Diabetes drug could be repurposed to treat skin sarcoidosis: Study
Blocking ramped-up energy production may a possible treatment strategy
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In cutaneous sarcoidosis, disease-driving immune cells ramp up their energy production, and blocking this energy production may be a useful strategy for treating the disease, a new study shows.
The study specifically points to metformin, a metabolism-modulating drug that’s widely used to treat diabetes, as a potential treatment for this form of sarcoidosis.
“Patients often suffer significantly — both physically and psychologically — from the extensive skin inflammation, which we can currently treat only symptomatically, as the disease mechanisms are not yet fully understood,” Mario Fabri, MD, the study’s senior author at Jena University Hospital, University of Cologne, and Max Planck Institute for Immunobiology and Epigenetics, in Germany, said in a press release from Jena University Hospital.
The research opens up new targets for causal therapy in granulomatous diseases [such as cutaneous sarcoidosis], added Henning Klapproth, the study’s co-first author at University Hospital of Cologne.
“In particular, drug repurposing of metformin is a possible strategy,” Klapproth said.
The study, “A STAT1/ETC/GBP1 axis represents a potential therapeutic target for noncommunicable granulomatous skin disease,” was published in Science Advances.
Cutaneous sarcoidosis marked by red-brown or purple bumps on skin
In cutaneous sarcoidosis, granulomas, or clumps of inflammatory immune cells, form in the skin, causing symptoms such as red-brown or purple bumps or raised patches that can appear anywhere on the body.
Macrophages, a type of immune cell, play a central role in the formation of granulomas in cutaneous sarcoidosis. Macrophages are also centrally involved in granuloma annulare (GA), another skin disorder marked by abnormal aggregates of immune cells.
Previous studies have suggested that a pro-inflammatory signaling molecule called interferon-gamma helps trigger macrophages to form granulomas. But it hasn’t been clear exactly how this inflammatory signaling molecule alters the biochemical activity of these immune cells.
To better understand exactly how interferon-gamma alters macrophage function in cutaneous sarcoidosis and GA, Fabri and colleagues reanalyzed published genetic data on both skin conditions and paired them with experiments using lab-grown human cells and tissue samples from cutaneous sarcoidosis and GA patients.
They found that interferon-gamma triggers macrophages to make more energy. Specifically, the inflammatory signaling molecule sent into overdrive a cellular process called oxidative phosphorylation (OXPHOS), where cells burn blood sugar (glucose) using oxygen to generate lots of energy.
This activation of cellular energy generation was key for the macrophages’ ability to produce other inflammatory signaling molecules that spur granuloma formation.
Signaling protein identified as potential biomarker
Data also showed that a signaling protein called GBP1 plays a central role in activating OXPHOS in macrophages exposed to interferon-gamma, indicating that this protein may be a useful biomarker and/or therapeutic target.
“GBP1 represents a central molecular link between metabolic remodeling toward OXPHOS and inflammatory immune activation,” the researchers wrote.
Manuel Huerta, the other co-first author of the study at University Hospital of Cologne and Jena University Hospital added: “For both diseases, we were … able to identify the protein GBP1 as a key player in this signaling process.”
Building off these findings, the team tested the effects of blocking GBP1 or OXPHOS in a human granuloma model in lab dishes. They found that suppressing GBP1 or OXPHOS significantly reduced the formation of granulomas in the model.
Of particular note, metformin — a diabetes drug that is known to block OXPHOS — reduced the size and number of granulomas, as well as the production of granuloma-driving signaling molecules.
Because metformin is widely used and has a well-established safety profile, the researchers suggested it would be relatively straightforward to run clinical trials testing whether metformin may help control cutaneous sarcoidosis and related diseases.
“Given that the [OXPHOS blocker] metformin showed effectiveness in our [granuloma model], a drug repurposing approach could be rapidly translated to the clinic,” the team concluded.
