Enteroendocrine K and L cells in healthy and type 2 diabetic individuals

Abstract

Aims/hypothesis Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. Methods In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age-and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. Results Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucosedependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. Conclusions/interpretation Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4450-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

EJE PRIZE 2018: A gut feeling about glucagon

“…In order to explore this hypothesis, we sampled jejunal biopsies from patients with type 2 diabetes (exhibiting grossly postprandial hyperglucagonaemic responses) and matched healthy controls and were able to show (1) the presence of PC2 mRNA and immunohistochemical PC2-positive enteroendocrine cells, (2) immunohistochemical co-localisation of PC2 and the proglucagon product GLP-1 and (3) 50% more PC2-positive cells in the jejunal epithelium of type 2 diabetic patients as compared to healthy controls (87). We confirmed these findings in a study investigating jejunal mucosa biopsies (obtained during Roux-en-Y gastric bypass surgery) from obese patients with type 2 diabetes and obese non-diabetic patients, respectively (88), and furthermore, we recently observed significantly greater expression of the gene encoding PC2, PCSK2, in the small intestine of individuals with type 2 diabetes compared with healthy individuals (4). Recent investigations by Jorsal and colleagues including immunohistochemistry using a new highly glucagon-specific monoclonal antibody and peptide extraction with application of a mass spectrometry-validated sandwich ELISA on human gastric mucosa biopsies found no or negligible signs of glucagon (Jorsal et al, unpublished observation).…”

“…For almost a century, the 29 amino acid hormone glucagon, derived from the precursor proglucagon encoded by the glucagon gene (1), has been considered a pancreas-specific hormone secreted from alpha cells in the islets of Langerhans (2,3). Of importance for the findings outlined in the present paper, proglucagon is also produced in enteroendocrine L cells found in the intestinal epithelium (4). In contrast to pancreatic alpha cells in which proglucagon is processed to 29 amino acid glucagon by prohormone convertase 2 (PC2), processing of proglucagon in enteroendocrine L cells is undertaken by PC1/3 leading to several active peptides including the glucose-lowering and satiety-inducing glucagonlike peptide 1 (GLP-1) and the intestinotrophic and glucagonotropic glucagon-like peptide 2 (GLP-2) (5) ( Fig.…”

Incretins in obesity and diabetes

“…In isolated perfused rat pancreas, GIP increased glucagon secretion at glucose concentration less than 5.5 mM (100 mg/dL), while it increased insulin secretion at glucose levels greater than 5.5 mM. 84 In addition to enteroendocrine L cells, GLP-1 protein has also been found in the nucleus of the solitary tract of the brain stem of rats, monkeys, and humans, and in taste cells within taste buds. 71 In type 2 diabetes, however, GIP administered at a concentration five times that of physiological levels increased glucagon secretion, which offset any glucose-lowering effects of GIP through insulin secretion.…”

“…82,83 GLP-1 is localized to L cells mainly within the crypts and mid-zones of glands with increasing density from the duodenum to the colon. 84 In addition to enteroendocrine L cells, GLP-1 protein has also been found in the nucleus of the solitary tract of the brain stem of rats, monkeys, and humans, and in taste cells within taste buds. [85][86][87] Additionally, GLP-1 production occurs in α cells within islet of Langerhans.…”

Augmented GLP-1 Secretion as Seen After Gastric Bypass May Be Obtained by Delaying Carbohydrate Digestion

“…The exact mechanisms behind the exaggerated gut hormone release are incompletely understood, but dietary carbohydrates, as compared to fat and protein, seem to be particularly powerful in stimulating L-cell secretion after the surgery (8,9). The enhanced GLP-1 secretion after RYGB is thought to arise from the delivery of ingested carbohydrates to the distal intestine (10,11), where L-cell density is high (12)(13)(14). In addition, the accelerated glucose absorption after the surgery may play a major role since enteroendocrine cells appear to respond to the glucose absorption rate rather than to the presence of glucose in the intestinal lumen (15)(16)(17)(18).…”