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Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes

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Cree-Green, Melanie, Bergman, Bryan C, Cengiz, Eda, Fox, Larry A, Hannon, Tamara S, Miller, Kellee, Nathan, Brandon, Pyle, Laura +6 more·2019·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2019-00129PMC PMC6584133
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Abstract

CONTEXT: Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. OBJECTIVE: Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. DESIGN: Double-blind, placebo-controlled clinical trial. SETTING: Multi-center at eight sites of the T1D Exchange Clinic Network. PARTICIPANTS: A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. INTERVENTION: Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. MAIN OUTCOME MEASURES: Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. RESULTS: Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. CONCLUSIONS: Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.

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  • Metformin improves insulin sensitivity and cardiovascular outcomes in people with type 1 diabetes.

    “Metformin improves insulin sensitivity and cardiovascular outcomes in people with type 1 diabetes.91,92”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [91]

    The Discussion reports improved whole-body and peripheral insulin sensitivity in adolescents with overweight or obesity and type 1 diabetes. The paper does not report improved cardiovascular outcomes in that group; its Abstract discusses reduced cardiovascular risk and mortality with metformin in adults with type 2 diabetes. The claim also generalizes the insulin-sensitivity finding beyond the youth studied. (LLM, conf=0.89)

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Authors
Cree-Green, M., Bergman, B. C., Cengiz, E., Fox, L. A., Hannon, T. S., Miller, K., Nathan, B., Pyle, L., Kahn, D., Tansey, M., Tichy, E., Tsalikian, E., Libman, I., & Nadeau, K. J.
Affiliations
  • Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
  • University of Colorado Anschutz (US)
  • Yale University (US)
  • Nemours Children's Clinic (US)
  • Indiana University Indianapolis (US)
  • Jaeb Center for Health Research (US)
  • University of Minnesota (US)
  • Colorado School of Public Health (US)
  • University of Iowa (US)
  • Children's Hospital of Pittsburgh (US)
Corresponding author
Miller, Kellee
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2019-04-02
Volume
104
Issue
8
Pages
3265-3278
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2019-00129
PMC
PMC6584133
OpenAlex
W2932901353
Cited by
101
References
4
Citations by year
2026: 9 · 2025: 13 · 2024: 9 · 2023: 17 · 2022: 16 · 2021: 19 · 2020: 13 · 2019: 5
FWCI
10.75
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • PMC
Funders
  • National Institutes of Health (UL1TR002535, UL1TR001857, UL1TR002537)
  • Juvenile Diabetes Research Foundation International
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
metformin, type 1 diabetes, insulin resistance, peripheral insulin sensitivity, adolescents, obesity, hyperinsulinemic-euglycemic clamp, lipolysis, endogenous glucose production, adipose tissue insulin sensitivity, hepatic insulin sensitivity, skeletal muscle insulin sensitivity
MeSH terms
Adipose Tissue, Adolescent, Adult, Blood Glucose, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Insulin Resistance, Liver, Male, Metformin, Young Adult

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