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

Abstract

A virtual metabolic human model is a valuable complement to experimental biology and clinical studies, because in vivo research involves serious ethical and technical issues. A whole-body dynamic model is required not only to reproduce a variety of physiological and metabolic functions, but also to analyze pathology and design drugs. I first proposed a virtual metabolic human model, a multi-organ and multi-scale kinetic model of the whole-body metabolism that formulates the reactions of enzymes and transporters with the regulation of enzyme activities and hormonal actions under prandial and rest conditions. To accurately simulate metabolic changes and robustness, the model incorporates nucleotide cofactors that are critically responsible for global feedback regulations to adapt to metabolic changes. The model predicted a two-phase hepatic fatty acid production that consists of the synthesis of malonyl-CoA and the NADPH-dependent synthesis of fatty acid. The model performed pathological analysis of type 2 diabetes. I divided type 2 diabetes into specific disorders of steatosis, β cell dysfunction and insulin resistance for each organ, and analyzed the effect of the individual disorders on the dynamics of plasma glucose (hyperglycemia) and hepatic TG (steatosis). The model suggested that a chronic or irreversible change in hepatic TG accumulation plays a critical role in disease progression. The model predicted a glycerol kinase inhibitor to be a new medicine for type 2 diabetes, because it not only decreased hepatic TG but also reduced plasma glucose, unexpectedly. The model also enabled us to rationally design combination therapy.

A multi-scale in silico mouse model for insulin resistance and humanoid type 2 diabetes

“…(33)), but just as for the corresponding rodent models, these top-level models do not interconnect with more short-term models and models for the other two levels (Fig 1A). On the organ-level, there are numerous glucose-insulin meal response models (34, 35), and also some models that describe fatty acids (36), and other metabolites (37). There are also some such meal response models that connect with intracellular models for the pancreas and insulin signaling in the adipocytes (38-40), but these models do not interconnect with long-term disease progression whole-body models.…”