Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells.

The enteroendocrine K and L cells are responsible for secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like-peptide 1 (GLP-1), whereas pancreatic α-cells are responsible for secretion of glucagon. In rodents and humans, dysregulation of the secretion of GIP, GLP-1, and glucagon is associated with impaired regulation of metabolism. This study evaluates the consequences of acute removal of Gip- or Gcg-expressing cells on glucose metabolism. Generation of the two diphtheria toxin receptor cellular knockout mice, TgN(GIP.DTR) and TgN(GCG.DTR), allowed us to study effects of acute ablation of K and L cells and α-cells. Diphtheria toxin administration reduced the expression of Gip and content of GIP in the proximal jejunum in TgN(GIP.DTR) and expression of Gcg and content of proglucagon-derived peptides in both proximal jejunum and terminal ileum as well as content of glucagon in pancreas in TgN(GCG.DTR) compared with wild-type mice. GIP response to oral glucose was attenuated following K cell loss, but oral and intraperitoneal glucose tolerances were unaffected. Intraperitoneal glucose tolerance was impaired following combined L cell and α-cell loss and normal following α-cell loss. Oral glucose tolerance was improved following L cell and α-cell loss and supernormal following α-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and α-cell loss as well as isolated α-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of α-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and α-cells.

A stem cell marker-expressing subset of enteroendocrine cells resides at the crypt base in the small intestine.

The spatial orientation of the enteroendocrine cells along the crypt-villus axis is closely associated with their differentiation in the intestine. Here we studied this relationship using primary duodenal crypts and an ex vivo organoid system established from cholecystokinin-green fluorescent protein (CCK-GFP) transgenic mice. In the primary duodenal crypts, GFP+ cells were found not only in the upper crypt but also at the crypt base, where the stem cells reside. Many GFP+ cells below +4 position were positive for the putative intestinal stem cell markers, leucine-rich repeat-containing G protein-coupled receptor 5, CD133, and doublecortin and CaM kinase-like-1, and also for the neuroendocrine transcription factor neurogenin 3. However, these cells were neither stem nor transient amplifying precursor cells because they were negative for both Ki-67 and phospho-Histone H3 and positive for the mature endocrine marker chromogranin A. Furthermore, these cells expressed multiple endocrine hormones. Tracking of GFP+ cells in the organoids from CCK-GFP mice indicated that GFP+ cells were first observed around the +4 position, some of which localized to the crypt base later in the culture period. These results suggest that a subset of enteroendocrine cells migrates down to the crypt base or stays localized at the crypt base, where they express stem and postmitotic endocrine markers. Further investigation of the function of this subset may provide novel insights into the genesis and development of enteroendocrine cells as well as enteroendocrine tumorigenesis.

Classification and functions of enteroendocrine cells of the lower gastrointestinal tract.

With over thirty different hormones identified as being produced in the gastrointestinal (GI) tract, the gut has been described as 'the largest endocrine organ in the body' (Ann. Oncol., 12, 2003, S63). The classification of these hormones and the cells that produce them, the enteroendocrine cells (EECs), has provided the foundation for digestive physiology. Furthermore, alterations in the composition and function of EEC may influence digestive physiology and thereby associate with GI pathologies. Whilst there is a rapidly increasing body of data on the role and function of EEC in the upper GI tract, there is a less clear-cut understanding of the function of EEC in the lower GI. Nonetheless, their presence and diversity are indicative of a role. This review focuses on the EECs of the lower GI where new evidence also suggests a possible relationship with the development and progression of primary adenocarcinoma.

GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness.

The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'.

Classification of gastric endocrine cells at the light and electron microscopical levels.

This review discusses the current concepts for the classification of gastric endocrine cells subdivided according to the type of mucosa in which they are located. In the oxyntic mucosa, the most important cell type is the ECL cell, involved in the synthesis and secretion of histamine. Proteins involved in many aspects of the biology of ECL cells including the response to the gastrin stimulus, membrane transport and docking, prevention of apoptosis, calcium homeostasis, autocrine activity, and maintenance of the differentiated cell phenotype have been localized to this cell type. Other cells of the oxyntic mucosa include: the D and EC cells producing somatostatin and serotonin, respectively, delivered through long cell processes; the X (or A-like) cells, possibly producing endothelin; and the D(1) and P cells of unknown function and possibly representing morphological variants of other cell types. In the antral mucosa, the three important cell types are represented by: the gastrin-producing G cells; the somatostatin-producing D cells, which are anatomically and functionally associated with G cells; and the serotonin-producing EC cells, which are located at the bottom of antral glands.

[Endocrine cells in the mucosal epithelium of the porcine large intestine]. / Endokrinotsity épiteliia slizistoi obolochki tolstoi kishki svin'i.

Using the methods of light and electron microscopy, mucosal epithelium in the colon of adult pigs was studied with special reference to the amount and distribution of endocrine cells. The total amount of endocrine cells tended to increase caudally. Four types of these cells were demonstrated including EC, L, D and D1. The proportion of EC-cells was found to fall from cranial segments of the colon to caudal ones. According to the results of ultrastructural analysis, endocrine cells in the mucosal epithelium of porcine colon, as well as the cells of the adjacent tissues, are in the state of functional exertion.

