts both hepatically and peripherally, and this is partly why people focus on it. Glucagon only acts significantly on liver, and blood ketones (beta-hydroxybutyrate) appear to play the role of master signaling hormone peripherally. When glucagon is persistently up the liver is in the fasted state, and pumps out ketones which signal the peripheral tissues in addition to providing fuel for them. And when glucagon is down so are ketones. They track.
It is glucagon that guarantees fuel for the brain, second to second and minute to minute. Its direct effect upon liver is more powerful than that of insulin, although insulin is also powerful. But insulin is not vital for life in the short term. Total lack of insulin removes the negative feedback action of ketones on the beta cells, which stimulate insulin secretion, which restrains glucagon secretion enough to prevent ketoacidosis in non-diabetics and those diabetics who produce any significant endogenous insulin at all.
So long-term T1Ds mostly require exogenous insulin to prevent ketoacidosis. Other than this one condition, diabetics live a long if shortened and poorer-quality life, and are able to reproduce and so forth. Insulin, an anabolic master hormone, is just not that vital in comparison to glucagon, THE master catabolic and life-sustaining hormone.

44

Mac - I appreciate your enthusiasm but what the data shows is lack of the robust release of insulin has a direct impact on liver glucose secretion. A major shortfall of the older studies is they could not emulate this release. Restoring the robust release puts the liver back in sync and that is what current users are seeing. Its hard arguing with the CGMs and their results. The alpha cell dysfuncion is a nice theory being the root cause of T2 but the readings show replace the robust insulin release and the glucogen dysfunction fixes itself. That was the reason for Dr. Alan Marcus’ comment I posted above.

Now I like “Engineer” Richard Bernstein and he has done a great deal for the world of diabetes. What Richard does with food is “avoid” the spike. Why? His insulin is too damn slow. What a robust insulin release does is blunt the spike. I was aware of his early comments about his concern about imprecise dosing but I thought he has now realized its not required with afrezza. If he has said something recently please let me know. In fact with afrezza its actually better to dose large as the liver will prevent the hypo. Basal insulin will effect the liver response so if taking a basal some care needs to be taken.

Because of the PK profile, afrezza obsoletes the need for Bernstein’s approach. Nothing wrong with reducing carbs and a good walk but the non-diabetic obese adapt through their beta cells. Let afrezza stop the spike and there is little need to avoid it. You can but its not necessary as non-diabetics demonstrate as a matter or course.

Now as far as Al Mann trying to sell his drug, I am pretty sure that was not Al’s driving goal. He was actually trying to solve the diabetic problem he saw with the insulin pumps he developed and help the PWDs. I know that sounds crazy but then again he put over $1B of his own money into it because he was a true believer. He knew they could develop great predictive algorithms and sensors but in simple terms the insulin including the RAA was too damn slow. I think the current Yale closed loop study will show the same. That should be available pretty soon for release.

As far as Mannkind surviving thats yet to be seen but afrezza will now that Cloud CGMs are becoming the norm and its hard hiding the CGM numbers. I think Amazon announced today, fitbit is working with Dexcom and Onduo has a number of big players all are doing Cloud CGM. Additionally, Ralph DeFronzo’s Qatar study is very exciting because it is showing what Al Mann showed in his studies which is beta cell regeneration by keeping non-diabetic TIR for the T2 with some beta cell functionality. That IMO is very exciting.

