A new study from Northwestern Medicine, published in Science Advances, has provided direct evidence in mice that the widely used diabetes drug metformin lowers blood sugar by interfering with mitochondria, the cell’s “powerhouse”. For years, scientists have been puzzled about how exactly metformin works, despite its use as a first-line treatment for Type 2 diabetes for over 60 years. This new research sheds light on the drug’s mechanism of action, demonstrating that metformin reduces glucose levels by blocking mitochondrial complex I, a key part of the cell’s energy-making machinery.

Here’s a breakdown of the key findings:

• Metformin inhibits mitochondrial complex I: By blocking this specific part of the mitochondria, metformin reduces the cell’s energy supply, which in turn lowers blood sugar.
• Targeted action: The drug’s effect on mitochondrial complex I allows it to target cells contributing to disease progression while limiting harm to healthy cells.
• Experimental evidence: Researchers used genetically modified mice expressing a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to metformin. These mice did not experience the same drop in glucose levels when given metformin as the control group, indicating that metformin’s glucose-lowering effect is dependent on its impact on mitochondrial complex I.
• Not the whole picture: While the NDI1-expressing mice showed resistance to the glucose-lowering effects of metformin, they were not completely resistant, suggesting that metformin might also target other pathways to some degree.
• Diverse effects: The study suggests that metformin’s diverse health benefits, including lowering glucose, decreasing inflammation, and potential anti-cancer effects, could be attributed to its inhibition of mitochondrial complex I. This is supported by previous research from the same group.
• Limited cellular access: Metformin’s access to the interior of cells is limited by the need for a transporter, affecting mainly cells in the gut, liver, and kidney.
• Clinical Significance: Metformin is an inexpensive, first line of defense for Type 2 diabetes patients globally and this research enhances our understanding of how this “wonder drug” works.

These findings could lead to further research into the potential of metformin and its mechanism of action to impact different diseases.

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