A Mathematical Model of Proximal Tubule Epithelial Cell Bioenergetics and Glycolysis/Gluconeogenesis Shifts in Diabetes

Source abstract

Diabetic kidney disease is associated with changes in proximal tubule (PT) cellular metabolism, and particularly changes in glucose metabolism. An increase in glycolysis may be expected, since filtration and reabsorption of glucose by PT epithelial cells is increased. However, counterintuitively, gluconeogenesis is also increased. The PT epithelial cells also shift to accumulating lactate instead of consuming it as a fuel. In order to better understand the mechanisms underlying these shifts, a mathematical model of proximal tubule cellular metabolism was developed that includes the main metabolic processes of the proximal tubule: glycolysis, lactate/pyruvate metabolism, gluconeogenesis, beta oxidation, citric acid cycle, and oxidative phosphorylation. From a steady‐state that matches literature values for each of these rates, we simulated a rise in glucose delivery and cellular concentration. The model predicts that these changes will increase PT glycolysis, lactate accumulation, and gluconeogenesis, in agreement with experimental observations. The simulations indicate the counterintuitive lactate accumulation and increased gluconeogenesis are driven by a rise in the NADH/NAD+ ratio that occurs as a result of increased glycolysis. This model can help quantitatively understand the metabolic alterations in the PT that occurs in diabetic kidney disease. In future, it can be used to simulate treatments such as SGLT2 inhibitors and predict their influence on cellular metabolism.