Metformin, a drug that has been around for a century and costs next to nothing, appears to help people with type 1 diabetes use significantly less insulin to control their blood sugar. A new clinical trial from the Garvan Institute of Medical Research is forcing scientists to rethink how the medication works in the body.
The study, published in Nature Communications, found that adults with type 1 diabetes who took metformin needed approximately 12% less insulin than those on a placebo over six months. That reduction matters enormously for the roughly 130,000 Australians living with the condition, for whom insulin management is a constant daily burden involving an estimated 180 decisions about monitoring and adjustment.
Type 1 diabetes is an autoimmune disease where the body attacks insulin-producing cells in the pancreas, forcing patients to inject insulin for life. Many develop insulin resistance over time, requiring ever-larger doses to keep blood sugar stable. Dr. Jennifer Snaith, an endocrinologist and co-lead of the research, noted that this resistance is more than just a management headache. "Insulin resistance is a growing problem in type 1 diabetes. Not only does it make regulating blood sugar levels difficult, but it is an underappreciated risk factor for heart disease, which is one of the biggest causes of health complications and deaths in those with type 1 diabetes."
The surprise is how metformin pulls off this trick. Researchers expected the drug would work by improving how the body responds to insulin, but their findings contradicted that assumption entirely.
Mystery Mechanism
Metformin has long been the standard treatment for type 2 diabetes and is already prescribed off-label to roughly 13,000 Australians with type 1 diabetes. Yet its actual mechanism of action has remained a mystery, even after a century of use.
The INTIMET trial was the first randomized controlled study of its kind, enrolling 40 adults with long-standing type 1 diabetes. Researchers administered either metformin or placebo for 26 weeks and used advanced "clamp study" techniques to map insulin resistance across different parts of the body with precision.
"Although we didn't find changes to insulin resistance from the use of metformin, we did show that people taking it used around 12% less insulin than those on placebo," Dr. Snaith explained. "Insulin is a relatively old treatment which, while lifesaving, comes with significant mental and physical burden. This means that lowering the amount of insulin used is a priority for many people living with type 1 diabetes."
The researchers were as puzzled as anyone. If the drug wasn't making the body more insulin-sensitive, what was it doing? "Metformin's mechanism of action remains unknown," Professor Jerry Greenfield, who co-led the work, said. "We would have expected that the observed reductions in insulin dose would be due to the body becoming more sensitive to insulin. But we have shown that is not the case."
One leading hypothesis centers on the gut microbiome. Scientists suspect metformin may alter gut bacteria in ways that influence how the body processes glucose. "There is increasing evidence suggesting that metformin may act on the gut," Dr. Snaith noted. The team is now investigating how the drug changes gut flora in type 1 diabetes, a line of inquiry that has not been pursued in this population before.
If researchers crack the code on metformin's hidden mechanism, the implications could reshape how millions manage the disease. A cheap, proven drug that cuts insulin demand by a tenth would remove one of the most exhausting elements of living with type 1 diabetes.
Author Jessica Williams: "A century-old drug delivering a new benefit for type 1 patients is exactly the kind of story that makes you wonder what else we've missed about medications hiding in plain sight."
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