Molecular mechanisms underlying nutrient detection by incretin-secreting cells

Abstract

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted postprandially from intestinal K- and L-cells, respectively. As incretins, these hormones stimulate insulin secretion from the pancreatic beta-cell, and have independently been implicated in the control of food intake and lipid metabolism. Whilst the enteroendocrine cells producing GIP and GLP-1 are therefore attractive targets for the treatment of diabetes and obesity, our understanding of their physiology is fairly limited. The mechanisms employed to sense the arrival of carbohydrate, fat and protein in the gut lumen have been investigated using organ perfusion techniques, primary epithelial cultures and cell line models. The recent development of mice with fluorescently labeled GIP or GLP-1-expressing cells is now enabling the use of single cell techniques to investigate stimulus-secretion coupling mechanisms. This review will focus on the current knowledge of the molecular machinery underlying nutrient sensing within K- and L-cells.

Fig. 1

Glucose triggered electrical activity in L-cells. a) Venus-labeled L-cells in an ileal tissue slice. Phase contrast image of intestinal cells in an ileal slice taken from a mouse transgenic for the yellow fluorescent protein Venus under the control of the proglucagon-promoter. Venus-fluorescence was excited at 480 nm. b) Venus positive cells in a 7 day old colonic epithelial culture. (left) phase contrast, scale bar 20 μm (right) fluorescence image overlay, with Venus (green) and DAPI (blue). c) Current clamp recording from a Venus positive cell in colonic epithelial culture. The cell was in perforated whole-cell current clamp. Application of 10 mm glucose, as indicated by the bar, resulted in an increased action potential firing rate from ∼0.3 to ∼1.1 Hz (see Reimann et al., 2008 for methodological details).

Fig. 2

Nutrient sensing machinery in K- and L-cells. As in other endocrine cells, secretion is triggered by an elevation in cytosolic Ca²⁺, which promotes fusion of hormone containing vesicles with the plasma membrane. This can be achieved in different ways: (i) Uptake: (left) Electroneutral uptake of nutrients increases metabolic flux and elevates cytosolic ATP-levels. These close ATP-sensitive potassium channels (K_ATP), permitting depolarization of the plasma membrane and opening of voltage gated sodium and calcium channels (Reimann et al., 2008), leading to an elevation in cytosolic Ca²⁺. (right) Electrogenic transport of nutrients directly depolarizes the plasma membrane and triggers all the subsequent steps. (ii) Alternatively nutrients might trigger hormone release without ever entering the cell by interaction with surface sensors. Examples for this type of detection involve activation of ligand gated ion channels (hence electrogenic (left) and feeding into the same triggering pathway as the depolarizing transport mechanisms) or (right) electroneutral activation of second messenger cascades. Examples of transporters/receptors identified in incretin-secreting cells are given for each of these mechanisms, with the colours corresponding to the macronutrients detected (see text for details).