45

OK George, I will look into these claims by reading up about Afrezza. They just don’t make much sense to me, given what I know about the fundamental endocrinology. But anything is possible with diabetes, I suppose.
Is there really no problem with iatrogenic hypoglycemia with Afrezza? I just do not see how there would not be, unless it has tremendously tissue-selective properties in vivo. This is always the problem with all forms of peripheral exogenous insulin therapies.
Hyperglucagonemia is generated in the ISLETS – this has been established since the 1970s, and merely confirmed over and over again to this day. This generates hormone imbalance that has been measured in the portal vein – an extrahepatic phenomenon. And the regulatory power of glucagon and insulin on liver is well characterized as well. So your explanation that rapidity of peripheral insulin infusion is so corrective just doesn’t make any sense to me.
I suppose that Afrezza could, in theory, somehow selectively target liver vs. peripheral tissues in some very potent way, thereby “swimming upstream” and somehow overwhelming the influence of imbalanced portal-blood islet hormones, while avoiding massive peripheral-blood hypoglycemia. In this model rapidity of action would have nothing to do with efficacy, but this is all that I can imagine could produce an overwhelmingly superior insulin-delivery treatment. In addition, in order to avoid portal hyperglucagonemia it would actually have to have the same effect in the islets! Otherwise, if only influencing liver, it would have to overcome portal hyperglucagonemia for a significant period of time (more than a few minutes).
Can you point me to any technical papers by Mann or others that attempt to explain mechanism of action of Afrezza? If it is really as good as you recommend, these should be published. I will look for myself, but please advise me if you know of good technical references somehow addressing my challenges.
Or, I suppose, there could be some unknown stunning effect on liver similar to that of pharmocological somatostatin (delta-cell secreted islet hormone) which is extensively used in islet/liver lab research for hormone clamping and isolation. This could be very corrective, since elimination of both portal glucagon and portal insulin can result in euglycemia (in mice, anyway), as Unger’s and others’ experiment well demonstrate. The BG influence of portal glucose alone is quite trivial.
As for Bernstein, you don’t have to convince me that he does not know all. In fact, he is unaware himself of hyperglucagonemia in diabetes – he has not read the basic research literature. In fact, he does not seem to know much of anything about the basic research in diabetes, islets and liver. But he has a lot of clinical experience. I do not know if he has tried to use Afrezza (with patients or himself), and would not put it past him to dismiss it apriori for some reason. So I guess I should read up and not do the same myself – I will get back to you – I am sufficiently curious now what these claims are all about.

46

George,

I reviewed the summarized trial data here:

https://www.afrezza.com/hcp/safety-efficacy-studies/

This looks like what I remembered from reviewing it years ago. HbA1c’s typically in the 7.5% to 10% range, and slightly inferior to insulin aspart (that’s Novolog, which I have used) and basal insulin in T1Ds in the trial. This is a guaranteed ticket to the complications of diabetes – miles away from my goal of frank tissue regeneration.

Of course, the trial cohorts are eating an ADA diet with much carb’s. Nothing will control BG’s with this kind of diet, but you were implying that Afrezza could.

My HbA1c is 5.0% to 5.2% on my own insulin therapy and diet. And there is substantial evidence that I have long-lived RBCs – my blood sugars are essentially normal, and with typical RBC lifetime I would probably be well under 5.0%, and close to normal (4.5% or so). My BG normally does not get up to 100mg/dL even at my prandial peak.

Roughly a third of T2Ds achieved <7% A1C in the trial. Sorry, again this is just not close to good enough to avoid diabetic complications.

Meanwhile, I find an unusual paucity of any serious technical publication at all on Afrezza. What little there is introduces nothing at all remarkable, it appears.

Are you familiar with Michael Brownlee’s well-established work on complications of diabetes? Anyway, almost anyone with an A1c of 7% or greater is undergoing prandial swings in excess of 200mg/dL regularly. It is the swings that do the damage to tissues. Going up a lot and coming down fast is not good enough.

I would like to see the postprandial BG time profiles of the Afrezza trial cohorts. Mann talks about A1c values, and those he talks about are ultra-high from my point of view. I am not interested in the ADA guidelines – just achieving their ideal targets (i.e. 7% A1c) will lead to diabetic complications and a shortened lifetime and a good possibility of a miserable late-stage life.

I listened to Mann and others. I heard nothing at all relevant to my basic challenges – indeed, because of the fairly poor performance of Afrezza they cite, they seem to confirm the validity of my challenges.

Trading off convenience (and I don’t think standard SC insulin injection is very difficult, by the way) for the complications of diabetes is not something I am interested in.

