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New Diabetic CURATIVE Small Molecules

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#1 Logjam

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Posted 21 July 2016 - 10:33 PM


Looks like this might be BIG.

 

Over the past few years, there have been about 5 compounds that are all DYRK1A inhibitors (supportive of the case) that induce beta cell replication in HUMAN beta cells.  These 5 compounds come from 3 independent research groups.  Getting beta cells to grow in mice is super easy.  Humans ... not so easy.

 

That's important because it's not artificially stimulating the same beta cells to produce more, stop them from dying, or reduce insulin resistance, urinating it out, or stop a liver from producing glucose.  No, it's inducing them to undergo mitosis, and several proteins related to proliferation limitation and senescence like p16 and p57 are reduced.

 

As you may know, human beta cells replicate during an early-age-window of something like birth to 5-10 years old.  After that, it's SEVERELY limited by various forms of replication inhibition.  Probably by p16 and p57 or similar. There are reports of accelerated telomere shortening, but these multiple studies call that into question.  The vast majority of donor cells would be from older patients.  They ALL proliferated.  Taking cycloastragenol might not be a horrible idea, but telomeres may not be the problem.

 

My guess is that in large animals with long life expectancies, this is a limiting system to prevent hypoglycemia and/or cancer.  According to  http://www.ncbi.nlm....les/PMC3904605/, p57 is involved.  This is not entirely surprising.  The cells we get typically take us to 20-30, which ensures species survival.   But we're living longer now.  Mice don't live so long.  The beta cells are not protected to the same level.

 

This is important, and possibly huge, actually.  Even if it's not used in humans, it would also be applicable to accelerate beta cell growth from lab-grown cells: http://diabetes.diab...6/1496.full.pdf

 

The compounds are:

  1. Harmine (well known natural DYRK1A inhibitor that is also an MAOI — http://www.ncbi.nlm....es/PMC4690535/)
  2. INDY (a lab-created compound — http://www.ncbi.nlm....es/PMC4690535/)
  3. GNF4877 (lab-created aminopyrazine compound — http://www.ncbi.nlm....es/PMC4639830/)
  4. GNF7156 (lab-created aminopyrazine compound — http://www.ncbi.nlm....es/PMC4639830/)
  5. 5-IT / 5-iodotubercidin (annotated adenosine kinase inhibitor — http://www.ncbi.nlm....ubmed/26953159)

It's important that all of these are also DYRK1A inhibitors, even if that's one of the off-target effects for what a compound was initially created or discovered for.  5-IT is an "annotated adenosine kinase inhibitor," but:

 
Since 5-IT is primarily annotated as an adenosine kinase inhibitor, we tested the effects of the structurally unrelated adenosine kinase inhibitor ABT-702, which has an IC50 of 1.7 nM (35, 36). We found that ABT-702, tested up to 20 μM, had no effect on EdU incorporation (Fig. 2A), suggesting that the mechanism of action of 5-IT in human beta cells may be different.
 
So basically it happens to be a DYRK1A inhibitor, and the other one isn't.
 
Which of these are actually safe to administrate to lab rats, if any?  The lab-created status of some of them would make me nervous, but lab rats of course.
 
5-IT (5-iodotubercidin) looks the most promising in some ways, but what is it and can it be obtained for rats?  Would anyone be tempted to test any of these compounds?

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Edited by Logjam, 21 July 2016 - 10:59 PM.

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#2 Logjam

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Posted 22 July 2016 - 12:54 AM

Post broke the links.  Repasted fixed below.  It's interesting that they all note that it's DYRK1A that does it.

 

EGCG is a DYRK1A inhibitor that is known to be a marginal antidiabetic agent as well, though it has not been investigated in this regard.

 

  1. Harmine (well known natural DYRK1A inhibitor that is also an MAOI — http://www.ncbi.nlm....es/PMC4690535/
  2. INDY (a lab-created compound — http://www.ncbi.nlm....es/PMC4690535/
  3. GNF4877 (lab-created aminopyrazine compound — http://www.ncbi.nlm....es/PMC4639830/
  4. GNF7156 (lab-created aminopyrazine compound — http://www.ncbi.nlm....es/PMC4639830/
  5. 5-IT / 5-iodotubercidin (annotated adenosine kinase inhibitor — http://www.ncbi.nlm....ubmed/26953159

Edited by Logjam, 22 July 2016 - 01:35 AM.

