Rapamycin induced insulin resistance and drop in testosterone

A physician colleague of mine reported his recent lab test results after taking Sirolimus for 9 months, at a dosage of 12 mg every two weeks (0.2 mg/kg). Of note, there were no other changes to his medications, diet, supplements, or exercise regimen during this time period.

His labs demonstrated a significant increase in insulin resistance (HOMA-IR doubled from 0.9 to 1.9 ; fasting insulin doubled from 4 to 8). Notably his fasting glucose only went from 90 to 92, and HbA1C went from 5.2 to 5.3, showing that these two blood glucose metrics are not sensitive enough to detect early signs of insulin resistance. He also experienced a 50% reduction in his free testosterone level, dropping from 14 ng/dl to 7 ng/dl. I recall a previous forum post in which someone reported a similar significant decline in their testosterone level while on rapamycin.

I suspect that mTORC2 inhibition due to chronic rapamycin treatment may be the culprit here. Similar results were seen in a paper from the Lamming Lab (attached). Perhaps this is why Matt Kaeberlein has previously stated that he takes rapamycin for 10 weeks, and then cycles off for a couple of months. If others on this forum have been following their HOMA-IR, insulin, and testosterone levels while on rapamycin, please share your results, rapa dosing regimen, etc. Thank you.

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system - Lamming Lab.pdf (574.9 KB)

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Metformin increases insulin sensitivity. I think this gives more importance to pairing Rapa and Metformin.

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I’ve seen data showing both positive and negative effects of Rapamycin on testosterone. We just need more data.

FWIW I’ve seen a significant decrease in body fat on Rapamycin and the research suggests testosterone and insulin sensitivity increase as body fat decreases.

In a subgroup of 57 men aged 70-80 years, testosterone levels correlated negatively with percentage body fat

@DeStrider your solution always seems to be another drug or supplement? You know what else increases insulin sensitivity?.. Exercise.

I contend that metformin enhances rapamycin’s effects in much the same way as GFJ, that is by inhibiting CYP3A4.

We show, therefore, a suppressive effect of metformin on PXR and other ligand-activated nuclear receptors in transactivation of the main detoxification enzyme CYP3A4 in human hepatocytes.

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@Maveric78 There are many solutions to each problem. Exercise is excellent. Some people can’t exercise due to different factors. If exercise is the solution to everything, why take Rapa? Exercise should handle it. Just seems like the pot calling the kettle black here…

Went out for a great 3 hour hike in the mountains with my family today but not sure if my insulin sensitivity is any better.

As an aside, I finally solved Einstein’s riddle. It took me 10 minutes. I think my cognitive abilities have improved as the last time I tried it many years ago, I gave up. It just seemed so simple today.

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Exercise is the foundation of any longevity protocol. Imo until your VO2 max is in the top 25% for your age you shouldn’t even think about supplements.

Yes, even a 30 minute walk improves insulin sensitivity. A week using a CGM will confirm that.

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I can understand and respect that opinion. I wish I could be as built as you probably are. For now I have to make do with a lower level of exercise plus supplements. Honestly, I should make the time to go to the gym and build up muscle mass but for me, throwing money at supplements that should positively affect my health seems like an easy first step to take.

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Very interesting anecdotal report and study. It raises several questions:

Is the insulin resistance issue constant over all users or does it vary according to the individual?
My insulin levels have been all over the place on rapamycin.

What is the definition of chronic therapy on rapamycin? Months? Years? Decades?

Would everolimus be a better choice?

Visceral fat is associated with insulin resistance. Are rapamycin users noticing an increase in waist size? Decrease?

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I always thought that it’s how transplant patients take it: every day, no breaks, and forever (as long as transplanted organ lasts). Is there a different understanding?

Good find.

“We observed no effect of intermittent rapamycin on glucose tolerance, while
daily rapamycin treatment caused a robust decrease in glucose tolerance”

I have been pulse dosing for many months with a ~2-month break after 10 months of fairly high pulse dosing. I am now on my second round. My lab tests show no measurable effects on my blood glucose.