I don’t see or hear any claims of extraordinary performance by Mann or others. I understand the monomer nature of delivery (i.e. yet another insulin analog – this is not the physiological form made in the endocrine pancreas, which is hexamer). This will reduce lifetime in vivo, and correspondingly increase rate of flux into tissues. This is not necessarily an overall advantage. My typical meal takes at least 4 hours to absorb, meaning that my prandial period is at least 4 hours in duration. So compensation must be durable for at least this long to suppress hyperglycemia. How is a short insulin lifetime advantageous for me? Like I said, I substituted human insulin for Novolog and improved prandial BG control as expected. Fast-acting insulin is only a futile attempt to cover carb’s.

It is possible that the short lifetime of the monomer reduces the incidence of severe hypoglycemia – that would make sense. But again, this does not translate to efficacy of correction or normalization of blood sugars.

Some guy on Youtube is now demo’ing his drop from a BG over 335mg/dL to 120mg/dL in one hour. Now I am willing to believe that this is relatively fast compared to what he was able to achieve with SC insulin. That is his point, but he is pitifully ignorant IMO. He is a young guy. Diabetic complications take many years to become obviously disabling – they are insidious.

Going up high and coming down faster will reduce HbA1c values (although not to levels I would consider acceptable). It is questionable how effective this would be in attenuating rate of tissue death from constant hyperglycemic transients, however. I would argue that the evidence is strong that it will not reduce rate of accumulation of complications that much. Again, it is the transients that do the damage. I commented on this already. Read Brownlee’s Banting award lecture:

http://diabetes.diabetesjournals.org/content/54/6/1615

Sorry, I still just do not get it. What is the big deal?

When I got involved in this thread it was to encourage Jamey to switch to insulin. He complained of adverse effects from the pitifully impotent combination of drugs an MD has had him using. I am familiar (from reading, not personal use) with these drugs, and unsurprised by the adverse effects. But my justification for using insulin, to Jamey, was to improve BG control and avoid later complications of diabetes. For this purpose Afrezza is clearly inadequate, and offers no performance advantage over conventional SC injection at best.

Bernstein certainly knows what he is talking about when he discusses requirements for avoidance of complications of diabetes and/or tissue regeneration afterward. I am in complete agreement with him that standard medical practice will shorten and worsen a diabetic’s lifetime – guaranteed. That is the bottom line. It is the individual diabetic’s choice whether to be satisfied with ADA guidelines or not. Afrezza appears to bring nothing to the party, from my own or Bernstein’s point of view.

47

P.S. In the Afrezza trial with T2D cohort, the “control” group was on oral agent only (i.e. probably sulfonylurea).
IMO the evidence that sulfonylureas actually cause beta-cell decline is strong enough to avoid them under all circumstances. In addition, they are an inadequate hypoglycemic agent for a T2D, and certainly not comparable to SC insulin.
For my own case the “standard of care”, in the unusual circumstance that a monogenic diabetic is treated by someone who knows anything about this condition, is oral secretagogue by a restricted subset of sulfonylureas or meglitinides. But these oral agents are five times more effective for HNF-type diabetics than for T2Ds. Indeed, this is a cheap form of diagnosis of HNF-type mutations, short of full gene sequencing.
I have reviewed the literature for HNF1-alpha cohorts followed for many decades, and concluded that sulfonylureas are not safe even in the 20% doses that these patients use them in, although rate of average decline of beta cells is much slower than in T2Ds. Meglitinides look potentially safe, based upon the smaller amount of data on HNF1-alpha diabetics using these drugs. Their mechanism of action is prandial, unlike that of sulfonylureas.
The clearcut alternative for me to consider would be meglitinides – not Afrezza. I am content with insulin, for the time being, but not without concerns. Peripheral blood insulin is supraphysiological with insulin therapy, necessarily. That concerns me a bit. And I have noticed some renal effects in my bloodwork as a result. I have a renal biomarker for HNF1-alpha, and this marker was the one affected. HNF1-alpha is a major regulatory gene in kidney.
I have normal kidney function (i.e. no renal complications of diabetes), fortunately.

48

Mac - the 175 trial is not going to tell you anything. It was designed by the FDA and afrezza was taken on average 15 minutes prior to meal and was under dosed in almost all cases. The oral was metformin.

