Nutrient detection by incretin hormone secreting cells

Abstract

The hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulintropic polypeptide (GIP) are secreted after a meal. Like other enteroendocrine hormones they help to orchestrate the bodies' response to the availability of newly absorbable nutrients and are noteworthy as they stimulate postprandial insulin secretion, underlying what is known as the incretin effect. GLP-1-mimetics are now widely used in the treatment of type 2 diabetes and advantages over older insulinotropic therapies include weight loss. An alternative treatment regime might be the recruitment of endogenous GLP-1, however, very little is known about the physiological control of enteroendocrine responses. This review focuses on the molecular mechanisms to detect nutrient arrival in the gut that have been implicated within the incretin secreting cells.

Fig. 1

Incretin secreting cells. A) Glucose dependent insulinotropic polypeptide (GIP) is secreted from enteroendocrine K-cells found in highest density in the duodenum, whereas glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L-cells found in highest density in the more distal intestine, the ileum and colon. B) K- and L-cells are both “open-type” cells, making direct contact with the intestinal lumen via their apical microvilli, presumably enabling them to directly assess the content composition. Proximally located cells are in an ideal position to assess postprandial nutrient availability, whilst stimulation of more distally located cells probably also involves humoral and/or neural signals (arrow in A). C) Phase contrast image of intestinal cells in a slice through colonic crypts from a mouse transgenic for the yellow fluorescent protein Venus under the control of the proglucagon-promoter. Venus-fluorescence was excited at 480 nm and the two positive cells in the field of view are indicated by the white arrows (photograph by Gareth Rogers).

Fig. 2

Current model of L-cell nutrient sensing. Nutrients can be taken up by electrogenic transport at the apical pole of the cell (e.g. SGLT-1 for glucose). This directly depolarises the plasma membrane and triggers action potentials, eventually opening voltage-gated Ca²⁺-channels. The subsequent rise in cytosolic Ca²⁺ triggers fusion of GLP-1 containing vesicles. Alternatively intracellular Ca²⁺ might be raised downstream of the activation of G_q-coupled receptors (e.g. FFAR2/GPR43 for propionate), which would also be expected to activate protein kinase C. Strong stimulation of GLP-1 secretion is, however, also seen upon elevation of cyclic adenosine monophosphate (cAMP), which physiologically would be expected to occur upon stimulation of G_s-coupled receptors such as GPR119 and GPBAR.