Manu Tomar1, Pramod R Somvanshi2, Venkatesh Kareenhalli3. 1. Department of Chemical Engineering, Indian Institute of Technology, Bombay, Powai, Mumbai, India. 2. Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India. 3. Department of Chemical Engineering, Indian Institute of Technology, Bombay, Powai, Mumbai, India. venks@iitb.ac.in.
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.
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.
Authors: John G Menting; Jonathan Whittaker; Mai B Margetts; Linda J Whittaker; Geoffrey K-W Kong; Brian J Smith; Christopher J Watson; Lenka Záková; Emília Kletvíková; Jiří Jiráček; Shu Jin Chan; Donald F Steiner; Guy G Dodson; Andrzej M Brzozowski; Michael A Weiss; Colin W Ward; Michael C Lawrence Journal: Nature Date: 2013-01-10 Impact factor: 49.962