Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes

Abstract

AbstractA virtual metabolic human model is a valuable complement to experimental biology and clinical studies, becausein vivoresearch involves serious ethical and technical problems. I have proposed a multi-organ and multi-scale kinetic model that formulates the reactions of enzymes and transporters with the regulation of enzyme activities and hormonal actions under prandial and rest conditions. The model consists of 202 ordinary differential equations for metabolites with 217 reaction rates and 1132 kinetic parameter constants. It is the most comprehensive, largest and highly predictive model of the whole-body metabolism. Use of the model revealed the mechanisms by which individual disorders, such as steatosis, β cell dysfunction and insulin resistance, were combined to cause type 2 diabetes. The model predicted a glycerol kinase inhibitor to be an effective medicine for type 2 diabetes, which not only decreased hepatic triglyceride but also reduced plasma glucose. The model also enabled us to rationally design combination therapy.