In the cytoplasm, the insulin dissociates from the IR, and the dissociated insulin is degraded.
The recovery of the IR is accomplished either by the dissociation of insulin from the IR or via an internalization of the entire complex (endocytosis), which moves the complex into the cytoplasm. The cell maintains the capability to tight regulation by recycling of the phosphorylated IR homodimer. The binding of insulin to the IR triggers autophosphorylation of the intracellular IR domain, and the autophosphorylation initiates a signaling cascade for the regulation of glucose uptake. Upon a very fast binding event of insulin to the extracellular binding site of the IR homodimer, a slower rate-limiting phase occurs that manifests with a conformational change in the complex. Initially, insulin binds and activates the insulin receptor (IR) located as a homodimer in the membrane of the cell. Standard medical diagnosis of diabetes, insulin resistance, and other disorders of the energy metabolism include the testing of the glucose-insulin regulatory system, e.g., by an oral or intravenous glucose tolerance test. The secreted insulin triggers the uptake of glucose in adipose and muscle tissue. In response to elevated blood glucose levels, pancreatic beta cells located in the islets of Langerhans secrete insulin. Physical activity and insulin control the energy metabolism in mammalian cells. The Petri net approach confirms the experimental results of insulin-stimulated degradation of the insulin receptor, which represents a common feature of insulin-resistant, hyperinsulinaemic states. Moreover, we computed the quasi-steady states of these subnetworks and demonstrated that they are fundamental to understand the dynamic behavior of the system. The transition invariants decomposed the model into overlapping subnetworks of various sizes, which represent basic functional modules.
Additionally, using a graph-theoretical approach, we analyzed the structure of the regulatory system and demonstrated the close interrelation of structural network properties with the kinetic behavior. We developed a time-resolved, discrete model to describe stochastic dynamics and study the approximation of non-linear dynamics in the context of timed Petri nets. Thus, the recycling of the insulin receptor has been intensively investigated, experimentally as well as theoretically. Finally, the role of genetic variation in these transporters on drug exposure will be presented with implications for individual drug response.The insulin-dependent activation and recycling of the insulin receptor play an essential role in the regulation of the energy metabolism, leading to a special interest for pharmaceutical applications. In this review, we will summarize the current knowledge of the molecular functions and substrate profiles of cloned hepatic OCTs, OATPs and OATs and discuss recent advances in understanding variable expression and function. These mechanisms include transcriptional regulation, disease-dependent regulation and genetic variation. It is therefore important to elucidate mechanisms affecting membrane transporter expression and function. The well-documented interindividual variability of expression and activity of these transporters translates into interindividual variability in drug pharmacokinetics and drug response. Organic cation transporters (OCT), organic anion transporting polypeptides (OATP) and organic anion transporters (OAT) from the solute carrier (SLC) family play an essential role in the uptake of endogenous compounds and drugs into the hepatocytes and other cell types.
0 kommentar(er)
