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

Abstract

Summary A virtual metabolic human model is a valuable complement to experimental biology and clinical studies, because in vivo research 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 hormonal actions at postprandial and postabsorptive states. The computational model consists of 202 ordinary differential equations for metabolites with 217 reaction rates and 1,140 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 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.

Digital twin predicting diet response before and after long-term fasting

“…The new model can describe all of those data ( Fig 2C , grey). Later models by us [ 23 , 42 ] and others [ 43 , 44 ] have produced more refined versions, which also describe glucose uptake subdivided into the different organs. Our model maintains this capacity and describes organ-specific insulin clearance and EGP contributions ( Fig 2E ).…”

“…Some other related previous models have instead focused on the detailed metabolism of the liver [ 45 – 47 ], but such models have had no realistic meal response part. There are also various detailed models which have had little to no quantitative agreement with data, especially independent validation data [ 44 , 48 ]. Also, neither of these meal response models has described more long-term changes, such as the build-up or breakdown of glycogen over days.…”

Digital twin predicting diet response before and after long-term fasting

“…Our model can describe all of those data (Fig 2C,grey). Later models by us (Nyman et al, 2011, Herrgårdh et al, 2021 and others (Maas et al, 2015, Kurata, 2021 have produced more refined versions, which also describe glucose uptake subdivided into the different organs. Our model maintains this capacity and also describes organ-specific insulin clearance and EGP contributions (Fig 2E).…”

“…Some other related previous models have instead focused on the detailed metabolism of the liver (König et al, 2012, Berndt et al, 2018, Ashworth et al, 2016, but such models have had no realistic meal response part. There are also various detailed models which have had little to no quantitative agreement with data, especially independent validation data (Kurata, 2021, Xu et al, 2011. Also, neither of these meal response models have described more long-term changes, such as build-up or breakdown of glycogen over days.…”

The transition between acute and chronic infections in light of energy control: a mathematical model of energy flow in response to infection

“…The systems biology community has developed theories and software tools that incorporate energy conservation laws into biochemical networks based on thermodynamic principles [10][11][12][13]. At the same time, mathematical models of metabolic energy regulation, with complexities ranging from simple glucose control loops to neural-endocrine control of appetite involving various kinds of nutrients, have been extensively studied in the field of diabetes and obesity [14][15][16][17], as well as in sports physiology [18].…”