Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Open accessAbstract
Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.
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OPC-163493 decreases hepatic steatosis, lowers fasting glucose and HbA1c, increases nitric oxide bioavailability, and reduces vascular oxidative stress in multiple rodent models of metabolic syndrome.
“Kanemoto and colleagues272 described a liver-localized mitochondrial uncoupler, OPC-163493, which was shown to have various benefits in multiple rodent models of the metabolic syndrome, such as decreasing hepatic steatosis and lowering fasting levels of glucose and HbA1c, as well as increasing nitric oxide bioavailability and reducing oxidative stress in blood vessels.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [272]
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- Authors
- Kanemoto, N., Okamoto, T., Tanabe, K., Shimada, T., Minoshima, H., Hidoh, Y., Aoyama, M., Ban, T., Kobayashi, Y., Ando, H., Inoue, Y., Itotani, M., & Sato, S.
- Affiliations
- Otsuka (Japan) (JP)
- Corresponding author
- Kanemoto, Naohide
- Venue
- Nature Communications
- Published
- 2019-05-15
- Volume
- 10
- Issue
- 1
- Pages
- 2172-2172
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6520346
- OpenAlex
- W2945783425
- Cited by
- 55
- References
- 68
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 3
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Otsuka Pharmaceutical
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitochondrial uncoupling, antidiabetic effect, type 1 diabetes, type 2 diabetes, hepatic steatosis, liver-targeted drug delivery, oral bioavailability, energy expenditure, glucose metabolism, hypertension, stroke, blood pressure, nitric oxide bioavailability, mitochondrial reactive oxygen species, renal function, pharmacokinetics
- MeSH terms
- Administration, Oral, Animals, Blood Pressure, Cricetulus, Diabetes Mellitus, Disease Models, Animal, Fatty Liver, Female, Humans, Hypertension, Hypoglycemic Agents, Kidney, Liver, Male, Mitochondria, Oxidative Phosphorylation, Uncoupling Agents, Survival Analysis, CHO Cells, Rats, Sprague-Dawley, Stroke, Mice, Rats, Hep G2 Cells
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