Metformin fails to improve insulin resistance in type 1 diabetes

By Dr. Priyom Bose, Ph.D.Reviewed by Lauren HardakerNov 26 2025

A 26-week trial reveals that metformin, long viewed as a promising add-on therapy, lowers insulin needs but leaves tissue-level insulin resistance unchanged.

Study: Effect of metformin on insulin resistance in adults with type 1 diabetes: a 26-week randomized double-blind clinical trial. Image credit: pimpampix/Shutterstock.com

A recent study in Nature Communications investigated the effect of metformin on insulin resistance in adults with type 1 diabetes. Even after twenty-six weeks of metformin treatment, no improvement in insulin resistance in liver, muscle, or adipose tissue was observed in patients with type 1 diabetes.

Insulin resistance in type 1 diabetes

Type 1 diabetes is an autoimmune disorder in which the immune system attacks the pancreas, destroying the insulin-producing beta cells. As a result, blood glucose levels rise significantly and must be controlled with insulin therapy. Insulin resistance is an important metabolic disorder associated with type 1 diabetes, which is partially caused by an impaired portal-peripheral insulin concentration gradient resulting from the subcutaneous route of insulin delivery.

Multiple studies have established an association between insulin resistance and cardiovascular risk. These studies have failed to determine whether this association is driven by muscle or liver insulin resistance. Understanding this would help create targeted interventions, combined with adjunctive therapies, to reduce insulin resistance, which may also confer cardioprotection in type 1 diabetes.

Metformin is an inexpensive and safe oral medication commonly prescribed for type 2 diabetes and sometimes used as an adjunctive, off-label therapy in type 1 diabetes to manage insulin resistance. Although it is a widely used medication for type 2 diabetes, its mechanism of action remains unclear.

A previous study has revealed that metformin alters glucose metabolism in muscle and liver to manage type 2 diabetes. Additionally, it increases the circulation of growth differentiation factor 15 (GDF15), a stress-regulated hormone involved in appetite suppression and the regulation of weight and glucose levels. Multiple studies have highlighted the role of metformin in reducing cardiovascular risk and mortality.

To date, no studies have directly assessed the effect of metformin on insulin resistance in adults with type 1 diabetes using the gold-standard hyperinsulinemic–euglycemic clamp technique.

Quantifying insulin resistance with metformin treatment in patients with type 1 diabetes

Twenty adults without diabetes were recruited for baseline studies only. Researchers focused on identifying biochemical and clinical features linked with muscle and liver insulin resistance. Subsequently, the Insulin Resistance in Type 1 Diabetes Managed with Metformin (INTIMET) study was conducted, a single-site, phase 3, randomized, placebo-controlled trial lasting six months.

INTIMET was designed to test the hypothesis that adding metformin to insulin would decrease hepatic insulin resistance in adults with type 1 diabetes compared to a placebo. Furthermore, this treatment could improve cardiometabolic measures without inducing any adverse effects.

A total of 40 participants with type 1 diabetes and 20 without a diabetes diagnosis were recruited for the study. Participants with type 1 diabetes were between 20 and 55 years of age and had fasting c-peptide levels of less than 0.3 nmol/L and an HbA1c level of less than 9.5 % (80 mmol/mol). In contrast, control participants met only the age and general health criteria. None were current smokers or had been exposed to metformin within the last 30 days of the study.

After baseline studies were complete, participants with type 1 diabetes were randomly assigned to either the metformin or placebo group. Both groups received identical-looking medication: 500 mg tablets for 7 days, followed by 1000 mg for 7 days, and finally 1500 mg for the remaining 26-week treatment period.

Dietary data, retinal photographs, and urine albumin-creatinine ratio (ACR) were collected. Hepatic and adipose insulin sensitivity was measured using endogenous glucose production (EGP) and non-esterified fatty acids (NEFA), respectively. Muscle insulin sensitivity was assessed based on glucose infusion rate (GIR) data. Relationships between muscle insulin resistance and cardiovascular risk markers, including arterial stiffness and lipid profiles, were also evaluated.

Efficacy of metformin against type 1 diabetes

In the type 1 diabetic cohort, the mean age of the participants was 37.4 years, 60 % were male, type 1 diabetes duration was approximately 22.9 years, BMI 26.3 kg/m², HbA1c 7.5, and total daily insulin dose 0.6 units/kg/day. A similar proportion of participants with type 1 diabetes used multiple daily insulin injections and insulin pumps.

Similarly, in the healthy cohort, participants were approximately 37 years of age, 60 % male, with a BMI of 26.2 kg/m² and an HbA1c of 5.1. It is worth noting that participants with and without type 1 diabetes did not differ in terms of sex, age, or anthropometric characteristics.

At baseline, the type 1 diabetes group exhibited significantly greater insulin resistance in the liver, adipose tissue, and muscle compared with control participants. They showed higher EGP than the control and elevated NEFA in the low-dose phase at 0.08 mmol/L and 0.02 mmol/L, respectively. This finding implies impaired insulin-mediated suppression of hepatic glucose release and lipolysis. These participants also exhibited lower GIR during the high-dose phase, at 61.9 µmol/kgFFM/min and 87.7 µmol/kgFFM/min, indicating impaired insulin-stimulated glucose uptake by skeletal muscle.

Baseline assessments also revealed higher serum levels of soluble intercellular adhesion molecule 1 (sICAM-1) and GDF15 in participants with type 1 diabetes. In addition, these patients exhibited lower uric acid, insulin-like growth factor-1 (IGF-1), and triglyceride levels, as well as higher sex hormone-binding globulin (SHBG) and high-density lipoprotein (HDL) cholesterol concentrations. Muscle insulin resistance showed strong associations with cardiovascular risk factors, highlighting its possible role as a key driver of vascular complications in type 1 diabetes.

Of 40 participants, 37 completed the 26-week intervention period, with similar medication adherence rates across the two groups. Metformin treatment did not significantly alter EGP. Although GIR increased over time in both groups, the between-group differences were not significant. Furthermore, no significant difference in NEFA was observed between groups from baseline to 26 weeks of intervention.

Metformin significantly reduced the total daily insulin dose compared to placebo, regardless of age, sex, baseline HbA1c, baseline BMI, and insulin delivery method. No difference was observed between the trial groups for HbA1c or glycemic variability over the 26 weeks. Metformin intervention did not affect fasting glucagon levels or glucagon response to insulin during the clamp. Metformin also significantly increased circulating GDF15, consistent with its known biological effects.

Metformin safe, but ineffective at improving tissue-specific insulin resistance

Metformin was found to be well-tolerated, with no significant side effects. Although metformin treatment for 6 months did not improve directly measured insulin resistance, it reduced insulin dose requirements.

Insulin sparing and reduced peripheral hyperinsulinemia may still offer long-term cardiovascular benefits, even in the absence of improvements in clamp-measured insulin sensitivity. However, the study is limited by a modest sample size, limited ethnic diversity, and exclusion of individuals with higher HbA1c, which may affect generalizability.

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