Intestinal hormone secretion and action
The intestinal epithelium is scattered with enteroendocrine cells, which, although only accounting for less than 1% of this tissue, can be considered the biggest endocrine organ in the body. Some of the peptides secreted have important regulatory roles for metabolism; glucagon-like peptide-1 (GLP-1) for example, secreted from intestinal L-cells, boosts postprandial insulin secretion and is the basis for mimetics with improved plasma half-life now widely used in the treatment of diabetes. GLP-1 and the co-secreted polypeptide YY also reduce food intake, and elevated plasma levels of these hormones correlate with the positive effects of gastric bypass surgery for the treatment of obesity.
Our lab, which works in close collaboration with Fiona Gribble’s group, has in recent years made a number of transgenic mice in which cells expressing specific hormones are tagged by fluorescent reporters or Cre-recombinase, allowing identification and/or manipulation of these cells. We use electrophysiological and live-cell imaging techniques to identify the mechanisms underlying the secretion of GLP-1, glucose-dependent insulinotropic peptide (GIP) and somatostatin, with the aim to eventually therapeutically manipulate hormone release for the treatment of diabetes and obesity. More recently we have started to make mice tagging the cells expressing the receptor for GLP-1, which we found to be expressed on enteric neurons and vagal and spinal afferent fibres with somata in the nodose and dorsal root ganglia, respectively. As these would be exposed to high GLP-1 levels secreted from nearby L-cells before the hormone is exposed to inactivation by dipeptidyl peptidase 4 (DPP4) in the vasculature, they are likely to play important roles in the enteroendocrine system and we have begun to characterise them further.
Diakogiannaki, E., Pais, R., Tolhurst, G., Parker, H.E., Horscroft, J., Rauscher, B., Zietek, T., Daniel, H., *Gribble, F.M. and *Reimann, F. Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor. Diabetologia 56, 2688-2696 (2013). *joint communicating
Moss, C.E., Marsh, W.J., Parker, H.E., Ogunnowo-Bada, E., Riches, C.H., Habib, A.M., Evans, M.L., *Gribble, F.M. and *Reimann, F. Somatostatin Receptor 5 and Cannabinoid Receptor 1 activation inhibit secretion of glucose-dependent insulinotropic polypeptide from intestinal K-cells. Diabetologia 55, 3094-3103 (2012). * joint communicating
Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., Cameron, J., Grosse, J., *Reimann, F. and *Gribble, F.M. Short chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein coupled receptor FFAR2. Diabetes 61, 364-371 (2012). * joint communicating