Metformin Improves Mitochondrial Function and Glucose Uptake in Atherosclerotic Macrophages via Akt-AS160 Pathway
Type 2 diabetes doubles the risk of coronary heart disease, and accelerated atherosclerosis—the hardening and narrowing of arteries—is a key reason why. Yet intensive glucose control alone doesn’t always reduce cardiovascular deaths, leaving researchers searching for other ways to target the disease. Now, a 2019 study on the diabetes drug metformin offers new clues: it may fight atherosclerosis by fixing the metabolism of immune cells called macrophages, which drive inflammation in diseased arteries.
Why Macrophages Matter in Atherosclerosis
Macrophages are the “garbage collectors” of the immune system, but in arteries damaged by high cholesterol, they turn harmful. When exposed to oxidized low-density lipoprotein (Ox-LDL)—a modified form of “bad” cholesterol linked to plaque buildup—macrophages shift to a pro-inflammatory M1 state. These cells pump out chemicals like TNF-α and IL-6 that worsen inflammation and plaque growth. In contrast, anti-inflammatory M2 macrophages help heal tissue by clearing debris and reducing swelling. An imbalance favoring M1 cells is a hallmark of unstable, dangerous plaques.
Cell metabolism fuels this shift: M1 macrophages rely on glycolysis (a fast, inefficient energy pathway), while M2 cells use mitochondrial oxidative phosphorylation (OXPHOS)—a slower, more efficient process that produces less damaging reactive oxygen species (ROS). Fixing this metabolic imbalance could reverse macrophage inflammation—and slow atherosclerosis.
Metformin: A Familiar Drug with New Anti-Atherosclerosis Clues
Metformin has been used to treat type 2 diabetes for over 60 years and is recommended as first-line therapy by the American Diabetes Association. It’s also linked to lower heart disease risk in people with diabetes, but how it affects macrophages—key players in atherosclerosis—was unclear.
To find out, researchers led by Xuan He and Qian Gao from Nanjing University’s Medical School (with co-authors from Wenzhou Medical University) studied RAW264.7 mouse macrophages, a common model for atherosclerosis research. They exposed cells to Ox-LDL (to mimic the pro-inflammatory environment of diseased arteries) with or without metformin (15 mmol/L) for 24 hours. They then measured:
- Inflammation markers (M1 vs. M2 genes)
- Mitochondrial function (ROS, ATP, DNA copy number, and fusion/fission proteins)
- Metabolism (lipid oxidation, glucose uptake, and signaling pathways)
Key Findings: Metformin Reprograms Macrophages for Healing
The results showed metformin did more than just lower blood sugar—it reprogrammed Ox-LDL-damaged macrophages to be anti-inflammatory and metabolically healthy:
-
Shifts to Anti-Inflammatory M2 Macrophages
Ox-LDL alone reduced levels of the anti-inflammatory marker IL-10 by 21% and Retnla (a protein that limits plaque growth) by 30%. Metformin reversed this: IL-10 rose by 24% and Retnla tripled compared to Ox-LDL alone. M1 pro-inflammatory markers (TNF-α, IL-6) stayed the same—meaning metformin targeted the healing pathway without worsening inflammation. -
Fixes Mitochondrial Dysfunction
Ox-LDL damaged mitochondria (the cell’s “powerhouses”): it increased ROS (harmful free radicals) by 16%, lowered mitochondrial membrane potential (a sign of poor function) by 28%, and cut ATP (energy) production by 35%. Metformin fixed these issues:- ROS dropped by 14%
- Mitochondrial membrane potential rose by 28%
- ATP production increased by 35%
It also boosted mitochondrial DNA copy number (a marker of mitochondrial health) by 148% and increased Mfn2—a protein that helps mitochondria fuse and work efficiently—by 38%.
-
Boosts Lipid and Glucose Metabolism for OXPHOS
Metformin helped macrophages use fuel more efficiently:- Lipid oxidation: It increased CPT-1b (a protein that burns fat for energy) by 56% and p-ACC (a marker of reduced fat synthesis) by 77%.
- Glucose uptake: Ox-LDL cut glucose consumption by 25%, but metformin reversed this—glucose uptake rose by 14%. Crucially, metformin reduced lactic acid (a byproduct of inefficient glycolysis) by 25%, meaning more glucose was used for OXPHOS (the healthy energy pathway) instead of fueling inflammation.
-
Akt-AS160 Pathway Drives Glucose Uptake
How did metformin increase glucose uptake? It activated the Akt-AS160 pathway, a signaling chain that moves the glucose transporter GLUT1 to the cell membrane. Ox-LDL reduced Akt phosphorylation (a sign of inactivity) by 57%, but metformin restored it to normal levels. This, in turn, doubled AS160 phosphorylation—key for GLUT1 transport. Unlike in other cells, metformin didn’t rely on the AMPK pathway here—showing a macrophage-specific mechanism.
What This Means for Diabetes and Heart Disease
For people with diabetes, who face a 2x higher risk of heart disease, these findings add a critical piece to the metformin puzzle: its benefits go beyond lowering blood sugar. By fixing macrophage metabolism—improving mitochondria, boosting anti-inflammatory signals, and driving healthy energy use—metformin could slow the progression of atherosclerosis.
The study also highlights a new approach to treating chronic inflammation: targeting immune cell metabolism. Macrophages are central to many diseases (from arthritis to cancer), so drugs that rewire their metabolism could have wide-ranging benefits.
Limitations and Next Steps
This study was done in mouse cells, so more research is needed to confirm the effects in humans. The team also notes that the link between reduced ROS and increased mitochondrial DNA copy number needs further exploration—and whether Akt is the direct target of metformin in macrophages requires more testing.
Final Takeaway
Metformin is more than a diabetes drug—it’s a metabolic regulator that can heal the immune cells driving atherosclerosis. For people with diabetes, this research offers hope that a familiar medication could do double duty: lower blood sugar and protect arteries. For researchers, it opens a new door to treating chronic disease by targeting the metabolism of immune cells.
The study was published in the Chinese Medical Journal in 2019. For more details, visit doi.org/10.1097/CM9.0000000000000333.
Was this helpful?
0 / 0