Cited by 283Liver Disease Diagnosis and TreatmentMetabolism, Diabetes, and CancerDiabetes Treatment and Management

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

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Perry, Rachel J., Zhang, Dongyan, Zhang, Xian-Man, Boyer, James L., Shulman, Gerald I.·2015·Science

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol (DNP) has beneficial effects on NAFLD, insulin resistance, and obesity in preclinical models but is too toxic for clinical use. We developed a controlled-release oral formulation of DNP, called CRMP (controlled-release mitochondrial protonophore), that produces mild hepatic mitochondrial uncoupling. In rat models, CRMP reduced hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. It also normalized plasma transaminase concentrations, ameliorated liver fibrosis, and improved hepatic protein synthetic function in a methionine/choline-deficient rat model of NASH. Chronic treatment with CRMP was not associated with any systemic toxicity. These data offer proof of concept that mild hepatic mitochondrial uncoupling may be a safe and effective therapy for the related epidemics of metabolic syndrome, T2D, and NASH.

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  • Global glucose tolerance was improved in DNP-treated rats, an effect resulting from an increase in liver- and muscle-insulin sensitivity.

    “Global glucose tolerance was also improved in DNP-treated rats, an effect resulting from an increase in liver- and muscle-insulin sensitivity [277].”
  • Rats exposed to 1 mg/kg DNP using an orally available, controlled-release formulation exhibit decreased fasting plasma glucose, fatty acids (by 30%), TAG concentrations, HDL concentrations (by 30%), and hyperinsulinemia (50%).

    “Rats exposed to 1 mg/kg DNP using an orally available, controlled-release formulation of DNP exhibit a decrease in fasting plasma glucose, fatty acids (by 30%), TAG concentrations, HDL concentrations (by 30%) and hyperinsulinemia (50%) [277].”
  • DNP treatment prevents NAFLD development in rats by reducing fasting plasma glucose as well as concentrations of non-esterified fatty acids and insulin, accompanied by a 50-90% decrease in TAG concentrations in plasma, liver, and skeletal muscle.

    “DNP treatment also prevents NAFLD (Non-Alcoholic Fatty Liver Disease) development in rats by reducing fasting plasma glucose as well as concentrations of non-esterified fatty acids and insulin, accompanied by a 50–90% decrease in TAG concentrations in plasma, liver, and skeletal muscle [277].”
  • DNPME and CRMP decrease liver triglyceride accumulation and improve insulin sensitivity in rat models of type 2 diabetes and NAFLD.

    “Both DNPME and CRMP decreased triglyceride accumulation in liver and improved insulin sensitivity in rat models of T2DM and NAFLD266,267.”

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Authors
Perry, R. J., Zhang, D., Zhang, X.-M., Boyer, J. L., & Shulman, G. I.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Yale University (US)
Corresponding author
Shulman, Gerald I.
Venue
Science
Published
2015-03-13
Volume
347
Issue
6227
Pages
1253-1256
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W1974677595
Cited by
283
References
17
Citations by year
2026: 8 · 2025: 21 · 2024: 25 · 2023: 19 · 2022: 19 · 2021: 29 · 2020: 32 · 2019: 33 · 2018: 22 · 2017: 25 · 2016: 38 · 2015: 12
FWCI
25.25
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (R01 DK-40936, R24 DK-085638, U24 DK-059635, T32 DK-101019, P30 DK-45735, P30 DK-34989, UL1 TR-000142)
  • Novo Nordisk Foundation Center for Basic Metabolic Research
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
2,4-dinitrophenol, controlled-release formulation, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, type 2 diabetes, insulin resistance, hepatic steatosis, hypertriglyceridemia, liver fibrosis, methionine-choline-deficient diet, metabolic syndrome, oral drug delivery
MeSH terms
Animals, Blood Glucose, Delayed-Action Preparations, Diabetes Mellitus, Type 2, Glucose Tolerance Test, Insulin Resistance, Liver Cirrhosis, Male, Mitochondria, Liver, Oxidation-Reduction, Random Allocation, Rats, Zucker, Muscle, Skeletal, 2,4-Dinitrophenol, Lipid Metabolism, Mice, Rats, Proton Ionophores, Non-alcoholic Fatty Liver Disease

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