A Garvan Institute of Medical Research-led clinical trial has found that using the type 2 diabetes (T2D) drug metformin reduces insulin needs in type 1 diabetes (T1D), a finding that could potentially point to improved management of the disorder. For years, doctors have prescribed metformin, an old but common and inexpensive type 2 diabetes medication, to treat insulin resistance in type 1 diabetes. This use has been largely based on anecdotal evidence. The newly reported Garvan-led clinical trial 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.
The 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. In their published paper in Nature Communications (“Effect of metformin on insulin resistance in adults with type 1 diabetes: a 26-week randomized double-blind clinical trial,”) the team, co-led by endocrinologist Jennifer Snaith, PhD, and professor Jerry Greenfield, PhD, wrote, “These results do not support prescribing metformin to reduce insulin resistance in adults with type 1 diabetes but suggest that metformin may reduce insulin dose via mechanisms independent of insulin resistance.”
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. “Type 1 diabetes is characterized by immune-associated destruction of insulin-producing pancreatic beta cells resulting in a lifelong reliance on insulin replacement,” the authors wrote. Managing blood sugar levels with insulin is not easy, with estimates indicating 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,” said Snaith. “Insulin resistance is of interest in type 1 diabetes as studies, including those with surrogate measures of cardiovascular disease, report an association between insulin resistance and cardiovascular risk,” the authors further commented.
To address this, a Garvan team led by Snaith and Greenfield undertook the world’s first randomised controlled trial—the Insulin Resistance in Type 1 Diabetes Managed with Metformin (INTIMET) study—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. “Metformin, an inexpensive and safe oral medication, is an ideal candidate to address insulin resistance in type 1 diabetes,” the authors suggested. “Although used first-line in the pharmacological management of type 2 diabetes, its mechanisms of action are not entirely understood.”
Greenfield further explained, “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.” The authors added, “Forty adults with type 1 diabetes, and twenty adults without diabetes were studied in a baseline-only cross-sectional study assessing insulin resistance using the two-step hyperinsulinemic-euglycemic clamp.”
Unexpectedly, the study results indicated that the use of metformin did not lead to improvements in insulin resistance or changes to blood sugar levels. This suggests that, unlike for 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 there was no evidence of an effect on measures of insulin resistance, metformin was associated with a reduction in total daily insulin dose by 0.1 units/kg/day relative to the placebo group,” the investigators reported. “Our findings suggest that in adults with type 1 diabetes, metformin may have metabolic impacts that translate to sparing of insulin requirements via effects independent of insulin resistance.”
“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,” Snaith said. “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.”
The team is now investigating how metformin may work to lower the amount of insulin needed by those with type 1 diabetes. Greenfield noted, “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.” The authors added, “The potential cardiovascular benefits of insulin sparing and reducing peripheral hyperinsulinemia warrant further study.”
Snaith further stated, “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.”
