I have H1AC at 5.7% sitting in the lower-range of pre-diabetics and taking rapa alone would likely increase it by killing more pancreatitics beta-cells, but luckily there’s research showing that taking together with GLP-1 inhibitors (Liraglutide/Semaglutide) would protect beta-cells.
I wrote some consideration about it here Glucose and Rapamycin for Anti-Aging – Hacking Biology .
In my stack there’s Rapa - Metformin - Acarbose - Liraglutide - Ertuglifozin and my open question is about the interaction between Liraglutide (GLP-1 inhibitor) and Acarbose (GLP-1 enhancer) .
How would you see the interaction between those two drugs, and how would you mix (or don’t mix) together?
Liraglutide has an half-life of 12-15hours, while Acarbose of 2hours, Rapa roughly 5 days, maybe it’s possible to alternate the uses of Acarbose and Liraglutide in a way that does not overlap and stop Liraglutide in the >5 days before new doses?
Please let me share your tought
Fabio
4 Likes
Hi @Hackingbiology.com , sorry I am unfamiliar with Liraglutide. I will read your article, but briefly: what is it/ does it do; and, why do you take it for longevity? Thank you 
This is new info. What is the source of this conclusion?
1 Like
Since most of us here do our best to avoid the dosing of Rapamycin required for immune suppression, there may still be an issue with Rap and pancreatic health…
I don’t see the dose used for islet transplantation in this article but further down they reference studies on various cancers with a daily dose of 10mg. Compare that with typical longevity dosing. But that does not appear to be the whole story.
Furthermore, in a large-scale randomized control trial of immunosuppressive regimens in renal transplantation, sirolimus was associated with the highest incidence of hyperglycemia (5 vs. 4.7% low-dose tacrolimus vs. 4.4% high-dose cyclosporine vs. 2.9% low-dose cyclosporine), although the incidence of NODAT was higher in the tacrolimus group (16). However, as patients in these studies also received other immunosuppressants, including corticosteroids, it is not possible to determine the exact influence of rapamycin on the development of NODAT. However, as part of their U.S. Renal Data System study, Johnston et al. (10) analyzed the risk of NODAT in renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil (MMF) or azathioprine versus those receiving tacrolimus and sirolimus. This demonstrated a hazard ratio of 1.25 (95% CI 1.03–1.52), suggesting an increased risk for NODAT from sirolimus independent of any effect of tacrolimus.
1 Like
There’s a pretty good outcome that of GLP-1 inhibitor (such as Semaglutide famous for ozemic drug, but i prefer pills in form of Liraglutide/Rybelsus drug) provide several aging hallmark intervention benefits.
Furthermore GLP-1 inhibition sounds to be the only way (up to know, from what i read) to reduce pancreatitic beta-cells killing by rapamycin increasing diabetics risks.
Fabio
1 Like
I tried to summarize this in the blog post Glucose and Rapamycin for Anti-Aging – Hacking Biology from “Tacrolimus- and sirolimus-induced human β cell dysfunction is reversible and preventable” that bring GLP-1 inhibitors as a way to save reduce the rapamycin impact on pancreatitics beta-cells.
I think that’s a serious topic to be tackled down, especially for who’s in pre-diabetics or diabetics conditions.
Fabio
6 Likes
Thank you! I have read and liked your post (had to create a WordPress profile).
This is very interesting as (even though I was never pre-diabetic or diabetic) I take metformin, canagliflozin and arcabose for longevity (with weekly dosing rapamycin).
I am starting mounjaro next week for the anti-inflammatory effects (and to target visceral fat, which I want to reduce even more).
1 Like
cl-user
#8
I think you have it backward They are all GLP-1 agonists not inhibitors:
List of GLP-1 agonists
GLP-1 agonist medications currently available on the U.S. market include:
There’s also a similar class of medications called dual GLP-1/GIP receptor agonists. There’s currently one of these medications on the market. It’s called tirzepatide (Mounjaro®).
4 Likes
@Hackingbiology.com Thanks. Side effects are the boogeyman for me. I’m now only taking Rapa 1x/2 weeks with a week off every 5th week. Rapa is a serious drug. I may drop to less frequently at some point. And/or have longer holidays. I’ll keep my eye on this topic.
The referenced paper was about daily dosing for immune suppression and cancer treatment. I am actively trying to NOT have that effect on an ongoing basis. Hit and run is all I want.
1 Like
Very interesting: not sure what to make of this. But here’s my experience, FWIW and a couple of suggestions:
I was concerned about prediabetic levels of FBG going back more than ten years, and a recent Ha1C of 5.9. Particularly concerned that fasting insulin and C-Peptide were very low. Wondered if I had some form of T1DM but got tested and am negative for antibodies so it’s not T1DM. Endocrinologist said he would test for “monogenic diabetes” if OGTT came back high. But it came back slightly elevated. However, that propelled me to read about monogenic diabetes and I discovered a syndrome called Glucokinase MODY-- which I won’t go into here as I have written about it in another thread if you’re interested. Anyway, this seemed to be consistent with everything I knew about myself.
But along the way, when I was wondering about T1DM I came across the work of Andrew Stewart at Mt. Sinai whose lab found that Harmine could increase beta cell replication – but it also increased alpha cell replication. But if given with a GLP agonist, the impact on beta cells was magnified significantly. I took a very tiny does of Rybelsus plus Harmine for about 6 weeks. I lost weight and felt sick the whole time. It did not seem to have any impact on FBG (nor has metformin, but that is consistent with GLK MODY).
Also the work of Paresh Dandona at Buffalo has shown that ten T1DM patients who took a GLP1 agonist were able to reduce their need for insulin or get off it altogether.
So, long story short, GLP agoinists do appear to increase pancreatic beta cells. You may want to read more about Andrew Stewart’s work and also read about GLK MODY.
This is a problem. Many here have had rising blood sugar with rapa use. It is hard not to link this rise to the toxic effect of rapa on pancreas beta cells. That is bad. Here is something to keep in mind - we cannot blindly rely on the fact that mice in the ITP did well on rapa, because as the papers state, mouse pancreas beta cells are apparrently not nearly as susceptible to rapa toxicity as human cells are, and the clearance rates are dramatically faster.
Which is a reminder that we have to be very cautious with translating intervention effects from animal models to human. As I wrote in another post, the dosages of rapa used in mice when translated to human doses using the accepted translational formulas, came out as extremely and unsustainably high for humans. Clearly rapa in mice is not rapa in humans.
Now, high daily dosage in cancer or transplant use is not how many use rapa for longevity. But look at those papers again. Even very short exposures of beta cells to rapa are quite deleterious. Caution strongly advised.
What to do? Using metformin, SGLT2i, acarbose, or other glucose production inhibition or disposal drugs merely tries to deal with the downstream effects of pancreatic damage. What we need is something that addresses the damage directly. Based on these papers, it appears that the OP is right, GLP-1RA are candidates for at least partial protection of the pancreas from rapa toxicity in humans. In any case this is something to take seriously. I wonder how folks like Matt Kaeberlein evaluate this issue - longer pulsing, and longer rapa holidays?
5 Likes
Update after 4 months on 1000mg metformin (half morning, half evening), 200mg acarbose (half morning, half evening), already had my ha1c dropped from 5.7% to 4.9%, looking forward adding SGLTi + GLP-1a (all low doses) to reach some 4.2/4.3% range, then introduce rapamycin to check it out how it does fluctuate.
2 Likes
I have 2 T1DM clients using Tz and they have both reduced their insulin requirement significantly. Something is going on with this.
1 Like
