Research Article Details
| Article ID: | A26446 |
| PMID: | 20460912 |
| Source: | Dig Dis |
| Title: | Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. |
| Abstract: | The pathogenesis of type 2 diabetes involves both insulin resistance and defects in insulin secretion. Although obesity and physical inactivity have precipitated the epidemic of type 2 diabetes, the metabolic abnormalities associated with a sedentary lifestyle are better predictors of type 2 diabetes and cardiovascular disease than obesity alone. Some of these metabolic abnormalities, which are either causes or consequences of insulin resistance, have been called the metabolic syndrome. Fat accumulation in the liver due to non-alcoholic causes (non-alcoholic fatty liver disease) has also been shown to be an obesity-independent predictor of type 2 diabetes in multiple prospective studies. Since the liver is a key site of action of insulin, it seems reasonable to postulate that subjects who deposit excessive amounts of fat in the liver are those who also are at risk of developing the metabolic syndrome. Mechanistic studies support this hypothesis. Once fatty, the liver is resistant to the actions of insulin to inhibit both production of glucose and very-low-density lipoprotein, which results in mild hyperglycemia, compensatory hyperinsulinemia and hypertriglyceridemia. The latter leads to lowering of high-density lipoprotein cholesterol and formation of atherogenic small dense low-density lipoprotein particles. These data suggest that the metabolic syndrome and non-alcoholic fatty liver disease are essentially two definitions of the same problem. In subjects who cannot sustain hyperinsulinemia to maintain glucose concentrations in the nondiabetic range, overt hyperglycemia, i.e. type 2 diabetes, develops. |
| DOI: | 10.1159/000282087 |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| 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 |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |