Data Support Use of Diabetes Medication Metformin to Treat IPF

Data Support Use of Diabetes Medication Metformin to Treat IPF

The type 2 diabetes medication metformin suppresses the production of collagen, and induces a switch in lung fibroblasts that is associated with quickened recovery from fibrosis, according to a preclinical study. The findings support the use of this medication in patients with idiopathic pulmonary fibrosis (IPF).

The research, “Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis,” was published in the journal Nature Communications.

Previous work identified lipofibroblasts — fibroblasts containing lipid (fat) droplets — as the precursors of myofibroblasts, which are the key cell type in the accumulation of extracellular matrix (matrix that provides structural and biochemical support to cells) in people with IPF.

In turn, the anti-diabetic therapy rosiglitazone (Avandia) showed anti-inflammatory effects in a pig model of lung injury, suggesting that such compounds might be clinically relevant in this disease. The link between fibrosis and metabolic alterations in the lung further supported this hypothesis.

Furthermore, a study showed that metformin, a treatment used in combination with rosiglitazone in patients with type 2 diabetes, quickly reversed PF in a mouse model and eased fibrosis in lung tissue of PF patients.

Aiming to assess the precise molecular mechanisms and cell types associated with such benefits, the scientists conducted in vitro experiments with lung fibroblasts and tissue derived from IPF patients, as well as a genetic analysis in the bleomycin mouse model of lung fibrosis.

In fibroblasts collected from IPF patients, metformin led to an increase in the lipogenic markers PPARgamma and PLIN2, as well as an accumulation of lipid droplets. In turn, levels of the marker COL1A1 — indicating cell differentiation into myofibroblasts — were reduced.

Subsequent analysis of gene expression revealed that metformin primarily acted on metabolic pathways in lung fibroblasts, including key pathways in the production and metabolism of fatty acids.

To better mimic in vivo settings, the investigators used lung slices to show that metformin improved lung structure and eased collagen deposition — a key event in lung fibrosis — associated with increased lipid-droplet accumulation and less COL1A1.

Subsequent experiments in mice showed that oral treatment with metformin led to an increased recovery from lung fibrosis, which correlated with higher levels of lipid droplets, and an overall conversion of myofibroblasts to lipofibroblasts.

At the molecular level, the team found that BMP2, involved in the suppression of smooth muscle cell growth, was the gene showing the most significantly increased expression with metformin treatment. Analyses in human lung fibroblasts further revealed that the BMP2 protein induced lipogenic differentiation via activation of PPARgamma, and inhibited collagen production via the AMPK signaling pathway.

“We show that metformin alters the fate of myofibroblasts, and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation,” the researchers stated.

“Mechanistically, metformin induces lipogenic differentiation in myofibroblasts via a mechanism involving bone morphogenetic protein 2 (BMP2) up-regulation and PPARγ activation, and inhibits TGFβ1-induced collagen production via AMPK activation,” the team added.

In contrast to metformin, neither pirfenidone nor nintedanib — two approved IPF therapies marketed as Esbriet (by Genentech) and Ofev (by Boehringer Ingelheim), respectively — increased the production of lipogenic markers or the accumulation of lipid droplets in human lung fibroblasts.

“Our data highlight the potential for using metformin to treat IPF patients,” the scientists said. “Given its low cost and the fact that it is well-tolerated in humans, it will be useful to test the curative effect of metformin, either alone or in combination with other anti-fibrotic agents, in non-diabetic IPF patients.”

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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11 comments

  1. M C Butler says:

    I am very interested in your article on Metformin as a treatment for IPF. How can anyone be treated with this drug when it is only available for diabetics? Is there any chance it will be acceptable as treatment for IPF soon? As a sufferer myself we all desperately need answers ASAP. Thank you for your time. M C Butler.

  2. jaime L manriquez says:

    Its remarkable, the metformin findings, I will start the treatment right now, Great news for us the IPF patients and thanks to the scientific community that made that possible

    • Hi Jaime, How much of the metformin would do it? Currently, I am on Metformin 500mg tablet a day, I would like to take twice tablets. Tomorrow I will talk to my docto about it and see if I can get a a new prescription.. Good luck to you Jaime. Thank you! (sorry for my rustic English,I am an spanish speaking person)

  3. Peter Blake says:

    As an IPF person and diabetic on 2 x metformin 500 daily how much metformin is required to stabilise the PF.I am one of those that cannot tolerate esbriet or nimtem .. so yes I am very interested if just upping my dose will help

  4. Ed says:

    I was prescribed Metforman for weight control. It was used to help control spikes in blood sugar levels. I do not have IPF but my wife has CHP. Hope this info helps.

  5. Robert McGrath says:

    I have IPF. Diagnosed 7.5 years ago. My pulmonologist said Monday I should be dead. SURPRISE! I take both Ofev and Esbriet. I figured that since they both work differently it couldn’t hurt. My doc agreed. Had a script for Esbriet but had him change to Ofev. The reason is that Pirfenidone is available through Canada at a cost of roughly $160.00 a month (go figure). I started taking Metformin 500 mg bid about a year ago when I read the first study results of its use in mouse models. Again, my doc said ok. It is also available by mail through Canadian pharmacies. As I recall it’s about $50.00 a month. I’m on 4 lpm oxygen at dead rest, 8 lpm for shopping and 12-15 with exertion like bush trimming, gardening, and long walking. My FVC is 36 and has been stable for 9 months. Haven’t had a DLCO in a while. I’m a white 67 year old male..
    For the last 3 months I have been seeing a Chinese doctor educated in traditional medicine at the University of Traditional Medicine in China. Former member and consultant at University of Chicago associative arts committee. Taking fe fu khan ( spelling?) which is adjusted every once in a while depending on symptoms. There is reliable clinical evidence that this herbal mix works in IPF pathways. Their views are very different than Western medicine but he does not want me to stop my regular meds. This herbal medicine is made by him with plants from China. There are 3 basic types of this medication and as I said adjusted periodically so don’t waste your time looking for it on-line. Find a Chinese physician and go from there. It’s my life and I’m exploring every avenue. I’m slightly adverse to the Weii products often mentioned because it’s “one size fits all” which really isn’t the way traditional Chinese medicine works. Do you have cold feet or hands? This is a sample question I was asked and, in fact, did have cold feet that I noticed when I went to sleep every night but no more. Who knows?
    I was a participant in the last phase 3 trial of Pirfenidone so I’ve been on that since the first half of 2013.
    I am currently in the “ clean-up” study at Loyola. Involves taking Bactrim (antibiotic) 800/160 mg bid and 5 mg of folic acid as Bactrim depletes it. The postulate is that it will decrease the number and/or severity of exacerbations from IPF. I haven’t had any exacerbations while taking it for about 11 months.
    To be sure my life isn’t what it was. Fatigue, breathlessness, etc. still exist. But I woke up today!!!

    • D says:

      Robert, I have taken WEI Lab herbs at 3 different times with great success for my IPF. A bit pricey but they work. They have about 6 or 7 different herbs for different lung diseases. What is your Chinese source? Thanks.

  6. Robert McGrath says:

    I also had surgery in 2017 for left lung adenocarcinoma and was diagnosed with squamous cell carcinoma or right lung in 2018 treated with radiation. Both type 1. Clean since. Just thought to mention for full picture…..

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