Hyperglycemia caused by rapamycin

#21

You might interested to see the pioglitazone thread where I posted a study showing the combination of telmisartan and pioglitazone resulted in no weight gain from pio and no impingement on the insulin sensitizing of pio from telmi. There are more studies there that I posted, which seem to indicate that telmisartan and pioglitazone are a good combination. Of course, if you have no need/use for BP lowering, then it’s irrelevant. However, I have an ever so slight tendency to BP excursions into the 130/80 territory, and I think a judicious addition of telmi might be indicated for me - this would avoid the need to use a GLP1-RA.

And yes, my issue seems to be excessive liver gluconeogenesis, which results in elevated dawn effect, as well as elevated BG readings right after exercise. There are no real excursions in response to meals. This issue has been bedeviling me for over 10 years now, where I hover in the pre-diabetic 5.7-5.9 range no matter what I do. So far, I have not noticed any effect from rapamycin, oddly enough.

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#22

sir any update on magenta line?? & which combo worked best??

#23

Fascinating thread, and thanks for sharing so many test results, all nicely laid out and explained. Better than some published case reports, haha.

That said, I do have a couple thoughts:

  1. What do the numbers look like with no medication? You’re on 4 different “glucose-lowering” medications, but it’s not clear how much any of them are contributing. As others have said, SGLT2i and a low carb diet is going to make you have to ramp up gluconeogenesis - your liver is working hard to keep you conscious and alive, haha.

  2. The OGTT results are good, so it doesn’t look like insulin resistance. and seemingly your body just likes to make more glucose - so why do you think that’s a problem? I think for most people the issue is that their body weight creeps up, they become insulin resistant, and they can’t clear the glucose. None of those seem to apply to you, right? How’s your fasting insulin level?

Same question to you, if you don’t mind. I am very curious why you consider it to be an issue that needs to be dealt with? I’m not a pro in this area (since I’ve been fortunate enough to always have A1C of 4.8-5.0% no matter what I do, sorry!), but my understanding is that this is mostly an issue when you can’t control post-prandial glucose, or when you have no ‘sinks’ like muscle mass to soak up glucose. In your case, and your liver is outputting more glucose, is that actually a bad thing?

#24

My latest numbers from 08/08/25, are: FBG 98 mg/dL; A1c 5.7; fasting insulin 8.2 uUI/mL (lab range 2.6 - 24.9). Note: this is after 3 months of empagliflozin 25mg/day escalated from 6 months of 12.5mg/day, and my best numbers in years.

Why is this bad? Well, A1c of 5.7 is prediabetic. Having consistent high blood sugar is very destructive to your tissues, particularly microvasculature. Having a fasting BG of almost 100 while fasting insulin is at 8.2, means I’m insulin resistant. All this is associated with higher ACM and shorter lifespan. That’s what the stats say.

Instead, best longevity numbers are FBG no higher than about 82 mg/dL, A1c below 5%, fasting insulin no higher than 6-7 uUI/mL.

I am clearly out of range, in fact officially prediabetic (above 5.6), which requires treatment if unable to correct with diet and lifestyle (exercise, weight management, visceral fat, fat/muscle ratio).

If your BP is above 120/80, the newest recommendation is to get below those values.

Same here. My A1c and insulin sensitivity are out of whack, and need treatment.

When I initiated empagliflozin at 12.5mg/day, initially my numbers also improved, but eventually drifted back up to FBG 108 mg/dL, A1c 5.8 and fasting insulin 8.6 (after 6 months of 12.5mg/day of empagliflozin).

My next tests are coming up in late October, and I’m expecting my numbers to have drifted up again (after several months of 25mg/day of empagliflozin) - my liver seems to adjust with greater neoglucogenesis to bring my numbers back into a shittier range.

Come Februrary 2026, I will add pioglitazone 7.5mg/day. I have to wait, because I had dental implants installed, and pioglitazone suppresses osteoblasts and the osteoclasts in that scenario lead to decrease in bone density and growth, which is obviously undesirable when you need the implant titanium to osseointegrate with your jaw bone tissue.

Once that is settled, I can chance low dose pioglitazone. I’m planning on offsetting some of the undesirable side effects of pioglitazone with telmisartan (currently on 20mg/day, aiming for 80/160mg/day).

If after a few months my glucose and insulin numbers continue to be hot garbage, I will pull out more guns from the armamentarium. This is just one battle in a long war. The fight continues.

