Research Article Details
| Article ID: | A00447 |
| PMID: | 35079935 |
| Source: | Mol Biol Rep |
| Title: | Physiological significance of bistable circuit design in metabolic homeostasis: role of integrated insulin-glucagon signalling network. |
| Abstract: | BACKGROUND: Insulin and glucagon signalling pathways operate in a synchronised manner to regulate metabolic homeostasis in different physiological conditions (like postprandial, fasting & exercise). Non-linear positive feedback loops involving effector molecules such as AKT and PKA in anabolic and catabolic signalling modules have a key role in eliciting bistable response in these networks. METHODS: We have reviewed literature on insulin and glucagon signaling pathways in metabolic regulation along with the relevance of bistability in homeostasis. An ODE-based integrated signalling network model is used to simulate insulin and glucagon resistance conditions. Modifications in homeostatic to anabolic and catabolic switch activation thresholds are analyzed, indicating the effectiveness of insulin and glucagon signalling pathways in normal and diseased conditions. RESULTS: Perturbation analysis of the kinetic model provides valuable insights on bistability and its characterization with respect to endocrine inputs. Disturbance in bistability is linked with dysregulation of plasma macronutrient levels (glucose, fatty acids and amino acids) in abnormal conditions like insulin and glucagon resistance, which is associated with obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. CONCLUSIONS: This article highlights the role of Systems biology approach in explaining plausible mechanisms underlying metabolic abnormalities. It captures essential crosstalk and feedback mechanisms that play a key role in inducing bistable response in a variety of physiological situations, as well as hints at how to reverse insulin and glucagon resistance. |
| DOI: | 10.1007/s11033-022-07175-w |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| 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 | |
|---|---|---|---|---|---|
| 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 | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D155 | Glucagon | Biological drug | DB00040 | GCGR agonist | Antidiabetic drug | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |