Rapamycin impact on glucose, rapamycin clearance, cycling, and eating habits the day of dosage

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#1

Hey all,

I am 26 (as of yesterday), male, and for about 6 months been taking 5-6mg of rapa once weekly. I am also taking 25mg of Acarbose daily and 20mg Atorvastatin for genetically high cholesterol levels. Healthy and fit in any other way.

I recently did an Hba1c test and received a 5.5% result. The previous result from 6 months ago (about 1 month into Rapa) was 5.1%. I know one of rapamycin’s (and of statins) side effects is increased blood glucose, but the result quite surprised me. My dose of statins actually decreased by half since my last blood work (with no impact on my cholesterol), so I am attributing this spike in Hba1c to rapa (all other lifestyle habits remained largely the same).

This result made me wonder if people taking rapa are:

On that second point, I just did 2 tests to measure the speed of cleared of Sirolimus of my body (tested 24h after a 6mg dose to find 1.8ng/mL and 6 days after the dose to find ~0ng/mL). That took me to estimate that I fully clear rapa at around 72h after my dose.

So curious here if others have done similar measurements and if you change your eating habits around your dose intake.

#2

I wouldn’t make too much of going from 5.1% to 5.5% over 2 tests. How does the 5.5% compare to where you are historically? Lab tests also have error bars, and, from personal experience, the error bar for Hba1c is around plus/minus 0.2 for 90% certainty (just a guess). Maybe your tests are essentially the same, when you take into account error bars.

My personal experience is that rapamycin does not affect my blood sugar, which I track both by Hba1c and, 6 times a day, blood glucose, for my type 1 diabetes. Over 2.5 years of rapa use has not changed my blood glucose numbers or how much insulin I use.

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#3

I don’t mean to be disagreeable, but if you have type one diabetes and take exogenous insulin, rapamycin would not impact your glucose control if the mechanism of action is through endogenous insulin secretion.

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#4

Most people think the rapa effect is through insulin resistance, and this would affect me equally.

#5

I don’t know what most people think. My read is that rapamycin impacts the insulin output by affecting pancreatic islet cells. It might affect their size as it does in rps6(-,-) mice. My conclusion based on what I have read is that rapamycin impact on glucose is mediated by an effect more like weak T1DM (lower insulin) than like T2DM (insulin resistance). Obviously increasing insulin sensitivity or reducing glycemic load would help either way, but my hypothesis generates a testable prediction: rapamycin should have no impact on a person with T1DM because their pancreatic islet cells are already incapacitated.

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#6

Consider skimming these two abstracts:

And if you have all day, try reading this paper!

https://www.sciencedirect.com/science/article/abs/pii/B978012800174500017X

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#7

@Barnabas any other thoughts for OP regarding diet day of consumption and cycling?

#8

That’s a good question. I am not an expert. There are medical doctors on here who will have ideas.

This paper looked at hyperglycemia induced by everolimus:

Quoting from the abstract:

Everolimus did not affect insulin sensitivity in the liver, skeletal muscle, or the adipose tissue. In contrast, everolimus impaired insulin secretion and thereby increased basal hepatic glucose production. These findings further our understanding of the role of mTOR in glucose homeostasis in humans and provide insights for treatment strategies against everolimus-induced hyperglycemia.

Quoting from the paper itself:

This result suggests that the inhibition of mTOR in the insulin-producing pancreatic beta-cells was the main cause of glucose intolerance in the present study. … Indeed, rapamycin, an mTOR inhibitor, decreases insulin secretion from mice and human islets. … Everolimus induces reversible hyperglycemia, both in diabetic and non-diabetic patients, by impairing insulin secretion with no concomitant effect on insulin sensitivity.

I view that as supportive of the hypothesis I proposed above. The question remains what to do about it. Metformin inhibits hepatic gluconeogenesis. Empagliflozin inhibits hepatic gluconeogenesis. (Not all gliflozins do.)

The question in my mind would be how quickly the insulin suppression of rapamycin appears and disappears with weekly dosing and how quickly the inhibition of hepatic gluconeogenesis can be generated with whatever adjunct therapy one would choose. E.g. can you just take a metformin ER at the same time you take your weekly rapamycin dose, or do you need a different dosing schedule to align the effects.

I bet some people on here would have thoughts!

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#9

Here is what ChatGPT has to say on the subject.

