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Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review
Open accessAbstract
Aims/hypothesis Insulin resistance, which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake, is a core defect in type 2 diabetes. Metformin and the peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones (TZDs), both lower glucose, although their mechanism of action is still subject to debate. This review analyses the evidence relevant to these mechanisms in vivo.Materials and methods A systematic search of MEDLINE identified a total of 42 clinical studies that investigated the effects of TZDs (n=23) and/or metformin (n=19) on endogenous glucose production (using tracer glucose techniques) and peripheral glucose disposal (using the euglycaemic-hyperinsulinaemic clamp) in patients with type 2 diabetes (n=549). The original variables assessed were converted into standardised units and their mean group values were listed separately for open and placebo-controlled studies. Statistical analysis was scarried out, treating mean group values as individual values and comparing results (both as absolute values and percentage changes from baseline) across study categories (open vs placebo-controlled, TZDs vs metformin).Results Both TZDs and metformin enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance. TZDs, but not metformin, also improve insulin-mediated glucose uptake at all insulin levels.Conclusions/interpretation In patients with type 2 diabetes, metformin improves fasting hepatic insulin sensitivity and glucose clearance; TZDs improve fasting hepatic insulin sensitivity and glucose clearance, and potentiate glucose disposal under insulinised conditions.
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“an increased insulin suppression of endogenous glucose production by the liver(44, 45)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [44]
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“reduction of glucose absorbtion by the gastro-intestinal tract(44, 45)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [44]
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“a decreased in hepatic glucose production by suppression of gluconeogenesis(44, 45)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [44]
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Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic controlPreprint
Sebo, Z. L., Chakrabarty, R. P., Grant, R. A., D’Alessandro, K. B., Koss, A. R., Blum, J. L. E., Davidson, S. M., Reczek, C. R., & Chandel, N. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.02.678294 · Cited by 2
Sarah, E. H., Omri, N. E., Ibrahimi, A., & Jaoudi, R. E. (2020) · Gene Reports · doi:10.1016/j.genrep.2020.100787 · Cited by 2
Li, H., Chen, H., Kan, J., Awad, S., Ibrahim, A., Zalán, Z., & Du, M. (2025) · Food & Function · doi:10.1039/d5fo01005e · Cited by 1
HEART: A database on health and ethnomedicinal traditions of Indian tribes
Ghosh, S., Mondal, A. S., Saha, S., & Podder, S. (2025) · Ethics Medicine and Public Health · doi:10.1016/j.jemep.2025.101188 · Cited by 1
Nb, G., Rajesh, D., & Muppala, T. (2015) · International Journal of Pharmacy and Pharmaceutical Sciences · Cited by 1
The effect of pioglitazone on non-pregnant female genital tract in experimental diabetes mellitus.
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Metadata
- Authors
- Natali, A., & Ferrannini, E.
- Affiliations
- University of Pisa (IT)
- Corresponding author
- Ferrannini, E.
- ORCID
- Natali, A.
- Venue
- Diabetologia
- Published
- 2006-02-14
- Volume
- 49
- Issue
- 3
- Pages
- 434-441
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2123472586
- Cited by
- 377
- References
- 32
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 5 · 2023: 27 · 2022: 24 · 2021: 27 · 2020: 23 · 2019: 22 · 2018: 25 · 2017: 23 · 2016: 20 · 2015: 20 · 2014: 13 · 2013: 27 · 2012: 17
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- metformin, thiazolidinediones, type 2 diabetes, hepatic glucose production, insulin resistance, glucose uptake, insulin sensitivity, glucose clearance, peroxisome proliferator-activated receptor gamma agonists, insulin-stimulated glucose disposal
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Glucose, Humans, Liver, Metformin, Thiazolidinediones
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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