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.”