Regulation of Adipose Tissue Metabolism in Humans: Analysis of Responses to the Hyperinsulinemic-Euglycemic Clamp Experiment

The suppression of lipolysis is one of the key metabolic responses of the adipose tissue during hyperinsulinemia. The failure to respond and resulting increase in plasma fatty acids could contribute to the development of insulin resistance and perturbations in the fuel homeostasis in the whole body. In this study, a mechanistic, computational model of adipose tissue metabolism in vivo has been enhanced to simulate the physiological responses during hyperinsulinemic-euglycemic clamp experiment in humans. The model incorporates metabolic intermediates and pathways that are important in the fed state. In addition, it takes into account the heterogeneity of triose phosphate pools (glycolytic vs. glyceroneogenic), within the adipose tissue. The model can simulate not only steady-state responses at different insulin levels, but also concentration dynamics of major metabolites in the adipose tissue venous blood in accord with the in vivo data. Simulations indicate that (1) regulation of lipoprotein lipase (LPL) reaction is important when the intracellular lipolysis is suppressed by insulin; (2) intracellular diglyceride levels can affect the regulatory mechanisms; and (3) glyceroneogenesis is the dominant pathway for glycerol-3-phosphate synthesis even in the presence of increased glucose uptake by the adipose tissue. Reduced redox and increased phosphorylation states provide a favorable milieu for glyceroneogenesis in response to insulin. A parameter sensitivity analysis predicts that insulin-stimulated glucose uptake would be more severely affected by impairment of GLUT4 translocation and glycolysis than by impairment of glycogen synthesis and pyruvate oxidation. Finally, simulations predict metabolic responses to altered expression of phosphoenolpyruvate carboxykinase (PEPCK). Specifically, the increase in the rate of re-esterification of fatty acids observed experimentally with the overexpression of PEPCK in the adipose tissue would be accompanied by the up-regulation of acyl Co-A synthase.