Research Article Details

Article ID: A11741
PMID: 30770030
Source: Diab Vasc Dis Res
Title: Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift.
Abstract: While few dispute the existence of the metabolic syndrome as a clustering of factors indicative of poor metabolic health, its utility above that of its individual components in the clinical care of individual patients is questioned. This is likely a consequence of the failure of clinicians and scientists to agree on a unifying mechanism to explain the metabolic syndrome. Insulin resistance has most commonly been proposed for this role and is generally considered to be a root causative factor for not only metabolic syndrome but also for its associated conditions of non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), obesity-related type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). An alternative view, for which evidence is mounting, is that hyper-responsiveness of islet β-cells to a hostile environment, such as westernised lifestyle, is primary and that the resulting hyperinsulinaemia drives the other components of the metabolic syndrome. Importantly, within this new conceptual framework, insulin resistance, while always a biomarker and state of poor metabolic health, is not considered to be harmful, but a protective adaptive response of critical tissues including the myocardium against insulin-induced metabolic stress. This major shift in how metabolic syndrome can be considered puts insulin hypersecretion into position as the unifying mechanism. If shown to be correct, this new conceptual framework has major implications for the future prevention and management of the metabolic syndrome, including its associated conditions of NAFLD, PCOS, obesity-related T2D and ASCVD.
DOI: 10.1177/1479164119827611

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
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
D248 Obeticholic Acid Chemical drug DB05990 NR1H4 activator; NR1H4 agonist; FXR agonist Enhance lipid metabolism Approval rejected Details
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details