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#3 Logjam

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Posted 22 July 2016 - 08:24 PM

The latest paper out of Joslin and Harvard is here: https://www.research...l_proliferation

 

Here, we show that 5- iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human beta-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle (CDC)-like (CLK) kinase families. Induction of beta-cell proliferation by either 5- IT or harmine, another natural-product DYRK1A inhibitor, was suppressed by co-incubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and NFAT signaling. Gene-expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes beta-cell proliferation in human islets grafted under the kidney capsule of NOD- scid IL2Rgnull mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human beta-cell proliferation. 

 

Does this say what I think it does?  If so, which substances look the most promising and safest?  

 


Edited by Logjam, 22 July 2016 - 08:26 PM.


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#4 Logjam

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Posted 25 July 2016 - 08:52 PM

I guess nobody is as interested in I am about the fact that some small molecule actually succeeded in downregulating some kinase and triggering mitosis, probably by downregulating various tumor suppressors that induce perpetual quiescence.

 

Beta cells don't grow after you're 5.  Since they haven't been dividing constantly, I doubt they can't do a little more dividing.  It's just that your body is either preventing hypoglycemia or cancer.

 

Does anyone have any thoughts?  I thought this was much bigger.


Edited by Logjam, 25 July 2016 - 08:56 PM.


#5 erzebet

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Posted 26 July 2016 - 05:48 PM

In your first post you said 'Getting beta cells to grow in mice is super easy.  Humans ... not so easy.' - does this mean those 5 compounds were tested in:

1 human beta cells

2 mice beta cells

3 humans

4 mice ?

 

And coming back to your final post here, it's not that the information is not important, it's that this topic is so niche that few people can discuss it. I have no experience with lab rats and I can't tell you which of those 5 compounds would best suit this biological model. Were any of these 5 substances tested in other types of cells - human or otherwise?



#6 Logjam

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Posted 27 July 2016 - 02:02 AM

In most studies, compounds were tested in mice, mouse beta cells in a petri dish, human beta cells in a petri dish, and human cells tranplanted into immunosuppressed mice.  As far as I know, this is the furthest any compound has gotten, and curing diabetes would be a big deal for public health.  Actually, I think the one out of Joslin didn't do the implantation into mice, but it was human cells of all ages, including 60 year olds.  They all replicated.  That blows a hole in the idea that telomeres are the problem or similar.

 

So:

 

1. Human beta cells (yes)

2. Mice beta cells (yes)

3. Humans (not tested yet) -- but human cells transplanted into immunosuppressed mice, yes.

4. Mice (yes)

 

I'm curious if a trained eye can see large defects in the studies.  This has clearly been a problem for awhile.  Thank you for reading.  To me it's not niche because it's a very large public health issue.   Interestingly, they all attributed the finding to the same mechanism.

 

They're all inhibitors of the same enzyme.  DYRK1A.

 

The graphs attached show the compounds in 1 study in humans and mice.  It works better in mice, but get something like 1-2% of human beta cells to replicate.  Unless the researchers are publishing fraudulent studies, this is a big deal for aging and public health.  Diabetes itself seems to result from a flawed assumption that we only will live 30 years anyway, and that we don't need more beta cells than we produce in the first 5 years of life.

 

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Edited by Logjam, 27 July 2016 - 02:33 AM.


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#7 Logjam

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Posted 28 July 2016 - 05:28 PM

Last time I'll ping this one.  Does anyone have any mice or rats and have access to any of those chemicals?  In theory they could be procured by lab chemical suppliers, but not in usable quantities.   Even an  experiment without a sham that got 3-4 rats (preferably with human beta cells implanted but let's keep our expectations reasonable here) to recover insulin normoglycemia, it would be data that these compounds work.  I'm not optimistic that anyone will be able to get human islets though.

 

5-Iodotubercidin is a well known compound.  Harmine is easily procured, I think, since it's a natural part of various plants.  INDY, I don't know what INDY is.  There's also a prodrug for INDY called proINDY, which I assume is orally available.

 

So we'd want:

1. Harmine HCl

2. ProINDY

3. 5-Iodotubercidin.

 

I'd want to help fund some of the study if anyone is interested.

 

The the other 2 "GNF" compounds are not easy to find, but the supplement ( http://www.ncbi.nlm....omms9372-s1.pdf ) incidentally shows how to synthesize both materials in section:

 

Supplementary Methods

Compound synthesis. Synthesis of GNF7156, GNF6324 and GNF4877

 

Is anyone this ambitious?  If any of these compounds actually work, it's actually probably a cure for a type2 and some type1s with residual beta cells.


Edited by Logjam, 28 July 2016 - 05:34 PM.


#8 corb

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Posted 28 July 2016 - 08:08 PM


5-IT also increased glucose-dependent insulin secretion after prolonged treatment.

 

 

That's more interesting than what effect it has on beta cell proliferation because most people suffering from diabetes have type 2.

The question is - if the increased insulin production is the result of increased beta cell numbers is the effect sustainable?
Forcing your beta cells to proliferate over their normal rate might not be a good idea in the long term. If the effect is sustained they might have something good there.

 

As for type 1 diabetes, they'll have to figure out a way to stop the immune system from targeting the beta cells otherwise I'm not sure if this method will be severely successful.


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#9 Logjam

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Posted 28 July 2016 - 08:53 PM

If you got them to replicate enough, you could stop taking the pill entirely.  It would be a complete cure.  There are some recent studies that allude to "master control" beta cells that might exist, but let's ignore that for now: http://www.eurekaler...rst071816.php. It's nor proven.  Maybe you'd stick on the Metformin just in case because it can't hurt.

 

@Corb Why is it more interesting than just more producing the same amount of insulin per cell?  Many instances of T2DM also are a result of a reduced beta cell count.  They die over time or under stress or poisoned by AGES, methylglyoxal, etc.  Having more cells, even with insulin resistance, would yield some higher C-peptides, but better metabolic health nonetheless.

 

More beta cells will yield more insulin regardless, no?  Interestingly, quiescent/senescent cells also produce more insulin according to some studies: http://www.nature.co...ll/nm.4054.html

 

There are 2 reasons it will be applicable to T1DM.  In the cases where T1DM treatments are encapsulated into implants, these growth factors will accelerate the growth for mass production.  An author considers that here in a survey of the various recent studies: http://diabetes.diab...6/1496.full.pdf

 

These pharmacological agents could be used either to treat human islets before transplantation or to

supplement protocols that transform stem cells into trans-plantable human islets. Alternatively, they could be used as oral medication to enhance b-cell proliferation once safety concerns are fully addressed.

 

I'm also not sure we REALLY know whether a t1DM case is going to happen again immediately.  We know beta cells don't grow very well for anyone, so how do we know how fast they really died?  Maybe the cells will last for 5 years before a strong autoimmune relapse.  The problem is that beta cells just don't grow after 5-10 years because they begin to express things like p57, p16, etc.  Suppress them and they replicate again, apparently.

 

I wonder if they'd grow in a 10 year old mouse if we could have one.  The same studies that work on mice growing beta cells back would also work on humans of mice age.  Maybe it's just the aging program.


Edited by Logjam, 28 July 2016 - 09:16 PM.

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#10 corb

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Posted 28 July 2016 - 09:42 PM

More beta cells will yield more insulin regardless, no?

 

Not necessarily. There is a growing group of people in the 20 to 50 age group which also suffer from Type 2. About 5% (which is a damn big number) in select countries. I doubt they have a beta cell deficiency.
The other problem is insulin resistance. If you look at a graph with people surviving to 80 and above they seem to be the ones without insulin resistance problems. So in the case of age induced type 2 there might be a completely different cause for the disease, or at the very least another cause which is just as important.

 

As a pathway to promote proliferation after implantation it's a good technique that's true.


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#11 Logjam

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Posted 29 July 2016 - 12:14 AM

I'm still not sure it wouldn't help.  Hyperinsulimia probably isn't optimal, but I think most would agree it's better than hyperglycemia.  If you have more beta cells, you'll probably have fewer spikes after a donut or three, or have more capacity for basal release.

 

Probably shouldn't be eating donuts anyway, though.

 

What makes you think it won't help?  Lots of older people compensate for increasing insulin resistance by producing more insulin -- because they happen to be able to.

 

The problem is what if you can't?


Edited by Logjam, 29 July 2016 - 12:15 AM.


#12 corb

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Posted 29 July 2016 - 01:00 AM

Lots of older people compensate for increasing insulin resistance by producing more insulin

 

Yeah, and ironically enough the increased production of insulin ends up with them developing legitimate diabetes. It's not a solution.

I'm not saying it won't do anything good in some cases. I am saying it will not cure diabetes though.


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#13 Logjam

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Posted 29 July 2016 - 01:29 AM

Agreed.  But since there are studies I've found that indicate many older adults do have reduced beta cell populations it seems that multiple solutions are in order.  T1Ds need it anyway, even if the cells are encapsulted to prevent immune attack.

 

Either way, if we do find a way to increase beta cells by a % AND find a way to increase sensitivity, it's likely to be useful for T2s and solve a lot of problems.  Maybe you'd have to stay on metformin or a Thiazolidinedione.  Big deal.


Edited by Logjam, 29 July 2016 - 02:21 AM.


#14 RWhigham

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Posted 05 September 2017 - 11:52 PM

 Efficacy of natural diosgenin on cardiovascular risk, insulin secretion, and beta cells in streptozotocin (STZ)-induced diabetic rats. pubmed abstract. Full text available.

STZ induced diabetic rats had a fasting glucose greater than 250 mg/dL. 10 mg/kg of oral diosgenin reduced this to a normal 90 mg/dL after 30 days!!!!

 

Quotes from the full text

 

levels were significantly (p < 0.05) reversed back to normal in diabetes induced rats after 30 days of treatment with diosgenin.

 

Electron microscopical studies of the pancreas revealed that the number of beta cells and insulin granules were increased in streptozotocin (STZ) induced diabetic rats after 30 days of treatment with diosgenin. In conclusion, the data obtained from the present study strongly indicate that diosgenin has potential effects on cardiovascular risk, insulin secretion and beta cell regeneration in STZ induced diabetic rat.

 

It stimulates the renewal of beta-cells in the pancreas or may permit the recovery of partially destroyed beta-cells

 

 Diosgenin is readily available at 81 mg/capsule from Wild Yam Root capsules containing 810 mg/cap standardized to 10% diosgenin.

The following image shows diosgenin could have replaced insulin injections for glucose control in these rats.
 

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Edited by RWhigham, 05 September 2017 - 11:56 PM.

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#15 MikeDC

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Posted 11 September 2017 - 01:18 PM

5-IT is genome toxic

Diosgenin is bad for thyroid.

https://www.ncbi.nlm...pubmed/28407664



#16 RWhigham

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Posted 12 September 2017 - 07:01 AM

5-IT is genome toxic

Diosgenin is bad for thyroid.

https://www.ncbi.nlm...pubmed/28407664

 

Notice that in study of induced diabetes in rats the dose that regrew pancreas beta-cells was 5 mg/kg or 10 mg/kg per day of diosgenin for 30 days.

 

In the rat study referenced by MikeDC the dose that appeared to cause thyroid damage was 250 mg/kg per day of fenugreek seed extract for 4 weeks.

 

Diosgenin is one of the three most abundant phytochemicals in fenugreek seed extract (FSE). The study did not quantitatively analyse the extract, so we don't know how much diosgenin it contained. Also, they did not single out diosgenin as culprit.

 

The 3 most abundant phytochemicals in FSE are 4-hydroxyisoleucine, trigonelline, and diosgenin.


Edited by RWhigham, 12 September 2017 - 07:05 AM.

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#17 MikeDC

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Posted 12 September 2017 - 12:47 PM

Agree. Just want people to be more cautious with plant based supplements. Almost all have some kind of toxicity. A long term clinical trial is needed.
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#18 MikeDC

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Posted 13 September 2017 - 12:25 PM

https://www.ncbi.nlm...pubmed/28255111

 

This paper shows Diosgenin increases sirt1 expression which was the reason for improving osteoarthritis. Could be the mechanism of action on diabetes is the same

through sir1 activation? Would NAD+ precursors be better since they increases sirt1 expression more effectively.

 


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#19 aribadabar

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Posted 13 November 2017 - 12:37 AM

 Diosgenin is readily available at 81 mg/capsule from Wild Yam Root capsules containing 810 mg/cap standardized to 10% diosgenin.

81mg per SERVING which is 2 caps ;)







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