Research Article Details
| Article ID: | A47154 |
| PMID: | 24797033 |
| Source: | Alcohol Clin Exp Res |
| Title: | Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury. |
| Abstract: | BACKGROUND: Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin. METHODS: Forty male Wistar rats weighing 200 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study. RESULTS: Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1α and PPAR-α activities were also restored. CONCLUSIONS: EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD. |
| DOI: | 10.1111/acer.12418 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T05 | Peroxisome proliferator-activated receptor gamma | PPARG | agonist | Nuclear hormone receptor | P37231 | PPARG_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D225 | Metformin | Chemical drug | DB00331 | PRKAB1 inducer activator; ETEDH inhibitor; GPD1 inhibitor | Improve insulin resistance | Under clinical trials | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D581 | sobetirome | Chemical drug | -- | Thyroid hormone receptor beta agonists | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D157 | Glucophage | Chemical drug | DB00331 | -- | -- | Under clinical trials | Details |