The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.

Intestinal hormones are key regulators of digestion and energy homeostasis secreted by rare enteroendocrine cells. These cells produce over ten different hormones including GLP-1 and GIP peptides known to promote insulin secretion. To date, the molecular mechanisms controlling the specification of the various enteroendocrine subtypes from multipotent Neurog3(+) endocrine progenitor cells, as well as their number, remain largely unknown. In contrast, in the embryonic pancreas, the opposite activities of Arx and Pax4 homeodomain transcription factors promote islet progenitor cells towards the different endocrine cell fates. In this study, we thus investigated the role of Arx and Pax4 in enteroendocrine subtype specification. The small intestine and colon of Arx- and Pax4-deficient mice were analyzed using histological, molecular, and lineage tracing approaches. We show that Arx is expressed in endocrine progenitors (Neurog3(+)) and in early differentiating (ChromograninA(-)) GLP-1-, GIP-, CCK-, Sct- Gastrin- and Ghrelin-producing cells. We noted a dramatic reduction or a complete loss of all these enteroendocrine cell types in Arx mutants. Serotonin- and Somatostatin-secreting cells do not express Arx and, accordingly, the differentiation of Serotonin cells was not affected in Arx mutants. However, the number of Somatostatin-expressing D-cells is increased as Arx-deficient progenitor cells are redirected to the D-cell lineage. In Pax4-deficient mice, the differentiation of Serotonin and Somatostatin cells is impaired, as well as of GIP and Gastrin cells. In contrast, the number of GLP-1 producing L-cells is increased concomitantly with an upregulation of Arx. Thus, while Arx and Pax4 are necessary for the development of L- and D-cells respectively, they conversely restrict D- and L-cells fates suggesting antagonistic functions in D/L cell allocation. In conclusion, these finding demonstrate that, downstream of Neurog3, the specification of a subset of enteroendocrine subtypes relies on both Arx and Pax4, while others depend only on Arx or Pax4.

Nutrition and L and K-enteroendocrine cells.

PURPOSE OF REVIEW: The review highlights the influence of nutrients over the secretion of several hormones produced by enteroendocrine cells in the gastrointestinal tract that secrete incretin hormones. These hormones influence glucose homeostasis; food intake; gastric, pancreatic and hepatic secretions; and gastric and intestinal motility, and these aspects are summarized in this review. RECENT FINDINGS: This study provides an overview of recent advances in our understanding of the physiology of the incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as of oxyntomodulin. A better understanding of the secretion and action of these hormones at their receptors was made possible by new techniques that allow investigation of individual enteroendocrine cells. SUMMARY: The better understanding of the function of the gastrointestinal incretin hormones and their implications for improving glucose homeostasis and perhaps influencing food intake and appetite as well, new research in this area will help combat metabolic diseases such as type 2 diabetes and obesity.

Células endócrinas do sistema gastroenteropancreático: conceitos, distribuição, secreções, ação e controle / Endocrine cells of the gastroenteropancreatic system: concepts, distribution, secretions, action and regulation / Células endocrinas del sistema gastroenteropancreástica:conceptos, distribuición, secreciones, acción y regulación

RESUMO: Os sistemas nervoso e endócrino estão integrados para controlar os eventos motores e secretores, envolvidos no processo de digestão e absorção dos nutrientes no trato gastrointestinal (TGI). Nesta revisão, foi enfocado o sistema gastroenteropancreático (GEP), como um sistema endócrino difuso, constituído por células endócrinas dispersas ao longo do epitélio de revestimento do trato gastrointestinal e no pâncreas.Sobre esse sistema foram abordados conceitos e formas de classifi cação, distribuição das células endócrinas ao longo do TGI, principais tipos de secreção dessas células e sua ação sobre os eventos da digestão, além de alguns processos regulatórios que controlam tal secreção

RESUMEN: Los sistemas nervioso y endocrino interactúan para el control de la motilidad y la secreción involucradas en los proceso de digestión y absorción de los nutrientes en el tracto gastrointestinal (TGI). Esta revisión fue enfocada en el sistema gastroenteropancreatico (GEP), el cual se caracteriza por ser un sistema endocrino difuso formado por células endocrinas dispersas a lo largo del epitelio de revestimiento del TGI y en el páncreas. Sobre este sistema fueron abordados conceptos y formas de laclasifi cación, así como la distribución de las células endocrinas a lo largo de TGI, principales tipos de secreción de éstas células y su acción sobre los eventos de la digestión, además de algunos procesos reguladores que controlan esa secreción.

ABSTRACT: The nervous and endocrine systems are integrated to control the motor and secretor events which are involved in the digestion and absorption process of the nutrients in the gastrointestinal tract (GIT). In this revision the gastroenteropancreatic (GEP) system was focused as a diffuse endocrine system constituted by endocrine cells dispersed along the epithelial lining of the gastrointestinal tract and in the pancreas. On this system, concepts and forms of classifi cation were discussed, as well as the distribution of the endocrine cells along the GIT, main types of secretion of these cells and their action on the events of the digestion, besides some regulatory processes which control such secretion