Most of the people on this forum are pulse dosing

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What’s interesting here is that he showed a significant increase in fasting insulin, when rapamycin supposedly inhibits insulin secretion. I would have expected to see decreased insulin, increased blood glucose and increased HbA1c along with the increased HOMA-IR (a kind of pseudo insulin resistance that would have in fact been due to impaired insulin secretion) when in fact what he’s showing is true IR. Any idea if he gained any visceral/abdominal weight over that period of time?

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No and no. Yes, my waist size has decreased since starting rapamycin. IMO it absolutely helps get rid of the hard-to-lose white fat.

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It is very concerning.

Yes very concerning indeed. Just another reason why Metformin and exercise are helpful. Obviously the latter is more helpful than the former but both are beneficial. If the cost of rapamycin is prohibitive, then it makes sense to use grapefruit juice. Otherwise I can see no reason to use grapefruit juice and many reasons not to do so.

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Is there any info if Rapa may negatively affect pancreas? I developed 3 pancreatic cysts per recent US. They are very small but if Rapa is a culprit they may grow. Trying to be proactive.

Davin8r, here’s some additional info: He is a fit individual who exercises daily (10-11% body fat, with a lean/muscular body habitus, and he experienced no visceral/abdominal weight gain while on rapamycin. No weight loss either, but he was already very fit prior to starting.) Prior to starting rapamycin, he was taking a small dose of metformin nightly (500 mg), well as acarbose and canagliflozin for their potential longevity benefits (no changes were made to their dosages after starting rapamycin). Prior to rapa, he always had stable fasting insulin levels of 4 mU/L, and HOMA-IR values of 0.9. No history of prediabetes or insulin resistance prior to starting rapamycin.

I found this article which reinforces my suspicion that mTORC2 suppression (due to chronic mTORC1 suppression by rapamycin) may be the cause of his new insulin resistance:

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“β cell-selective mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion

That’s what I was saying, though – mTORC2 inactivation impairs insulin secretion, so it’s puzzling that his insulin was elevated. I would have thought that impairment of insulin secretion by rapa should mimic a mild form of Type 1 diabetes (high glucose, insufficient insulin and no insulin resistance), but in your friend’s case it sounds like actual insulin resistance (with compensatory hyperinsulinemia i.e. pre-Type 2 diabetes).

Perhaps mTORC2 directly induces insulin resistance in fat/muscle to the extent that it overcame the impaired insulin secretion and the end result was still hyperinsulinemia?

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My colleague has stopped his biweekly Sirolimus dosing regimen and he will recheck his fasting insulin, HOMA-IR, and testosterone levels following a 60 day washout period. I’ll update the forum with his results when I receive them.

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Thanks for posting, Brandy.
This is very concerning to read indeed. How many of us may unknowingly experience the same issue? (Personally I’m only able to get my fasting glucose and Hba1c tested; I can’t get a HOMA-IR test).
A bit off-topic, sorry, but the potential effects of Rapa on Testosterone levels have been discussed before. Albeit feedback has been quite conflicting with that regard. I’m wondering if we have any idea about the effects Rapa may have on estrogen/progresterone.

DeStrider “I can understand and respect that opinion. I wish I could be as built as you probably are. For now I have to make do with a lower level of exercise plus supplements. Honestly, I should make the time to go to the gym and build up muscle mass but for me, throwing money at supplements that should positively affect my health seems like an easy first step to take.”
Off-topic again, but I ride a desk bike for 4-5 hours per day (besides my cardio sessions). Clearly it is not the same as active cardio training, but I feel it is better than nothing and basically I’m in movement a good part of the day.

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Does the dose of Metformin should be increased from a regular dose to counteract side effects of Rapamycin? How frequently one encounters these side effects: elevation of glucose, A1C, Insulin level and lipids?

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I should definitely get a desk bike for the office. We had one at home, but the boys kept breaking it. Not sure where it is now. Thanks for reminding me, and I’ll go dig it out!

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