|
|
Post by bobw on Feb 22, 2015 19:54:54 GMT -5
The question was asked on the other board that I will paraphrase here: Al Mann has stated that diabetics can increase their basal insulin when using Afrezza to achieve a lower fasting blood glucose (FBG) level. Why is Afrezzauser able to reduce his basal insulin and still achieve low FBG levels?
There is a body of research, contrary to what is commonly thought, that suggests that hyperinsulinemia causes insulin resistance that leads to T2DM (1). Correcting the hyperinsulinemia can result in the remission of the disease. This is shown in the article by comparing diabetic patients after Roux-en-Y gastric bypass (RYGB) surgery, which has the side effect of reducing hyperinsulinemia.
My hypothesis is that Afrezza, because of its short tail, reduces the excess insulin that is present after a meal is digested. This reduction of excess insulin leads to increased insulin sensitivity even in T1DM patients, resulting in lower FBG.
Figure 3 in the article shows that a week after RYGB, the fasting insulin level of diabetic patients an hour or more after a meal is almost the same as it is for lean non-diabetics, and glucose levels a week after the surgery resemble those of non-diabetics.
If the mechanism by which fasting glucose levels, when taking Afrezza, are lower are due to a reduction of insulin resistance caused by reduced insulin levels after a meal is digested, then Afrezza should become the insulin of choice for T2DM and T1DM. This would show that Al Mann is correct that T2DM patients should start a with fast prandial rather than basal insulin. Taking a basal insulin may contribute to hyperinsulinemia.
What do you think about this hypothesis?
From the article:
"Prior to the Roux-en-Y surgery, basal insulin levels in obese T2DM subjects are so high that the b-cells can no longer respond to food intake with additional insulin secretion (Fig. 3A). Within a week after the surgery, however, along with the correction of glucose levels and resolution of the T2DM, basal insulin levels return to normal and the food stimulated spike of insulin secretion is restored to levels equal to normal lean control subjects (Fig. 3B and C)."
"Conclusions and implications -- The hypothesis that hyperinsulinemia is the underlying mechanism causing diabetes is not new. Jesse Roth and colleagues (6,17) made a strong case for fasting hyperinsulinemia causing insulin resistance and development of diabetes. In her Banting Lecture at the 2011 American Diabetes Association Scientific Sessions, Dr. Barbara Corkey (18) (who has authored the “bench” contribution for this Bench to Clinic Symposia) presented convincing evidence in animals for the development of hyperinsulinemia and insulin resistance. Our contribution to the discussion comes from the observation in man that fasting insulin rises with the progression of T2DM and normalizes to levels like lean control subjects almost immediately after gastric bypass surgery. This correction of hyperinsulinemia after RYGB occurs simultaneously with the full and durable resolution of diabetes and is independent of changes in weight loss, insulin sensitivity, glucose, or free fatty acids. The primary manipulation in the surgery is exclusion of food from a portion of the GI track. Thus, it seems reasonable to propose that a diabetogenic signal from the gut to the islets is the cause of hyperinsulinemia. Remission of diabetes and correction of pathologically high fasting levels of insulin after RYGB is accompanied by reduced levels of lactate. From this we further propose that remission of diabetes is due to reduced lactate production in muscle and subsequent normalization of substrate driven glucose production through gluconeogenesis.
If this hypothesis, i.e., that the critical lesion in T2DM is hyperinsulinemia, is true, the treatment of T2DM with insulin needs review. While insulin may be required in the very late stages of T2DM when there is no longer enough b-cell reserve, it might be harmful to administer the hormone when the intrinsic fasting basal levels are still elevated. We do not treat hyperthyroidism with thyroxine or Cushing syndrome with cortisone; should we be treating T2DM, a disease characterized by hyperinsulinemia, with insulin?"
