Metformin Fails to Improve Insulin Resistance in Type 1 Diabetes

Metformin failed to present improvements in liver, muscle, or adipose tissue insulin resistance after treatment for 26 weeks in patients with type 1 diabetes (T1D), based on data from the Insulin in Type 1 Diabetes Managed with Metformin (INTIMET) study.1

Metformin is an inexpensive and safe oral medication used as a first-line treatment for type 2 diabetes. Previous studies have demonstrated metformin’s capacity to alter glucose metabolism in the muscle and liver in patients with type 2 diabetes based on hyperinsulinemic-euglycemic clamp data. Additionally, existing reviews of randomized controlled trials have demonstrated metformin’s capacity to reduce total daily insulin dose, which has been interpreted as an improvement in insulin resistance.2

“However, studies in type 1 diabetes using the gold-standard clamp technique to directly measure insulin resistance have only been performed in adolescents,” Jennifer Snaith, MBBS, B. Med. Sci, an endocrinologist and research fellow at the Garvan Institute of Medical Research, and colleagues wrote. “No study has employed the clamp technique to assess the effect of metformin on insulin resistance in adults with type 1 diabetes.”1

INTIMET began as a cross-sectional study in adults with and without T1D, aiming to quantify insulin resistance at muscle, liver, and adipose tissue and identify biochemical and clinical features associated with muscle and liver insulin resistance. Subsequently, Snaith and colleagues conducted a 6-month randomized controlled clinical trial to test the hypothesis that, among adults with T1D, relative to placebo, the addition of metformin to insulin would decrease hepatic insulin resistance and improve other cardiometabolic measures without increasing adverse effects.1

Male and female patients with T1D for ≥10 years were eligible for the trial, so long as they were between ages 20 and 55 with fasting c-peptide <0.3 nmol/L and HbA1c <9.5% (80 mmol/mol). Patients who were taking medications or who had conditions known to impact insulin sensitivity were excluded. During the trial, the team assessed insulin resistance via the 3-stage hyperinsulinemic-euglycemic clamp technique with isotope-labelled glucose. The primary outcome was the change in endogenous glucose production (EGP) during the low-dose phase of the clamp.1

A total of 40 patients were enrolled in the trial; of these, 20 had T1D and 20 did not. All patients underwent basic phenotyping assessment between November 2019 and December 2021. In the T1D cohort, the mean age was 37.4 +/- 8.8 years (mean +/- standard deviation [SD]), with a T1D duration of 22.9 +/- 8.9 years. The T1D cohort also had a mean BMI of 26.3 +/- 3.8 kg/m2, a mean total daily insulin dose of 0.6 units/kg/day, and a mean HbA1c of 7.5 +/- 0.9%. Of the 20 adults without T1D, mean age was 37 +/- 8.4 years, mean BMI was 26.2 +/- 4.3 kg/m2, and mean HbA1c 5.1 +/- 0.3%.1

The T1D group exhibited greater liver, adipose, and muscle insulin resistance compared to control, and participants with T1D had higher endogenous glucose production than controls (EGP; 5.9 +/- 2.2 µmol/kg fat free mass [FFM]/min and 3.6 +/- 1.7 µmol/kgFFM/min respectively; P = .0002) and higher non-esterified fatty acids (NEFA) in the low-dose phase (0.08 +/- 0.01 mmol/L and 0.02 +/- 0.02 mmol/L respectively; P = .001), which indicated impaired insulin-mediated suppression of hepatic glucose release and lipolysis, respectively.1

Ultimately, 37 of 40 enrolled participants completed the study. At 26 weeks, no significant difference was found in the change in EGP between the metformin and placebo groups (mean difference 0.2 µmol/kg FFM/min; 95% CI, -0.4 to 0.8; P = .53). There was also no increase in hypoglycemia or episodes of ketoacidosis in either group.1

“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,” Snaith and colleagues wrote. “The potential cardiovascular benefits of insulin sparing and reducing peripheral hyperinsulinemia warrant further study.”1

References

1. 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. Published 2025 Nov 24. doi:10.1038/s41467-025-65951-1

2. Liu YS, Chen CN, Chen ZG, Peng Y, Lin XP, Xu LL. Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta-analysis. Diabetes Metab Res Rev. 2020;36(6):e3334. doi:10.1002/dmrr.3334