Research Article Details
| Article ID: | A52760 |
| PMID: | 22351884 |
| Source: | Pediatrics |
| Title: | Toward a unifying hypothesis of metabolic syndrome. |
| Abstract: | Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. Reactive oxygen species accumulate, which cannot be quenched by adjacent peroxisomes; these reactive oxygen species reach the endoplasmic reticulum, leading to a compensatory process termed the "unfolded protein response," driving further insulin resistance and eventually insulin deficiency. No obvious drug target exists in this pathway; thus, the only rational therapeutic approaches remain (1) altering hepatic substrate availability (dietary modification), (2) reducing hepatic substrate flux (high fiber), or (3) increasing mitochondrial efficiency (exercise). |
| DOI: | 10.1542/peds.2011-2912 |
| 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 |
| 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 |
| I12 | 10763 | Hypertension | An artery disease characterized by chronic elevated blood pressure in the arteries. https://en.wikipedia.org/wiki/Hypertension, https://www.ncbi.nlm.nih.gov/pubmed/24352797 | disease of anatomical entity/ cardiovascular system disease/vascular disease/ artery disease | 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 |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D050 | Branched-chain amino acids | Biological drug | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |