Mathematical Modeling of Glucose-Lactate Metabolism in Adolescents with and without Obesity during Oral Glucose Tolerance Tests

Before 1984, with the development of the so called “Lactate-Shuttle theory” by Brooks et.al, lactate was considered a waste product of anaerobic glycolysis (i.e. the first process of glucose utilization), generated during muscle fatigue and hypoxia state. Thereafter, several studies on this molecule were conducted, showing its key role in human metabolism. From these studies, it emerged that lactate is always the final product of glycolysis, it can enter the mitochondria in which it is oxidized, and serves as a fuel in several human organs (e.g. heart, brain, liver and muscles), but also it has a signaling role, e.g. together with insulin and free fatty acids (FFAs). In pathological states characterized by insulin resistance (i.e. the impaired insulin effect on the endogenous glucose production and utilization), such as obesity, diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), the high circulating glucose is primarily processed through glycolysis thus producing lactate. The high lactate levels observed in these pathological states contributes to the development of liver inflammation, ultimately leading to liver fibrosis and cirrhosis. Thus, lactate can be used as a marker in such diseases, in fact it was proposed as the molecule connecting obesity with insulin resistance state. Mathematical modeling of lactate kinetic could be useful to estimate parameters related to its metabolism, enhancing the knowledge on this molecule and processes in which it is involved. Some minimal models (i.e. parsimonious models able to summarize the key characteristics of a biological process) were proposed to this aim. However, they have been validated during non-physiological tests, such as intravenous glucose tolerance tests (IVGTTs) or lactate infusions. This precluded the applicability of such models to more physiological post-prandial conditions. Also, to the best of our knowledge, none of the literature simulation models (i.e. models characterized by a large number of equations and parameters to fully implement the knowledge of the system under study) accounted for lactate kinetics. That is why, in this project, the first aim was to set up a minimal model of the glucose-lactate kinetics during a 4h oral glucose tolerance test (OGTT), able to estimate parameters related to the insulin resistance state (i.e. liver and disposal insulin sensitivities, SIL and SID, respectively) along with the glycolytic flux (i.e. lactate production rate, LPR) in a population of adolescents overweight/with obesity. Starting from the existing Single Tracer Oral Minimal Model (STOMM), proposed by Visentin et.al., we integrated a monocompartmental description of the lactate kinetic, showing that this was the best choice for predicting both glucose and lactate during an OGTT. We also showed that model parameters estimated during a 4h-protocol well correlated with those obtained from a 3h-protocol. This allows to increase the usability of the model and alleviate the burden for the patient. Finally, the model was successfully applied to an independent dataset of lean/overweight/obese adolescents, showing that it was able to account for differences related to the obesity degree. Moreover, the difference observed in some model parameters in adults and adolescents were concordant with those reported in the literature studies. Particularly, the correlations obtained between model parameters and subjects-specific anthropometric characteristics, along with the differences related to the age, opened the possibly to extend the minimal model to the nonlinear mixed-effect modeling, in which such characteristics could be directly integrated into the model. The second aim of this project was to develop a simulation model of lactate, together with glucose, insulin and C-peptide dynamics during an OGTT, extending the Type 2 Diabetes simulator (T2Ds) proposed by Visentin et.al...