Glucose sensing neuronal networks that control pancreatic islet hormone secretion and feeding behavior

Abstract

The control of glucose homeostasis involves complex mechanisms to correct hyperglycemia following glucose absorption and to prevent hypoglycaemia development in the postabsorptive period or during fasting. Because the brain uses glucose as an almost exclusive source of metabolic energy, many hypoglycemia sensing cells are located centrally. When activated, they trigger a hormonal response to restore normoglycemia, in particular by increasing the secretion of glucagon and epinephrine. This response is deregulated or even disappears during insulin treatment of diabetes, making iatrogenic hypoglycaemia a major threat to the diabetic patients. Central glucose sensing neurons are known to also regulate insulin secretion and beta-cell mass through the control of parasympathetic nerve activity. In addition to these homeostatic regulations of hormone secretion required for the minute-to-minute control of glycemia, central hypoglycaemia detection systems also control the motivation to seek and consume glucose-containing food in order to replenish the body glucose stores. My laboratory is identifying the mechanisms of central glucose detection, the cells involved, the neuronal circuits they form and the physiological functions they control.

These studies are in part focused on the study of neurons expressing the glucose transporter Glut2 and the glucose phosphorylating enzyme glucokinase. These studies lead us to uncover neuronal circuits controlling glucagon secretion in response to hypoglycaemia. Novel genes involved in hypoglycemia detection and glucagon secretion are also being identified through unbiased genetic screens of genetic reference populations (BXD mice). Our studies combine electrophysiological, optogenetic and physiological investigations. They provide a new description of the network of glucose sensing neurons that control metabolic health and are leading to new studies to investigate the deregulation of these mechanisms in metabolic diseases. Essential parts of these studies will be presented.