(1) WALTER J. PORIES, G. LYNIS DOHM, Diabetes: Have We Got It All Wrong?: Hyperinsulinism as the culprit: surgery provides the evidence, Diabetes Care December 1, 2012 35:2438-2442
care.diabetesjournals.org/content/35/12/2438.full.pdf+html
Diabetes-HaveWe Got It AllWrong-Hyperinsuli....pdf (710.36 KB)
|
|
|
|
Post by tripoley on Feb 23, 2015 19:02:09 GMT -5
In this group the stimulus for insulin secretion was from the gut (food) and reducing the uptake from the gut by the surgery reduced the stimulus and secretion of insulin. Makes sense but doesn't apply to most diabetics since most will digest food fine (except in diabetic gastroparesis but that's a different story). The study they cite that hyperinsulinemia causes insulin resistance applys well though. In T2's they have a dulled first phase insulin secretion so they have higher post-prandial BS but also higher insulin levels from the second phase insulin secretion trying to keep up with the BS. Afrezza should help to dull the second phase insulin secretion which would reduce the hyperinsulinemia in T2's. So what you are proposing may well ring true.
The unfortunate thing about the 175 study in T2's is that very few of those people (like 40?) were on metformin alone and most were on a second and third oral med. Many of those meds tend to cause hyperinsulinemia so it would be nice to see a study on Afrezza alone or metformin plus Afrezza. That study might show exactly what you're getting at.
|
|
|
|
Post by agedhippie on Feb 23, 2015 21:27:55 GMT -5
You become diabetic when you have an insulin deficiency around 60%, in Type 1 this is an absolute deficency - no insulin production, while in Type 2 it can be either relative - insufficient insulin production to overcome insulin resistance or absolute deficiency.
The thing with RYGB surgery in that population is that it dramatically reduces weight and hence insulin resistance. Suddenly you are the right side of the 60% line, usually by some distance, and in remission. The chances are if the delta on the weight is large enough, and the depending on age, the patient may die of old age before they hit that line again even allowing for the underlying progression. The problem is that the body destroys the now excess beta cells (the body builds beta cells to cope with insulin resistance - no extra resistance = no extra beta cells) so if you read the underlying papers to that paper you find that 12 months later 42% of the patients are already diabetic again despite maintaining their weight.
That's why I don't think the hypothesis doesn't check out, and why it got bypassed by the rest of the medical researchers (1 citation in two years is not good). The basic mechanics then come into play; your own insulin has perfect kinetics and dynamics, and offsetting glucagon for tight control. You want to use that for the difficult stuff and that role is not basal. If you can handle your basal with injected insulin it frees your own perfect insulin up to deal with what matters - food. That's the basis of why basal insulin precedes bolus insulin - far fewer hypos, and better control.
There is an argument, and research to support it, that *any* insulin given will reduce the load on the beta cells and help preserve then. It's fairly logical in that it avoids stressing the beta cells which is known to cause cell death.
|
|
|
|
Post by gomnkd on Feb 24, 2015 14:41:38 GMT -5
I believe I participated in that thread.
Today I met with Sam Finta for lunch. What a great guy! Shareholders and patients should be thanking him for his feedback and he has no financial interest in MNKD.
Here is a quick summary of things that I can share: Take it FWIW.
1) Afrezza is much better than what is seen in trials. Trials had a number of limitations, strict protocol. Give patients the freedom to tweak dosages, they'll get better results(at least the ones with CGM). Pt will show much better A1C's.
- I do believe this thesis.
2) Afrezza patients will eventually get better FBG control and will reduce basal doses. This due to lower insulin resistance(hyperinsulinemia).
3) Afrezza will be viewed as resulting in less hypos;
4) I saw how easy it was to use, it'll be a major selling point.
I'm even more convinced about Afrezza's potential. It'll be a loooooooooooooooong slog.
|
|
|
|
Post by otherottawaguy on Feb 24, 2015 16:18:25 GMT -5
Sam must be independently wealthy or very far along the 12 steps at Gamblers Anonymous to not be joining in the fun.
