Rapamycin induced insulin resistance and drop in testosterone

I have to take another look but it seems like the polling data from this site indicated that the effects on glucose were fairly uncommon, at least in this population of rapamycin users.

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Thank you, Rivasp. What about Matt Kaeberlein’s survey study, sorry if this has been discussed, but did they also look at potential effects of Rapamycin on glucose levels?

I always get my morning exercise. I wake up late each morning and then run like hell to catch my train to work.

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Ha-ha it’s a great way to wake up!

RapAdmin,
At around the 1 hr 15 min mark on this STEM-Talk podcast episode from last month, Matt Kaeberlein discusses his rapamycin dosing regimen:

HOMA-IR is not directly reported by most labs, however it can be easily calculated if you have fasting insulin and glucose values. Several free calculators online.

Regarding the definition of “chronic rapamycin treatment,” I was surprised to read an article (which I unfortunately did not save, so I can’t upload now) which showed that mTORC1 inhibition begins to inhibit mTORC2 activity within a day. Granted, the study wasn’t done in humans, but mechanistically this was surprising to me as I had previously thought that it would take many days or weeks of mTORC1 suppression to eventually affect mTORC2.

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Rivasp12,
If Dr. Green isn’t routinely checking fasting insulin levels in his patients and comparing them to their values prior to starting rapamycin, then he could easily be missing many cases of early or new insulin resistance. Case in point: simply checking my colleague’s fasting glucose and HbA1C would not have revealed any indication of the doubling of his fasting insulin and HOMA-IR after just 9 months on rapamycin. My colleague was already lean and muscular prior to starting sirolimus, but I could imagine a scenario whereby visceral fat loss caused by rapamycin may help counterbalance the insulin resistance caused by it.

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Vlasko,
For what it’s worth, he always gets his labs drawn around 9 AM in the morning, and he follows a regular sleep schedule. His total and free testosterone values both dropped by roughly 50% compared to prior to starting rapamycin.

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That is definitely not the case in humans. The data I’ve seen suggests that only with daily dosing of rapamycin for many weeks (I believe over 4 weeks) or longer does mTORC2 start to be inhibited in humans. I don’t have the quote/reference in front of me but will try to post it if I can find it.

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Here are some references:

In contrast to mTORC1, mTORC2 is relatively resistant to the effects of rapamycin both in vitro and in vivo*,* but can be disrupted by prolonged treatment

Source: Inhibition of the Mechanistic Target of Rapamycin (mTOR)–Rapamycin and Beyond - PMC

Rapamycin works through a gain-of-function mechanism in which it binds to the intracellular protein FKBP12 to generate a drug-receptor complex that then binds to and inhibits the kinase activity of mTORC1. Because FKBP12-rapamycin does not bind to mTORC2 (Jacinto et al., 2004,Sarbassov et al., 2004), rapamycin is thought to inhibit only mTORC1.

These results confirm that rapamycin affects mTORC1 and mTORC2 in different ways. mTORC1 is destabilized at all times after drug addition, consistent with the capacity of FKBP12-rapamycin to bind to it and weaken the raptor-mTOR interaction (Kim et al., 2002). On the other hand, prolonged treatment of cells with rapamycin leads to a progressive loss of the rictor-mTOR interaction to an extent that varies with cell type. Prolonged incubation of cell lysates with rapamycin did not disrupt the rictor-mTOR interaction (see Figure S1 in the Supplemental Data available with this article online), suggesting that rapamycin exerts its effects on a process that occurs within cells, such as mTORC2 assembly.

and:

Despite the high specificity of rapamycin for mTORC1 during acute treatment, chronic exposure can also inhibit mTORC2.

Source: Rapalogs and mTOR inhibitors as anti-aging therapeutics

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Thanks RapAdmin, I believe this was the article I had previously read. Note that the authors define “prolonged” exposure to rapamycin as 24 hrs (not days or weeks).