Hepatic gluconeogenesis, the process by which the liver produces glucose from non-carbohydrate sources, is a key metabolic pathway that is especially important during fasting or periods of low carbohydrate intake. Several drugs and supplements are known to inhibit this process, which can be beneficial in the management of conditions like type 2 diabetes. Here are some of them:

Drugs

  1. Metformin:
  • Mechanism: Metformin inhibits hepatic gluconeogenesis primarily through the activation of AMP-activated protein kinase (AMPK).
  • Dosing: Typically, the initial dose is 500 mg twice daily or 850 mg once daily, which can be titrated up to 2,000-2,500 mg per day depending on patient tolerance and response.
  • Timing of Effect: The onset of action is within a few days, but the full therapeutic effect can take up to 2 weeks.
  1. SGLT2 Inhibitors (e.g., Canagliflozin, Dapagliflozin):
  • Mechanism: These drugs inhibit sodium-glucose co-transporter 2 (SGLT2) in the kidneys, reducing glucose reabsorption and also indirectly reducing hepatic gluconeogenesis.
  • Dosing: Common doses are 100-300 mg daily for Canagliflozin and 5-10 mg daily for Dapagliflozin.
  • Timing of Effect: These drugs begin to lower blood glucose levels within hours of the first dose, with full effects observed within a few days.
  1. Thiazolidinediones (e.g., Pioglitazone, Rosiglitazone):
  • Mechanism: They improve insulin sensitivity, primarily in adipose tissue, muscle, and liver, thereby reducing hepatic gluconeogenesis.
  • Dosing: Pioglitazone is typically prescribed at 15-45 mg daily, while Rosiglitazone is dosed at 4-8 mg daily.
  • Timing of Effect: These agents take several weeks to achieve full effect due to their mechanism of action involving gene transcription.
  1. GLP-1 Receptor Agonists (e.g., Liraglutide, Exenatide):
  • Mechanism: These drugs enhance glucose-dependent insulin secretion and inhibit glucagon release, leading to decreased hepatic glucose production.
  • Dosing: Liraglutide is started at 0.6 mg daily and titrated up to 1.2-1.8 mg daily. Exenatide is typically dosed at 5 mcg twice daily, increasing to 10 mcg twice daily.
  • Timing of Effect: They start to work within hours, with significant effects on blood glucose levels seen within the first week.
  1. DPP-4 Inhibitors (e.g., Sitagliptin, Saxagliptin):
  • Mechanism: These drugs inhibit the enzyme DPP-4, increasing levels of incretin hormones like GLP-1, which in turn reduce hepatic gluconeogenesis.
  • Dosing: Sitagliptin is dosed at 100 mg daily, while Saxagliptin is typically 2.5-5 mg daily.
  • Timing of Effect: These medications generally start to lower blood glucose within the first few days of treatment.

Supplements and Natural Compounds

  1. Berberine:
  • Mechanism: Berberine activates AMPK, similarly to metformin, to inhibit hepatic gluconeogenesis.
  • Dosing: Common dosing is 500 mg two to three times daily.
  • Timing of Effect: Effects on blood glucose can be observed within weeks of regular use.
  1. Curcumin:
  • Mechanism: Curcumin suppresses hepatic gluconeogenesis through multiple pathways, including AMPK activation.
  • Dosing: Typically, 500-1,000 mg per day is recommended.
  • Timing of Effect: It may take several weeks to months to observe significant effects.
  1. Resveratrol:
  • Mechanism: Resveratrol inhibits gluconeogenesis by activating AMPK and other pathways.
  • Dosing: 250-500 mg daily.
  • Timing of Effect: Effects may be seen after a few weeks of consistent use.
  1. Omega-3 Fatty Acids:
  • Mechanism: These fatty acids improve insulin sensitivity and reduce hepatic glucose production.
  • Dosing: Commonly, 1-4 grams daily.
  • Timing of Effect: Significant effects can be seen after several weeks to a few months.
  1. Quercetin:
  • Mechanism: Quercetin inhibits hepatic gluconeogenesis directly.
  • Dosing: 500-1,000 mg daily.
  • Timing of Effect: Beneficial effects may be observed after a few weeks of use.
  1. Chromium:
  • Mechanism: Chromium enhances insulin sensitivity, thereby reducing gluconeogenesis.
  • Dosing: 200-1,000 mcg daily.
  • Timing of Effect: Improvements may be seen within a few weeks.
  1. Alpha-Lipoic Acid:
  • Mechanism: This antioxidant reduces glucose production in the liver.
  • Dosing: 300-600 mg daily.
  • Timing of Effect: Effects can be noted within weeks.

In summary, understanding the pharmacokinetics and pharmacodynamics of these agents is crucial for optimizing their use in clinical practice. Always consider the individual patient’s context and adjust dosing accordingly, monitoring for efficacy and side effects.

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