Modelling Glucose Sensing In Enteroendocrine Cells

Abstract

Obesity has become a major problem in New Zealand and around the world. With traditional diets failing to deliver long term results and surgical or pharmacological methods being dangerous and expensive, a new approach to appetite regulation is needed. The Foods for Appetite Control group at Plant and Food Research Ltd. is working on developing food additives that may modulate the body‟s intrinsic mechanisms of appetite regulation. One of the research targets is the ileal brake, a mechanism that induces significant appetite suppression upon arrival of macronutrients into the distal small intestine (ileum). The focus of this research is on understanding the action of this mechanism, particularly in response to sweet substances. There are two pathways thought to be involved in the sensing of carbohydrates in the ileum. One is mediated by the glucose transporter SGLT1, while the other involves detection via sweet taste receptors located in the gastrointestinal tract. Both models involve cellular depolarisation and an increase in intracellular calcium leading to secretion of satiety hormones. In the SGLT1 pathway co-transport of sodium into the cell with glucose provides the stimulus for calcium influx via plasma membrane calcium channels. The sweet taste pathway is a classic G-protein cascade in which carbohydrate binding to the sweet taste receptor initiates calcium release from internal stores. Existing mathematical models of the pathway components were used to construct models of both pathways. Model parameters were determined by fitting to sodium transients, calcium dynamics and hormone secretion measured in immortalised cell line models. The experimental results could not be entirely explained by either pathway in isolation. It was therefore concluded that both mechanisms play some part in the activation of the ileal brake. It was found that the SGLT1 mediated pathway has a low saturation and can account for the release of appetite surprising hormones at low concentrations of glucose. The sweet taste receptor pathway was found to be sensitive across a range of glucose concentrations, and could be responsible for sweet taste concentration dependent appetite suppressing hormone release observed. The predicted kinetics of the two mathematical models mimic the experimental data, with significant differences between the two pathways.