Wish him the best,
OOG
|
|
|
|
Post by kball on Feb 24, 2015 16:18:44 GMT -5
I believe I participated in that thread.
Today I met with Sam Finta for lunch. What a great guy! Shareholders and patients should be thanking him for his feedback and he has no financial interest in MNKD. Here is a quick summary of things that I can share: Take it FWIW. 1) Afrezza is much better than what is seen in trials. Trials had a number of limitations, strict protocol. Give patients the freedom to tweak dosages, they'll get better results(at least the ones with CGM). Pt will show much better A1C's. - I do believe this thesis. 2) Afrezza patients will eventually get better FBG control and will reduce basal doses. This due to lower insulin resistance(hyperinsulinemia). 3) Afrezza will be viewed as resulting in less hypos; 4) I saw how easy it was to use, it'll be a major selling point. I'm even more convinced about Afrezza's potential. It'll be a loooooooooooooooong slog. Interesting that he doesn't being such a fan and the first current spokesmodel (not counting Al). I mean, I've been a Costco shareholder for 20 years since i realized how it changed the way i shopped. And with Mannkind it changes the way you live w a disease. Which is far more impressive and positive imo |
|
|
|
Post by cretin11 on Feb 24, 2015 17:26:30 GMT -5
Today I met with Sam Finta for lunch. What a great guy! Shareholders and patients should be thanking him for his feedback and he has no financial interest in MNKD. Just wondering, did Sam comment on why he's not an investor in MNKD? |
|
|
|
Post by bradleysbest on Feb 24, 2015 17:49:17 GMT -5
He does not want his message lost in the fact that he would have a financial interest in MNKD. His concern is his health & not his bank account!
|
|
|
|
Post by gomnkd on Feb 24, 2015 18:04:06 GMT -5
Today I met with Sam Finta for lunch. What a great guy! Shareholders and patients should be thanking him for his feedback and he has no financial interest in MNKD. Just wondering, did Sam comment on why he's not an investor in MNKD? Yes, he said that if he told the FDA that he was an investor, they'll just ignore him and look at the ceiling. |
|
|
|
Post by zieg on Feb 24, 2015 19:22:01 GMT -5
Thanks for sharing Gomnkd!!
That is awesome!! Is he being hounded by many people? I hope he stays far away from people that probably wish him harm (Adam F).
He sounds like a great guy and truly has his heart in the right place. I'm impressed!!
When we think of what Al has done for the world, there are some similar characteristics. Al doesn't need the money and really wanted to make the world a better place. For a man his age to start a new company (EYES) during all this other stuff is really unbelievable.
Good job!! |
|
|
|
Post by cretin11 on Feb 25, 2015 0:44:43 GMT -5
Agreed, thx for sharing that, gomnkd
|
|
|
|
Post by tripoley on Mar 4, 2015 7:55:11 GMT -5
I posted this on Seeking Alpha in reply to someone who thought Afrezza wouldn't be beneficial to T2s. It seemed relevant to this thread: Actually there is some evidence showing that hyperinsulinemia causes insulin resistance and giving first phase insulin (Afrezza) actually may reduce hyperinsulinemia AND insulin resistance. bit.ly/1BH3dsg "We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance." bit.ly/1BH3dsk "It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of β-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents β-cell exhaustion after years of compensation for antecedent insulin resistance." bit.ly/1BH3eN2 "When type 2 diabetic subjects were administered identical amounts of insulin at mealtime within 30 minutes of the meal to mimic first-phase insulin secretion, or during the second 30 minutes after the meal, or as a constant infusion, only the insulin delivery that mimicked first-phase insulin secretion resulted in improved glucose tolerance and reduced subsequent endogenous insulin secretion." |
|
|
|
Post by gomnkd on Mar 4, 2015 10:59:06 GMT -5
|
|
