#21

Curious, do you feel that I or others on this thread are saying it is not rapa or that glucose insensitivity is not an issue in some of even many people when taking rapa? One of my first posts was about how it can be good to combine rapa with a glucose regulating med

I’m just saying that based on one day of data at 2mg we basically have very little signal to notice and for the OG poster to understand whether this impact exists and how big it is for him he needs more data

Question is, is it harmful, neutral, or beneficial?

Three parts of my thinking:

  1. I think the insulin (and related growth pathways like IGF-1) going down is beneficial

  2. And the effect of higher average glucose and glucose spikes is harmful and hence is good to address with complementary strategies

  3. Not doing anything about the glucose, may or may not make rapamycin net negative for a person given that mTORC1 down has several positives -so less clear, but given second part of (2) above, I don’t think we need to choose to let our glucose and sensitivity stay bad

Insulin and c-peptide remain low despite the elevated glucose.

At least a big part of the causation might go in the other direction. Glucose is higher because insulin is lower.

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#22

My apologies. That was probably too direct of a statement. I was going to bed and replying from my phone so was in a hurry to comment on the post.

In general, I think the metabolic downsides of rapa are understated/under appreciated. Especially in light of the fact that we know elevated glucose and cholesterol is harmful yet don’t have definitive evidence that Rapa is beneficial in otherwise healthy humans. Like everyone here, I’m still hopeful it works and the non-human data carries over.

The idea of benevolent/pseudo diabetes is intriguing, but (at least in me) my body’s response to a 5 day fast is much different than its response to Rapa so I don’t predict that Rapa is completely consistent with starvation diabetes. My biggest concern is longterm damage to the pancreas. If Rapa merely decreases insulin secretion thereby preserving long term function of the pancreas then that would be beneficial. Similar to an ACEI/ARB in CKD. Initial drop in GFR, but overall better longterm preservation of GFR. If it’s causing islet cell necrosis like you see in animal models the potential for DM1 in the future is concerning. I was hoping my personal labs would show elevated insulin/c-peptide signifying elevated glucose from insulin resistance (starvation induced) or increased hepatic gluconeogenesis (seen in animal models and also starvation induced), but unfortunately it showed insulin suppression. With serum labs alone you can’t differentiate depressed function from actual pancreatic injury. Maybe lipase/amylase could be checked but if the damage is specific to islet cells, I wouldn’t expect to see these elevated (acinar origin).

I’ve tried 4mg and 6mg doses. The effect is very consistent and lasts ~30 days from a single dose. Due to the pancreatic concern, I’m hoping I can find a micro-dose that may provide benefit without significant increase in glucose. Probably will trial 1 or 2mg next but wanted to take a break for a month or so.

Also interesting in that I’m not pre-DM2 or insulin resistant at baseline. My baseline A1c is 4.9-5.1. 175lbs, ~8% body fat, exercise every day. Despite these favorable factors Rapa trumps them all.

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#23

Thanks for expanding your thoughts. We are much closer in view here than it seemed.

Can you talk more to this and if possible point me to any literature would love to look into that more.

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#24

Btw, I could also be that it is mTOR down => IGF-1 (and GH) down => insulin down https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374394/#:~:text=IGF-I%20is%20an%20important,concentrations%20suppression%20of%20insulin%20secretion.

I’m not versed in the biology here enough to know how strong that effect is/can be from
above and/or from that the liver (where much of the IGF-1 machinery is) is also part of storing insulin, clearing insulin (and even co-producing insulin)

#25

@RapAdmin this seems like a very important subtopic to understand, I don’t believe I’ve seen it discussed on the forum - do you know if it has anywhere?

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#26

There’s a few papers that discuss it. Here’s one from 2022 where they tried to preserve pancreatic islets by pairing rapamycin with metformin with some success, but it still degraded them compared to the control group not on rapa.

In our study, RAPA-treatment in NcZ10 males led to further pancreatic islet degranulation, (Figure 4f), and reduced islet number (Table S3), resulting in reduction of total PIC (Figure 4g), compared with untreated NcZ10 males. RAPA/MET-treatment eventually protected the islet β-cells from RAPA-driven hyperglycemic hyperstimulation and tempered the islet degranulation that resulted from RAPA-treatment, but it did not comparably preserve total islet number and PIC, which may have been affected by the earlier elevation of circulating glucose during the first three months of treatment.

Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13666

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#27

Perhaps you should take metformin with your rapamycin because of the synergy between rapa and metformin in extending lifespan and the glucose-lowering effect of metformin.

I was taking metformin long before I started taking rapamycin.
At present, I am taking rapamycin 5mg/weekly with GFJ along with 500 mg of metformin. Of course, this means I am also probably getting a big boost in my metformin levels.

I don’t bother taking my glucose levels the day I take rapamycin because if nothing else, the GFJ is going to cause a spike. I wonder if taking acarbose at the same time as the GFJ would also be beneficial.
At this dosage, my next-day fasting glucose levels are always less than 100.

I am not convinced that an occasional glucose spike causes any harm.
If a glucose spike caused any significant harm I would be dead because for years when I was young, my favorite between-meal snack was a bottle of Coke and a Payday candy bar. Not to mention, when I was in the Navy I got hooked on Almond Joy candy bars and had one as a snack daily for quite a long time. I am not pre-diabetic and my A1C levels are good and below normal for my age.

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#28

Very helpful, thanks.

#29

How islet cells necrosis would manifest itself? Would it contribute to pancreatic cysts? I did develop a few pancreatic cysts, very small. I suspect Rapa bc I’m on it for 14 years. I take 0.5mg for 4-5 days and break for 5 days. This is the smallest dose I have ever had.

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#30

That is interesting, but its in a group that is already diabetic. What we really need to look at are non-diabetic populations I would think.

I found this interesting:

Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized.

from:

Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

https://www.nature.com/articles/ncomms5639

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#31

Sure, but the untreated diabetic group still had healthier islets than the diabetic group treated with rapamycin.

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#32

Here are some pathways that lead to islet cell necrosis.

Via https://www.researchgate.net/figure/Mechanisms-of-islet-cell-death-Flow-chart-depicts-apoptotic-and-necrotic-beta-cell-death_fig2_6336327

image
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Caption: Mechanisms of islet cell death. Flow chart depicts apoptotic and necrotic beta cell death cascades along with possible modes of intervention. Causes/agents of beta cell death are indicated in red while agents/strategies for prevention of beta cell damage are indicated in blue. Red arrows stand for possible sites of intervention.

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#33

Evidence of Rapamycin Toxicity in Pancreatic B-Cells and a Review of the Underlying Molecular Mechanisms. Barlow, et al. 2013.

Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion. Asahara, et al. 2022.

The top paper is what peaked my interest in this topic. Also the fact that Rapamycin induced DM is only partially reversible by discontinuation (lab animals) leads me to believe this is something more than physiologic insulin resistance that occurs in a starvation scenario. The latter is completely resolved, not partially, by restoring energy balance in the subject.

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#34

What are people’s thoughts?

Yes, given how important glucose regulation and overall metabolic health is for longevity it seems crucial to gain as much understanding here as we can.

Do the potential permanent changes to pancreatic function due to rapa occur from current “longevity dosing” or only from “transplant level dosing”?

Both papers are linked below and with abstract. It does seems like the first one and more recent ones of that nature are key to understand.

@Krister_Kauppi can you ask your various rapa experts about this and you interview them?

2013 Review

Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms

Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.

2022

Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion

Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes.

At the same time, however, it remains controversial whether mTOR provides a benefit or a risk to pancreatic β-cells [29]. Therefore, in this review, we introduce reports on the role of mTOR in pancreatic β-cells and focus on the positive and negative effects of mTOR on them.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138643/

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Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets
#35

For today’s update, my fasting glucose overnight and before my first meal went from 80-95 pre-rapamycin to 95-110 post-rapamycin @ 2mg taken 24 hours ago.

It no longer goes down to the mid 90s 6-7 hours after a meal but stays at 100-110.

Edit- I’ve noticed my gums are a very healthy pink. I noticed this morning when I brushed my teeth and again tonight. I don’t have gingivitis or any dental issues but my gums were a bit darker pink than it is now. Could be nothing but I’m aware of the oral health study happening at UW, and it’d make sense that rapa would lower gum inflammation.

#36

For what it might be worth, this is my 8th day on rapamycin 1mg per week, so my second dose today. Started with a CGM in Jan, then daily X 4 months. I was surprised with excursions of my BS to 200 mg/dl range after a “normal meal” despite an A1c of ~5.7. So changed my diet abruptly to no added sugars and lots of fats/protein (so bacon & eggs, half-n-half, heavy cream, lots of nuts, lots of meat at dinner). I fast ~16 hrs/day but for many years.

Re: exercise, some might call my exercise regimen as “heavy exercise” but it’s been my daily regimen for years- 9000 steps on the backside of the local dam with 4500 up, 4500 down steps with no flat spots, no rest, then 50 pushups. I’m 72 yrs old, 6’2" 180 lbs.

Upon awakening, BS immediately rises about 10 points (probably in anticipation of my morning stairs) from maybe 97 to 107, and then during “my stairs”, it might drop to high 80’s, but then immediately pops up about 10 pts on completion of my stairs. I’ve not been on a CGM since started rapamycin but will break one out and monitor. I have been using a glucometer about 5x daily though and surprised that rapamycin has not appeared to raise my BS’s (but a CGM will more accurate).

Will update later with CGM data now that I am on rapamycin.

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#37

Freestyle Libre sensors are known to be inaccurate and you can’t calibrate them like you can with Dexcom sensors.

#38

Dr. Green’s Rapamycintherapy.com practice has consistently recommended Rapamycin combined with metformin…for me its been 500mg Metformin ER twice daily. I think Nir Barzili’s research and all testing combining R with acarabose/metformin spike longeivty results from 28% to 34%.
Age 70, male, on R and Metformin since 9/2017.
Best of luck to you!

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#39

Very interesting! I think this can be a question I dive into together with David Sabatini and Dudley Lamming. I think these two may give the best answer to the question. Let me know if you have any other people in mind because I think it may be to deep for other guests.

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#40

Update 24hrs after my rapamycin 1mg dose yesterday. I broke out a Dexcom G7 CGM and applied it. When I wore a CGM x 4 months, I captured the data and put it into SQL Server (a powerful database system) so that I could do queries (such as what is my average glucose from 1:00 pm to 4:00 pm; stuff like that). My G7 read 108 & my glucometer read 107, so it’s well calibrated. My BS, after 24 hrs seems to be running 8 mg/dl higher with rapamycin but I will need to monitor for longer.

I am on 1000mg metformin each evening and have been since I learned of my BS excursions.

My CGM showed this saw-tooth pattern last evening after eating with my blood sugar spiking up and then down, then up, then down, X 4 of these up/down patterns over 3 hrs. That is a new pattern. I will monitor.

Last Tues and then today (the day after 1mg dose) I had a very strong defecation reflex while exercising, so urgent that I had to return home early last week and then this morning, I had to resort to the porta-potty nearby. (Not to be too graphic, but I can see why homeless prefer the sidewalk over a porta-potty). I will monitor this possible side effect too (Do I have a choice?).

I am still getting daily runs of PVC’s, usually trigeminy, but tolerable and waxing and waning over maybe 30 min.

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