For the discussion we are having on afrezza working with the liver you want to look at the 118 trial results - cheers and enjoy
A Study Comparing Subcutaneous Rapid Acting Insulin and One Formulation of Inhaled Insulin in Subjects With Type 2 Diabetes - Full Text View - ClinicalTrials.gov

Here is a high level discussion from healthline - BTW I believe the doctor he refers to in the article is Richard Bernstein. Here is the Jay Skyler Al was talking with https://www.diabetesresearch.org/jay-skyler-md

www.healthline.com/diabetesmine/the-truth-about-afresa-inhalable-insulin-a-chat-with-al-mann#2

Per the 3Q2009 Quarterly call gives background in the article

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.

2 Likes
49

Thank you for your contributions to this topic. Your citations are appropriate and stretch my ability to learn the more technical scientific concepts presented. I find it healthy to re-examine my fundamental beliefs from time to time.

We had another mongenic diabetic active here a few years back. He also knew a great deal about the science regarding diabetes. I appreciate your patience and hope you continue to participate here.

1 Like
50

@niccolo I assume you mean… great guy, I wonder how he’s doing

51

Yeah, that’s him. I met him at a D-conference. Good guy.

52

Thanks Terry, and Sam. Interesting to hear about Niccolo – I only know of one other MODY3 case with whom I have privately corresponded by email a bit.
I am an advocate for prevention of diabetes complications – in this sense Richard K. Bernstein is the only well-known professional advocate that I am aware of.
RKB generally gives the correct advice, but is unaware of the underlying basic research and endocrinology. His vast clinical experience informs his advice, generally pretty well. Everyone else goes with ADA protocol which relieves them of any effort to analyze things like RKB. Although in all fairness, there is no workable economic model for MDs to practice like RKB either – that is a showstopper.
I pored through an awful lot of basic and clinical diabetes research for years before I discovered the most important stuff, some of which I have cited. I persisted because I knew the conventional models simply were inconsistent with the BG behavior of a diabetic (including myself).
“Glucose intolerance”, as the term is generally used in all medical research, appears to be the result of hyperglucagonemia. This includes metabolic syndrome. Maybe half of the population will never become diabetic, being able to increase beta-cell population without excessive apoptosis progressing into frank diabetes. But these people will suffer other consequences such as CVD, neurological degeneration (including dimentia, brain) and so forth.
We are not evolved to cope with any significant carb’s in diet, as modern hominids. This is clear from massive archeological and fossil stable-isotope data.
My brother’s wife has a niece who is a juvenile T1D. She has all the latest hardware, so that her mother can monitor her BGs on her smartphone. She has an insulin pump and CGM. But of course her BGs skyrocket when she eats carb’s. There is just no way to compensate for this, as of today.
I sent the girl’s parents info about Geho and his company. Their device, if it becomes commercially available, would partially compensate for some carb’s in a T1D. But it would only do so by adding the liver back into the equation somewhat as a BG buffer. It would not affect the hyperglucagonemia at all. I think it is better for a diabetic to minimize carb’s, but especially for children this approach has practical limitations.
To me it is critical to understand the underlying endocrinology in considering diabetes and medical interventions.
Anyway, it is nice to be able to discuss these things with others who are in a position to care (i.e. diabetics). For various reasons the medical community has ignored or largely forgotten about the role of glucagon, and does not teach it at all (with the exception of a few specialists of course).

1 Like
53

I have a referral for MODY testing myself… it’s going to require a trip to the big city though, so I’m not sure when it’ll happen… I am somewhat skeptical that it’s my underlying issue, although I suppose it could be…

54

Quest Diagnostics offers MODY testing.
The blood draw would not necessarily have to be done at a Quest Diagnostics patient service center (PSC) although that would be an option. Many Doctor offices can do the blood draw for Quest and then have the samples sent out. Either way whether at a PSC or a Doc’s office, the sample would ultimate be sent to a special lab as this is not a common test. I believe Quest would actually run the MODY testing from their lab in Marlborough, Massachusetts.

My guess is this is a test you would want to be sure is covered by insurance in advance.

55

Nearest quest labs is about 250 miles away… I’d have no qualms about just refusing to pay for it;)

My doc has a private practice in that city and he has some arrangement with the Mayo Clinic labs… I don’t know the details. He works as a contractor for the small hospital where I live, they can’t do the testing or honor his private practice arrangements as far as I understand…

56

You should be able to get the draw at a local Doc’s office and just have them send it out.
Either way it is going to be flown to Massachusetts (if Quest is running the test).

