Berberine and Its More Biologically Available Derivative, Dihydroberberine, Inhibit Mitochondrial Respiratory Complex I
Open accessAbstract
OBJECTIVE: Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy. RESEARCH DESIGN AND METHODS: AMPK phosphorylation was examined in L6 myotubes and LKB1(-/-) cells, with or without the Ca(2+)/calmodulin-dependent protein kinase kinase (CAMKK) inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative, dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet. RESULTS; We have made the following novel observations: 1) BBR dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, similar to that observed with metformin and rosiglitazone; 2) activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKbeta, consistent with major regulation at the level of the AMPK phosphatase; and 3) a novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation, and insulin resistance in high-fat-fed rodents. This effect is likely due to enhanced oral bioavailability. CONCLUSIONS: Complex I of the respiratory chain represents a major target for compounds that improve whole-body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.
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Several studies have confirmed that berberine possesses properties that ameliorate dyslipidemia, insulin resistance, and hypertension.
“Several studies have confirmed that berberine possesses properties that ameliorate dyslipidemia, insulin resistance, and hypertension (Turner et al., 2008; Xu et al., 2014; Xu et al., 2017; Wang et al., 2018; Rondanelli et al., 2023; Yan et al., 2024).”
From Efficacy and safety of berberine on the components of metabolic syndrome: a systematic review and meta-analysis of randomized placebo-controlled trials (2025) · cites this paper as Turner et al., 2008
The Introduction (page unavailable) says berberine has insulin-sensitizing properties in rodent models and reports therapeutic potential for dyslipidemia in humans; the Discussion also reports improved symptoms in patients with dyslipidemia. Neither passage supports the hypertension part of the claim, and a search for hypertension and blood pressure found no supporting passage in our copy. (LLM, conf=0.87)
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- Authors
- Turner, N., Li, J.-Y., Gosby, A., To, S. W. C., Cheng, Z., Miyoshi, H., Taketo, M. M., Cooney, G. J., Kraegen, E. W., James, D. E., Hu, L.-H., Li, J., & Ye, J.-M.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Chinese Academy of Sciences (CN)
- Kyoto University (JP)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-05-01
- Volume
- 57
- Issue
- 5
- Pages
- 1414-1418
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2014742651
- Cited by
- 535
- References
- 26
- Citations by year
- 2026: 27 · 2025: 21 · 2024: 14 · 2023: 33 · 2022: 24 · 2021: 40 · 2020: 43 · 2019: 27 · 2018: 31 · 2017: 27 · 2016: 27 · 2015: 32 · 2014: 31 · 2013: 31 · 2012: 35
- FWCI
- 21.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Diabetes (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- National Science Foundation
- Diabetes Australia Research Trust
- Rebecca L. Cooper Medical Research Foundation
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- berberine, dihydroberberine, AMPK, insulin resistance, type 2 diabetes, LKB1, CaMKK, muscle mitochondria, oxygen consumption, oral bioavailability, high-fat diet, adiposity, triglyceride accumulation, glucose metabolism
- MeSH terms
- Adenylate Kinase, Animals, Berberine, Enzyme Activation, Insulin, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Phosphorylation, Rats, Wistar, Cyclic Nucleotide-Regulated Protein Kinases, Electron Transport Complex I, Mice, Rats
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