Metformin and sarcopenia

[Val Koganski]

I am confused with the way metformin been presented as damaging to muscle mitochondrial function.

From the data I have it is not affecting muscles mitochondria and works only on the liver in humans. Can also being studied for sarcopenia as a new indication.

Exploring the protective effect of metformin against sarcopenia: insights from cohort studies and genetics – PMC

2015 American Diabetes Association’s Scientific Sessions

And this are excerpts from the person with the most experience with Metformin Ralph A. Defronzo, MD (Professor of Medicine, Chief, Diabetes Division, Deputy Director, Texas Diabetes Institute) during his discussion with Peter Attia, MD:

• Everybody wants to know if metformin is geroprotective.

Remind people, metformin inhibits complex I of the electron transport chain

• This is still controversial
• In high doses, it does for sure
• In the doses you give metformin, it’s somewhat equivocal

Is the belief that metformin’s efficacy in diabetes is through reducing hepatic glucose output?

• That is 100% true

What’s the mechanism by which it reduces hepatic glucose output?

• Inhibiting the mitochondrial chain and inhibiting gluconeogenesis
  • For sure it inhibits gluconeogenesis
• Metformin gets in the cells through the organic cation transporter

⇒ The organic cation transporter doesn’t exist in muscle; it can’t possibly be an insulin sensitizer in muscle (you’re asking the drug to do something that’s impossible)

• Metformin enters cells using the organic cation transporter, and it does not exist in skeletal muscle or cardiac muscle ‒ so metformin cannot get into those tissues
• A rare complication that can occur when you have very low GFR and/or very, very high doses: lactic acidosis
  • Metformin is excreted by the kidney.

Can you please clarify your opinion and approach.

[Val Koganski]

• You can label metformin, give it, and see where it goes using PET studies
• You see it all accumulating in the liver in the first 3, 4, 5, 10 minutes [Ralph emailed the figure below]
  • Then it starts accumulating in the kidneys (because that’s where it’s excreted)

And another 5-10 minutes, you see it in the bladder

Figure 7. PET studies of labeled metformin show its uptake by the liver and kidneys. Image credit: 2015 ADA meeting abstract #128-LB

[Val Koganski]

I understand that metformin has detrimental effects on mitochondria, but published studies have shown that it is beneficial for sarcopenia, accumulates mostly in the liver, small intestines and small amount in the kidneys with minimal direct effect on the muscles:

Exploring the protective effect of metformin against sarcopenia: insights from cohort studies and genetics | Journal of Translational Medicine | Full Text

Study Shows Metformin Restores Muscle and Decreases Fat

Effects of anti-diabetic drugs on sarcopenia: Best treatment options for elderly patients with type 2 diabetes mellitus and sarcopenia – PMC

Metformin Biodistribution: A Key to Mechanisms of Action? | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic

 

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