How a cheap, century-old drug can improve life with type 1 diabetes

A Garvan-led clinical trial has found that using a common and inexpensive type 2 diabetes drug reduces insulin needs in type 1 diabetes, opening doors for improved management of the condition.

For years, doctors have prescribed metformin, an old but common type 2 diabetes medication, to treat insulin resistance in type 1 diabetes. This has been largely based on anecdotal evidence. Now, a clinical trial led by the Garvan Institute of Medical Research has found that metformin does not counteract insulin resistance in type 1 diabetes, but instead reduces the amount of insulin needed to maintain blood sugar levels in the ideal range.

Published in Nature Communications, these surprising findings could improve how doctors manage type 1 diabetes and ease the significant burden that people with the condition face when using insulin alone.

Can we overcome insulin resistance in type 1 diabetes?

Type 1 diabetes is an autoimmune condition affecting over 130,000 Australians in which the immune system incorrectly attacks the insulin-producing cells of the pancreas. As a result, people with type 1 diabetes need to administer insulin for the rest of their lives to regulate their blood sugar levels. Managing blood sugar levels with insulin is not easy. In fact, it is estimated that people living with type 1 diabetes have to make 180 extra decisions per day related to their diabetes management.

In some people with type 1 diabetes, long-term insulin use can lead to insulin resistance, where the body’s cells no longer respond effectively to the drug. This means that people need ever-increasing amounts of insulin to keep blood sugar levels under control.

“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,” says Dr. Jennifer Snaith, endocrinologist and co-lead of the study.

To address this, a Garvan team led by Dr. Snaith and Professor Jerry Greenfield undertook the world’s first randomized controlled trial in adults testing whether metformin, a cheap, oral drug normally used to counteract insulin resistance in type 2 diabetes, could do the same in type 1 diabetes. It is estimated that the drug is currently used off-label by up to 13,000 Australians with type 1 diabetes, but it remains unclear how exactly it works. This trial was called the Insulin Resistance in type 1 Diabetes Managed with Metformin (INTIMET) study.

“We randomized 40 adults with long-term type 1 diabetes to take either metformin or a placebo for six 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,” explains Professor Greenfield.

A surprise finding challenges assumption of metformin action

Unexpectedly, the team found that the use of metformin did not lead to improvements in insulin resistance or changes to blood sugar levels. This suggests that, unlike with type 2 diabetes, metformin does not work to counter insulin resistance in type 1 diabetes. However, metformin did decrease the amount of insulin people needed to keep their blood sugars stable.

“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. 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. We have shown that a very cheap, accessible medication may serve this purpose and this is very exciting,” Dr. Snaith says.

A role for gut microbes?

The team is now investigating how metformin may work to lower the amount of insulin needed by those with type 1 diabetes.

Professor Greenfield explains, “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.”

“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 type 1 diabetes. This has not been studied before in type 1 diabetes. 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 type 1 diabetes,” adds Dr. Snaith.