Effect of metformin on insulin resistance in adults with type 1 diabetes: a 26-week randomized double-blind clinical trial

Jennifer R. Snaith (), Nick Olsen, Jennifer Evans, Greg M. Kowalski, Clinton R. Bruce, Dorit Samocha-Bonet, Samuel N. Breit, Deborah J. Holmes-Walker and Jerry R. Greenfield
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Jennifer R. Snaith: Garvan Institute of Medical Research, Clinical Diabetes, Appetite and Metabolism Laboratory
Nick Olsen: University of New South Wales, Stats Central, Mark Wainwright Analytical Centre
Jennifer Evans: Garvan Institute of Medical Research, Clinical Diabetes, Appetite and Metabolism Laboratory
Greg M. Kowalski: Deakin University, Institute for Physical Activity and Nutrition, Metabolic Research Unit, School of Medicine
Clinton R. Bruce: Deakin University, Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences
Dorit Samocha-Bonet: Garvan Institute of Medical Research, Clinical Diabetes, Appetite and Metabolism Laboratory
Samuel N. Breit: University of New South Wales Sydney, St Vincent’s Healthcare Campus, Faculty of Medicine and Health
Deborah J. Holmes-Walker: Westmead Hospital, Department of Diabetes and Endocrinology
Jerry R. Greenfield: Garvan Institute of Medical Research, Clinical Diabetes, Appetite and Metabolism Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Insulin resistance is an underrecognized cardiovascular risk factor in type 1 diabetes. The effect of metformin on insulin resistance in adults with type 1 diabetes is unknown. 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. Participants with type 1 diabetes exhibited hepatic (EGP 64% higher), muscle (glucose infusion rate [GIR] 29% lower) and adipose (higher non-esterified fatty acids [NEFA]) insulin resistance. We then conducted a parallel group randomized, placebo-controlled trial to assess the efficacy of metformin 1500 mg (n = 20) versus placebo (n = 20) in reducing insulin resistance in adults with type 1 diabetes over 26 weeks. The primary outcome was change in endogenous glucose production (EGP) during the low-dose phase of the clamp. Thirty seven of 40 adults with type 1 diabetes completed the study. At 26 weeks, there was no difference in change in EGP between metformin and placebo groups (mean difference 0.2 µmol/kg fat-free mass [FFM]/min [95%CI, −0.4 to 0.8 µmol/kgFFM/min]; p = 0.53). There was no increase in hypoglycemia or episodes of ketoacidosis in either group. These results do not support prescribing metformin to reduce hepatic insulin resistance in adults with type 1 diabetes. Australian New Zealand Clinical Trials Registry identifier, ACTRN12619001440112.

Date: 2025
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DOI: 10.1038/s41467-025-65951-1

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