“…we hypothesized that cell lines with rapamycin-sensitive Akt/PKB phosphorylation should have very low amounts of intact mTORC2 complexes after prolonged rapamycin treatment. Indeed, cell lines with rapamycin-sensitive Akt/PKB phosphorylation (PC3, BJAB, Jurkat) had less intact mTORC2 following 1 hr of drug treatment and an almost complete loss of complexes by 24 hr (Figure 3A). In contrast, cell lines with rapamycin-insensitive Akt/PKB phosphorylation (H460, HeLa, LNCaP, 768-0) showed stable levels of intact mTORC2 after 1 hr of drug treatment and only a partial loss by 24 hr (Figure 3A).”

Also, see “Figure 1: Prolonged Treatment of Cells with Rapamycin Inhibits Assembly of mTORC2,” which shows a significant reduction of mTORC2 after just 24 hrs of rapamycin exposure.

Can you give me the link for the document from which you got that information?

It’s the article from your post above:

Yes - but this is an in-vitro experiment, not in-vivo (the cells are being bathed in concentrated rapamycin for hours or days in a Petri dish). This is nothing like an in-vivo experiment where people dose rapamycin orally, and an hour later the blood/sirolimus levels peak, and then the blood distributes the the heavily diluted sirolimus/rapamycin thoughout the body (or at least some tissues and organs to some degree, but we really don’t know where and for how long the exposure is).

HeLa and PC3 cell lines were treated with 100 nM rapamycin for 1, 24, 48, or 72 hr and analyzed as above.

We know from human experience that mTORC2 is not quickly inhibited (i.e. definitely not in days). Lets see if we can find some human studies where they test for mTORC2 inhibition.

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Here’s an excellent summary of insulin resistance and its ramifications.

Most often associated with visceral fat, high triglycerides/ HDL , large waist size.

There’s some suggestion that rapamycin may lead to insulin sensitivity in the brain but resistance in the liver.

To me , it’s counterintuitive to think that rapamycin gives dysregulation of lipids, glucose, and insulin resistance, while at the same time giving mammals an increased health span and lifespan. We’ll have to see how dogs and marmosets do.

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It could be that the main reason the mice lived so long with Rapa is that Rapa is effective against cancer. And 80% of all mice in these studies die of cancer. People on the other hand are affected by lipids, glucose and insulin resistance.

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Blagosklonny has addressed that issue, but can’t rule it out.

You’ll see from the study I posted that IR comes in many flavors from the mild and asymptomatic to the severe.

In prior posts we saw studies showing protection from cardiovascular events in both liver and heart transplants on rapamycin.

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FWIW:
I am a relatively lean 81-year-old who has been taking relatively high doses of rapamycin for ~11 months. I am 6’2", 173 lbs, and fairly muscular. My current BMI is ~2.15

I have no interest in fasting glucose. Let us just say that I have read a great number of papers and watched Youtube videos featuring real MDs. There are just too many variables such as the morning effect, the influence of diets such as Keto or low carb, etc.

IMO the A1c test is the more valuable indicator for anyone on a low-carb diet or anyone taking rapamycin.

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But similar to fasting glucose, A1C will not tell you if you’re insulin resistant, which is where measurement of fasting insulin comes in. In early stages, your pancreas compensates for insulin resistance by cranking out more insulin, which keeps glucose and A1C more or less normal. Looking at fasting insulin (or even better, insulin levels during an oral glucose tolerance test?) gives you much better information since chronic hyperinsulinemia is bad in and of itself, even when glucose/A1C are within normal ranges.

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Just to be clear, my own fasting glucose and A1c are in the normal range, especially for someone my age. For anyone on Keto, low carb, or time-restricted feeding, fasting glucose readings are near meaningless unless they are way out of normal range.

I don’t think very many people who have normal A1c levels will have insulin resistance beyond what is normal for their age. As we age insulin resistance goes up but is mainly because of obesity and lack of exercise.

Do you have citations that give the percentage of people with normal A1c, but higher than normal age-adjusted insulin resistance?

I agree. Insulin resistance is on a spectrum. Some mild insulin resistance with normal A1C readings over time, along with a height/ waist ratio under 0.5, and no elevated markers of inflammation is probably of no real clinical significance.

The average A1C of centenarians is 5.7. By definition they’d be considered pre diabetic and insulin resistant.

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