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An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models
Tsugumasa Toma1, Nobukazu Miyakawa2, Yuiichi Arakaki1
1Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Aims/Hypothesis:
Appropriate management of blood glucose levels and the prevention of complications are important in the treatment of diabetes. We have previously reported on a compound named HPH-15 that is not only antifibrotic but also AMP-activated protein kinase (AMPK)-activating. In this study, we evaluated whether HPH-15 is useful as a therapeutic medication for diabetes.
Methods:
We examined the effects of HPH-15 on AMPK activation, glucose uptake, fat accumulation and lactic acid production in L6-GLUT4, HepG2 and 3T3-L1 cells, as a model of muscle, liver and fat tissue, respectively. Additionally, we investigated the glucose-lowering, fat-accumulation-suppressing, antifibrotic and AMPK-activating effect of HPH-15 in mice fed a high-fat diet (HFD).
Results:
HPH-15 at a concentration of 10 µmol/l increased AMPK activation, glucose uptake and membrane translocation of GLUT4 in each cell model to the same extent as metformin at 2 mmol/l. The production of lactic acid (which causes lactic acidosis) in HPH-15-treated cells was equal to or less than that observed in metformin-treated cells. In HFD-fed mice, HPH-15 lowered blood glucose from 11.1±0.3 mmol/l to 8.2±0.4 mmol/l (10 mg/kg) and 7.9±0.4 mmol/l (100 mg/kg) and improved insulin resistance. The HPH-15 (10 mg/kg) group showed the same level of AMPK activation as the metformin (300 mg/kg) group in all organs. The HPH-15-treated HFD-fed mice also showed suppression of fat accumulation and fibrosis in the liver and fat tissue; these effects were more significant than those obtained with metformin. Mice treated with high doses of HPH-15 also exhibited a 44% reduction in subcutaneous fat.
Conclusions/Interpretation:
HPH-15 activated AMPK at lower concentrations than metformin in vitro and in vivo and improved blood glucose levels and insulin resistance in vivo. In addition, HPH-15 was more effective than metformin at ameliorating fatty liver and adipocyte hypertrophy in HFD-fed mice. HPH-15 could be effective in preventing fatty liver, a common complication in diabetic individuals. Additionally, in contrast to metformin, high doses of HPH-15 reduced subcutaneous fat in HFD-fed mice. Presumably, HPH-15 has a stronger inhibitory effect on fat accumulation and fibrosis than metformin, accounting for the reduction of subcutaneous fat. Therefore, HPH-15 is potentially a glucose-lowering medication that can lower blood glucose, inhibit fat accumulation and ameliorate liver fibrosis.
Insights
The novel compound HPH-15 effectively lowers blood glucose and improves insulin resistance in diabetic mice. HPH-15 also demonstrates superior fat-lowering and antifibrotic effects compared to metformin, suggesting its potential as a diabetes therapeutic.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic Diseases
Background:
- Diabetes mellitus management requires controlling blood glucose and preventing complications.
- AMP-activated protein kinase (AMPK) activation is a key target for diabetes therapeutics.
- HPH-15 is a previously identified compound with antifibrotic and AMPK-activating properties.
Purpose of the Study:
- To evaluate HPH-15 as a potential therapeutic medication for diabetes.
- To assess the effects of HPH-15 on AMPK activation, glucose uptake, and fat accumulation.
- To compare the efficacy of HPH-15 with metformin in preclinical models.
Main Methods:
- In vitro studies using L6-GLUT4, HepG2, and 3T3-L1 cell models to assess AMPK activation, glucose uptake, fat accumulation, and lactic acid production.
- In vivo studies using mice fed a high-fat diet (HFD) to evaluate glucose-lowering, fat-suppressing, antifibrotic, and AMPK-activating effects.
- Comparison of HPH-15 efficacy against metformin at equivalent or higher doses.
Main Results:
- HPH-15 significantly increased AMPK activation, glucose uptake, and GLUT4 translocation in cell models, comparable to metformin.
- In HFD-fed mice, HPH-15 reduced blood glucose levels and improved insulin resistance.
- HPH-15 demonstrated superior suppression of fat accumulation and liver fibrosis compared to metformin, with high doses reducing subcutaneous fat by 44%.
Conclusions:
- HPH-15 activates AMPK at lower concentrations than metformin, both in vitro and in vivo.
- HPH-15 improves blood glucose control and insulin resistance, and ameliorates fatty liver and fibrosis more effectively than metformin.
- HPH-15 shows promise as a multi-action therapeutic for diabetes, addressing hyperglycemia, insulin resistance, and associated complications like fatty liver and excessive fat accumulation.
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