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#25

I also get elevated FPG with Rapa. It takes 4-6 weeks
To resolve after a single dose of Rapa which is interesting because drug levels at 48hrs are undetectable. Not sure how to explain the prolonged effect similar to your curve still elevated 2 weeks post Rapa.

#26

I’m 74, using 5 mg Rapamycin on Mondays with a break every 6 weeks.
My Levine phenotypic age is 69, and I feel great.
I exercise, sleep 8 hours/night, and have good social contacts.
I’m Pre diabetic with HbA1C averaging 5.6 over the last 5 years.
Metformin 500mg tid x 5 years
My HbA1c now seems the same as it was before I started Rapamycin - 2 years ago.
Other medications include Rosuvastatin, Ezetimibe, Doxycycline, Finasteride, Melatonin
I eat a mostly vegan (some fish), relatively low carb diet.
I take a lot of supplements, including Vita D, multi B, and more than a gram per day of Vitamin C.
My point… doing all we can to lower glucose, keep in mind that Vitamin C supplementation lowers AGE (Advanced Glycation End product) levels with likely long term benefit.

Vitamin C supplementation lowers advanced glycation end products (AGEs) and malondialdehyde (MDA) in patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled clinical trial - PMC

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#27

Thanks for the reply. It’s interesting, because you’re sort of treating glucose/HBA1C a bit like ApoB, trying to reduce the area under the curve. That’s not something I had really conceptualised (since obviously low glucose is extremely dangerous), and the intake/production is more direct than ApoB. (i.e. exercise releases glucose).

But yes, I do agree with you that the higher A1C coupled with higher fasting insulin is bad and you should act on it. Thanks for the explanation.

Again, I have been lucky in that my glucose disposal has never been an issue (yet), but one thing I noticed has made a difference in my family members is gaining muscle. My brother in law went from being pre diabetic to HBA1C of ~5.1% from lifting weights 3x per week. He packed on a ton of muscle, particularly in the legs, ass and back (squats, deadlifts, pull-ups etc) and it’s made a huge difference to his glucose handling.

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#28

Right. If you can get your metabolic health fixed with diet, exercise and lifestyle, that’s the first thing to try. But just as with lipids, there are genetic factors outside your full control. (Pre)diabetes is a very complex disorder. There are polymorphisms along the glucose handling pathways which can result in defects at any juncture. There can be insulin sensitivity issues in the liver, muscles, adipose tissue, brain. Some you can fix through careful diet (excess adipose - energy intake), or exercise (muscle and body composition), but some you really can’t. I exercise and have decent muscle mass with a BMI of 21 and lowish fat mass, but exercise acutely raises my serum glucose levels and my problem is persistent high neoglucogenesis by my liver, which I am unable to control through diet and exercise. As an example, I did an experiment, where I went on an eight day water only fast while continuing to exercise - and my blood glucose kept being high throughout. My liver is a glucose factory.

Just as with lipids, it is good to emphasize and recommend diet, exercise and lifestyle as the first levers to access. But always be aware that there are those who will need pharmaceutical intervention.

That is the case for me with both lipids and glucose. No amount and kind of lifestyle interventions are able to get me to my biomarker goals without the assistance of pharmaceuticals.

This may seem a very bleak situation, and in some ways it is. But I keep in mind one thing. Brian Kennedy had a rather interesting observation, which he shared in some interviews. He and his team did some data mining on the NHANES database. He took the people who had their metabolic and lipid numbers within healthy range, and sorted them into two groups. One group were those who had their numbers within the healthy range without any pharmaceuticals, i.e. naturally, and the second group were those who got their numbers to the healthy range with the help of pharmaceuticals (lipid lowering, glucose lowering, BP lowering etc.). The second group, the pharmaceuticals group lived longer and had younger phenotypes.

We are biochemical machines. Drugs are molecules which modify how our body chemistry works. It is not surprising, that careful targeting can compensate for defects and even result in superior outcomes. This is the premise of this site. Our longevity approach is to get lifespan and healthspan benefits by any means necessary, starting with optimizing lifestyle factors. Drugs are the next step in that intervention - a lot of it has good data behind it (lipid lowering), and a lot is speculative (rapamycin).

I am a big believer in a carefully tailored pharmaceutical approach. Some people eschew drugs on principle, which I think is silly (just my personal opinion), as it is the result that counts, however you get there. And I don’t think you can get to your stretch goals without drugs. Of course there will one day be better tools (genetic engineering), but for now, realistically, drugs are what is within reach. And so, I’m reaching - how far and how successfully, we’ll have to see. The fight continues.

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