Research Article Details
| Article ID: | A25881 |
| PMID: | 21356259 |
| Source: | J Hepatol |
| Title: | Insulin resistance and liver microcirculation in a rat model of early NAFLD. |
| Abstract: | BACKGROUND & AIMS: Insulin contributes to vascular homeostasis in peripheral circulation, but the effects of insulin in liver microvasculature have never been explored. The aim of this study was to assess the vascular effects of insulin in the healthy and fatty liver. METHODS: Wistar rats were fed a control or a high fat diet (HFD) for 3days, while treated with a placebo, the insulin-sensitizer metformin, or the iNOS inhibitor 1400W. Vascular responses to insulin were evaluated in the isolated liver perfusion model. Insulin sensitivity at the sinusoidal endothelium was tested by endothelium-dependent vasodilation in response to acetylcholine in the presence or absence of insulin and by the level of liver P-eNOS after an insulin injection. RESULTS: Rats from the HFD groups developed liver steatosis. Livers from the control group showed a dose-dependent hepatic vasodilation in response to insulin, which was blunted in livers from HFD groups. Metformin restored liver vascular insulin-sensitivity. Pre-treatment with insulin enhanced endothelium-dependent vasodilation of the hepatic vasculature and induced hepatic eNOS phosphorylation in control rats but not in HFD rats. Treatment with metformin or 1400W restored the capacity of insulin to enhance endothelium dependent vasodilation and insulin induced eNOS phosphorylation in HFD rats. CONCLUSIONS: The administration of a HFD induces insulin resistance in the liver sinusoidal endothelium, which is mediated, at least in part, through iNOS upregulation and can be prevented by the administration of metformin. Insulin resistance at the hepatic vasculature can be detected earlier than inflammation or any other sign of advanced NALFD. |
| DOI: | 10.1016/j.jhep.2011.01.053 |
| 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 |
|---|
| 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 |
| D075 | Choline | Supplement | DB00122 | PLD2 product of; PLD1 product of | -- | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D157 | Glucophage | Chemical drug | DB00331 | -- | -- | Under clinical trials | Details |