Insulin Resistance in Type 1 Diabetes Remains a Key Cardiovascular Risk
A ROBUST clinical investigation has found that metformin does not improve hepatic insulin resistance in adults with type 1 diabetes (T1D), despite long-standing assumptions that it may offer metabolic advantages beyond glycaemic control. The study, which combined cross-sectional metabolic phenotyping with a randomised placebo-controlled trial, used the hyperinsulinaemic-euglycaemic clamp to assess insulin sensitivity at the level of the liver, muscle and adipose tissue.
Insulin resistance in T1D is increasingly recognised as an important cardiovascular risk factor, yet it remains underdiagnosed and undertreated in routine clinical practice.
Multi-Organ Insulin Resistance Confirmed in Cross-Sectional Analysis
In the cross-sectional component, 40 adults with T1D were compared with 20 adults without diabetes. Participants with T1D demonstrated substantial multi-organ insulin resistance, including higher endogenous glucose production, reduced glucose infusion rates reflecting impaired muscle insulin sensitivity, and elevated non-esterified fatty acids indicating adipose tissue insulin resistance. These abnormalities were evident despite intensive insulin therapy and highlight a significant metabolic burden that may contribute to long-term vascular risk.
Randomised Trial Shows No Benefit of Metformin
The subsequent randomised trial assigned 40 adults with T1D to either metformin 1500 mg per day or placebo for 26 weeks. The primary outcome was change in endogenous glucose production during the low-dose insulin phase of the clamp. Thirty-seven participants completed the study. After 26 weeks, there was no significant difference between the metformin and placebo groups in the change in endogenous glucose production. Confidence intervals indicated no clinically meaningful trend towards benefit. Rates of hypoglycaemia and ketoacidosis were similar across both groups, confirming that the treatment was well tolerated but ineffective for its intended metabolic effect.
Implications for Clinical Practice
These findings do not support the use of metformin to reduce hepatic insulin resistance in adults with T1D. While metformin continues to have a role in selected individuals for weight management or modest reductions in insulin dose, this study demonstrates that it does not modify hepatic insulin resistance, a key driver of cardiovascular risk. The results underscore the urgent need for therapies that target the distinct mechanisms of insulin resistance specific to T1D.
Reference
Snaith JR 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.