EDIT: I don’t quickly see pricing but it is likely in the thousands of dollars. It obviously is quite specialized testing.

57

While that may hold true for many or even most people with diabetes, it is not true for many of us. During the last six years (34 years T1D) I’ve witnessed over and over that getting my head around appropriate insulin dose timing, size, and profile (in a pump) makes a huge difference. I think your young relative’s experience is typical. Docs are so frightened of hypoglycemia, they will almost always counsel overly conservative insulin dosing.

Scott Benner is the father of a young teenage T1D daughter who was diagnosed at the age of two. The family decided it would be best for their daughter’s health for Scott to stay home and deal with his daughter’s diabetes as well as run the household. He produces the JuiceBox Podcast, a good view of a more aggressive yet sane way to deal with a child’s diabetes.

I know I follow a regimen not common among my fellow diabetics but there are more and more of us staying current on the latest techniques and reaping significant benefits including a high percentage of time in range and a good night’s sleep. I follow my diabetes data every day and use that info to drive my treatment decisions going forward. Here’s one realtime display I follow. It’s called NightScout:

22%20PM
22%20PM1439×787 84 KB

I am not alone in this attention to diabetes detail. The CGM in the Cloud FaceBook forum is tech-saavy with lots of smart people dealing well with diabetes.

3 Likes
58

Mac - sorry to hear about your sister-in-law’s niece. Both the pump and the CGM were developed by Al Mann. Al developed afrezza because he knew the limitation of current analogs including the RAAs. It is also why he did trials like the 118 and showed how the liver, alpha and beta cells interact.

There are a growing number of children using afrezza off label some with a pump but more moving in the Tresiba direction. There is also a juvenile trial which may still be recruiting. Some are reporting it as life changing especially when eating things like pizza which previously they could not eat.

Here are the JDRF’s findings with the AP and afrezza. You may want to pass this on https://www.youtube.com/watch?v=GGgGjtM5ipg

There is a similar active closed-loop trial going on at Yale. I also recently learned the original afrezza users have just past 13 years of use.

1 Like
59

We have found (learned through advice from other people sharing their experience) a 45 minute (Humalog) pre-bolus is extremely effective in handling the BG spike from carb heavy foods.
Certainly how this works in terms of timing is different for the individual.
Having a reliable cgm is quite helpful in this regard.

60

This is an interesting observation and would make sense if Al Mann’s 118 trail findings are correct and goes counter to the theory of alpha cell dysfuntion but rather that the loss of a robust first phase insulin release results in continued glucagon release until a certain insulin level is reached.

What is key is blocking glucagon release and the bottom line is no T2 orals do this. The PWD at meal time needs insulin to rise and glucagon to stop and then restart as BG approaches baseline basically decreasing glycemic variability (GV)

Here is an old article about the 171 and 175 trials. While these trials were not designed to show glucagon interaction there was some data hidden in the results.

“This type of data would support the position that a valid effectiveness endpoint could be a reduction in such type of hypoglycemic events if a novel insulin or insulin delivery system is associated with ultra rapid absorption. At the same time, an ultra rapidly acting insulin like Afrezza might be expected to produce less hyperglycemia immediately after a meal and less hypoglycemia late after a meal and result in little decline in the A1C. Such a drug could still be helping not only to mitigate glycemic lows and highs, but to also decrease glycemic variability (GV), even though GV has not been proven to be a true problem requiring treatment.”

61

Hi Sam,

That is interesting. If you are to be tested for HNF-type MODY, I think that the main ramification of a diagnosis would be high sensitivity to oral secretagogue, from a MD’s perspective.
You could ask a doc to prescribe a sample of one and do an OGTT with and without the small dose prescribed for this type of diabetic. High sensitivity to secretagogue is pretty much diagnostic of one of the three HNF forms of diabetes (and the converse, I think).
If you show high sensitivity you might want to do further testing. But otherwise you could avoid the trip.
Do/did you have a parent (and grandparent) with diabetes? That would be the other obvious factor to consider.