Reference - Detail
| RRC ID | 81906 |
|---|---|
| Author | Toma T, Miyakawa N, Arakaki Y, Watanabe T, Nakahara R, Ali TFS, Biswas T, Todaka M, Kondo T, Fujita M, Otsuka M, Araki E, Tateishi H. |
| Title | An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models. |
| Journal | Diabetologia |
| Abstract |
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. |
| Volume | 67(11) |
| Pages | 2568-2584 |
| Published | 2024-11-1 |
| DOI | 10.1007/s00125-024-06260-y |
| PII | 10.1007/s00125-024-06260-y |
| PMID | 39251430 |
| MeSH | 3T3-L1 Cells AMP-Activated Protein Kinases* / metabolism Adipose Tissue / drug effects Adipose Tissue / metabolism Animals Antifibrotic Agents / pharmacology Antifibrotic Agents / therapeutic use Blood Glucose / drug effects Blood Glucose / metabolism Diet, High-Fat* / adverse effects Disease Models, Animal Glucose Transporter Type 4 / metabolism Hep G2 Cells Humans Hyperglycemia* / drug therapy Hyperglycemia* / metabolism Hypoglycemic Agents / pharmacology Hypoglycemic Agents / therapeutic use Insulin Resistance / physiology Male Metformin / pharmacology Metformin / therapeutic use Mice Mice, Inbred C57BL |
| Resource | |
| Human and Animal Cells | Hep G2(RCB1648) |