Modelling of insulin secretion: from beta-cell physiology to sulphonylurea-mediated insulin secretion
Cronier, D. (1,5), E. Grenier (2), M. Lecomte (3), V. Autier (3), B. Ladstetter (4), L. J. Aarons (5), and J.P. Boissel (1)
1: RTH School of Medicine, Claude Bernard University and Institute for Theoretical medicine, Lyon, France. 2: ENS and Institute for Theoretical Medidine, Lyon, France. 3: MERCK Sante Research Center, Chilly Mazarin, France> 4: Global Nonclinical DMPK, MERCK KGAa, Grafing, Germany. 5: School of Pharmacy and pharmaceutical Sciences, University of Manchester, Manchester, UK.
One major aspect of the treatment of Non Insulin Dependent Diabetes Mellitus is the enhancement of insulin secretion by sulphonylureas or glinides. These act by activating the distal part of the insulin secretion pathway. However, these drugs have a number of side effects and there is now a general consensus for the need of new drugs that enhance insulin secretion more efficiently.
A prerequisite to the discovery of such new drugs is a better qualitative and quantitative understanding of both the insulin secretion pathway and its interaction with insulin secreting drugs. Therefore, we have developed a modelling framework describing the activity of SU upon insulin secretion. This framework consists of a first model describing the cellular events involved in the beta-cell insulin response to glucose. This model is then connected to a second model describing the local interaction between SU and their pharmacological target and finally to a PBPK model describing in situ SU concentration.
This whole integrated model is first able to reproduce the physiological insulin response of the endocrine pancreas to a glucose stimulus. Indeed, the simulated variables, especially the metabolic and electrophysiological oscillating patterns, as well as the biphasic time course of insulin secretion are consistent with the literature and experimental data. Secondly, when connected to SU pharmacokinetics, this model is also able to reproduce the different patterns of insulin secretion under SU stimulation as well as the uncoupling between glucose stimulation and insulin secretion, responsible for SU-mediated hypoglycaemia.
In conclusion, this model is one of the first examples of a whole integrated model including every major cellular event involved in the insulin response to glucose. Furthermore, its ability to reproduce both the physiological insulin response to glucose and the SU-mediated insulin secretion makes it an effective tool in the study of beta-cell physiology and in the investigation of new pharmacological targets.