Metformin Behaves Differently in Type 1 Diabetes

Doctors have prescribed metformin for decades, but a new study from the Garvan Institute shows it behaves differently in type 1 diabetes (T1D) than many assumed.

The trial found that metformin does not improve insulin resistance in adults with type 1 diabetes, but it does reduce the amount of insulin people need each day.

Metformin’s role in type 1 diabetes

T1D is an autoimmune condition that occurs when the immune system destroys the pancreas’ insulin-producing β-cells. Worldwide, around 9.5 million people live with T1D – and every one of them depends on insulin for life.

Yet for some, simply injecting insulin is not enough. Over time, the body’s tissues can become less responsive to insulin – a state known as insulin resistance. In T1D, insulin resistance has been recognized for years, yet the reasons behind it are still unclear.

“Insulin resistance is a growing problem in T1D. 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 T1D,” said lead author Dr. Jennifer Snaith, an endocrinologist and research fellow based at the Garvan Institute of Medical Research.

This uncertainty is one reason many people with T1D turn to metformin, a standard therapy for type 2 diabetes (T2D). It is known to support the body’s response to insulin and systematic reviews have reported that metformin in T1D tends to reduce total daily insulin doses, but without direct evidence that insulin sensitivity actually improves.

Snaith and the team wanted to test metformin properly in adults with long-standing T1D to understand how it acts in the body.

How the team tested metformin

The study involved 40 adults with T1D and a comparison group of 20 adults without diabetes. The researchers then ran a trial where half of the T1D group took 1,500 mg of metformin extended-release for 26 weeks and the other half took a placebo.

To track changes, the team used a controlled study method that measures how the liver, muscle and fat respond to insulin separately, giving a clearer picture of how metformin might act.

“We randomized 40 adults with long-term T1D to take either metformin or a placebo for 6 months. We examined whether their insulin resistance changed over that time through a sophisticated and comprehensive research technique, called a clamp study, that allowed us to map insulin resistance in different parts of the body,” explained corresponding author Dr. Jerry Greenfield, an endocrinologist and clinical researcher at the Garvan Institute of Medical Research.

Before treatment, the T1D group already showed signs of resistance across multiple tissues. Their livers produced more glucose, their muscles took up less glucose and their fat tissue released more fatty acids than in people without diabetes. These differences were present even though body mass and visceral fat were similar between groups.

After 26 weeks, metformin did not improve insulin resistance in any tissue. These results held after adjusting for age, sex and other factors.

However, those taking metformin needed less insulin each day.

“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. This is an important result,” said Snaith.

“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 T1D. We have shown that a very cheap, accessible medication may serve this purpose and this is very exciting,” she added.

Measures of blood sugar, including HbA1c and time-in-range, stayed stable across both groups.

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The trial also found higher levels of GDF15 in those taking metformin, a pattern seen in T2D research, along with a small drop in visceral fat that did not hold after further checks.

Appetite and calorie intake were unchanged, and metformin was well tolerated.

Metformin’s future in type 1 diabetes

The findings indicate that although metformin should not be used to treat insulin resistance in adults with T1D, its insulin-sparing effect is still meaningful. Using less insulin can reduce day-to-day burden and the long-term use of high insulin doses has been linked to insulin resistance. Cutting doses could lower cardiovascular risk.

The work also suggests that metformin acts through a different route in T1D than in T2D. Current ideas now focus on the gut, including changes in gut bacteria and signals produced in the digestive tract. The rise in GDF15 seen in the study also fits these ideas.

However, the number of participants was modest and most participants had HbA1c levels below 9.5%, so people with poor glucose control were not represented. The group was also mostly Caucasian, which narrows generalizability.

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Understanding why metformin lowered insulin needs is now a priority.

“Metformin has been available in various forms for around 100 years, but its mechanism of action remains unknown. We would have expected that the observed reductions in insulin dose induced by metformin in our study would be due to the body becoming more sensitive to insulin, that is, becoming less insulin resistant. But we have shown that is not the case. Our priority is now working out how metformin is achieving this effect,” explained Greenfield.

“There is increasing evidence suggesting that metformin may act on the gut. This is why we are now investigating how metformin changes gut flora, also known as the microbiome, in people with T1D. This has not been studied before in T1D,” said Snaith.

“We’re hoping this will provide clues on metformin’s mechanism of action, so that it can be more widely used in the management of T1D,” he added.

Reference: Snaith JR, Olsen N, Evans J, et al. Effect of metformin on insulin resistance in adults with type 1 diabetes: a 26-week randomized double-blind clinical trial. Nat Commun. 2025;16(1):9884. doi: 10.1038/s41467-025-65951-1

This article is a rework of a press release issued by the Garvan Institute of Medical Research. Material has been edited for length and content.