Research Article Details
| Article ID: | A26138 |
| PMID: | 21040936 |
| Source: | Metabolism |
| Title: | The association between the metabolic syndrome and alanine amino transferase is mediated by insulin resistance via related metabolic intermediates (the Cohort on Diabetes and Atherosclerosis Maastricht [CODAM] study). |
| Abstract: | The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we investigated to what extent the association between the metabolic syndrome and alanine aminotransferase (ALT, as a surrogate of NAFLD) can be explained by different metabolic intermediates of the metabolic syndrome. Cross-sectional analyses were performed in 434 subjects from the Cohort on Diabetes and Atherosclerosis Maastricht study (264 men; mean age, 59.5 ± 7.1 years). We used multiple linear regression analyses to investigate the association between the metabolic syndrome and ALT and the mediation role of potential mediators herein. The mediators considered were insulin resistance (homeostasis model assessment), an inflammatory adipokine score (based on interleukin-6, serum amyloid A, intercellular adhesion molecule, adiponectin, and leptin), an endothelial dysfunction score (based on E-selectin, vascular cell adhesion molecule, and von Willebrand factor), and plasma levels of NEFA. All analyses were adjusted for age, sex, smoking, alcohol consumption, and use of medication. Subjects with the metabolic syndrome (53.7%) had significantly higher levels of ALT (β = 0.67 SD [95% confidence interval, 0.49-0.85], P < .001). Adjustment for insulin resistance attenuated this difference by 77.3% (to 0.15 SD [-0.04 to 0.35]). Attenuation by adipose tissue-associated inflammation, endothelial dysfunction, and NEFA was more modest (20.7%, 13.1%, and 9.5%, respectively). Part of the attenuation by NEFA, but not of the other mediators, was additional to that of insulin resistance. Insulin resistance constitutes a key pathophysiological mechanism in the association between the metabolic syndrome and NAFLD (measured as ALT), which may operate through adipose tissue-associated inflammation and endothelial dysfunction and to a lesser extent through NEFA, which may have an independent role in the development of NAFLD in subjects with the metabolic syndrome. |
| DOI: | 10.1016/j.metabol.2010.09.006 |
| 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 |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | 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 |
| I07 | 1936 | Arteriosclerosis | Build-up of fatty material and calcium deposition in the arterial wall resulting in partial or complete occlusion of the arterial lumen.https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C35768 | disease of anatomical entity/cardiovascular system disease/ vascular disease/ artery disease | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | 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 |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |