Surgery for Obesity and Related Diseases ] (2015) 00–00

Original article

Detailed characterization of incretin cell distribution along the human small intestine Tiago P. Guedes, M.D.a, Sofia Martins, M.Sc.a, Madalena Costa, B.Sc.a, Sofia S. Pereira, M.Sc.a, Tiago Morais, M.Sc.a, Agostinho Santos, M.D., Ph.Db, Mário Nora, M.D.c, Mariana P. Monteiro, M.D., Ph.D.a,* a

b

Department of Anatomy, Unit for Multidisciplinary Research in Biomedicine (UMIB), ICBAS, University of Porto, Portugal Instituto Nacional de Medicina Legal e Ciências Forenses (IMNL) and Faculty of Medicine, University of Porto, Porto, Portugal c Department of General Surgery, Centro Hospitalar de Entre o Douro e Vouga, Portugal Received December 10, 2014; accepted February 12, 2015

Abstract

Background: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide 1 (GLP-1), are physiologic stimulants of insulin release that have been implicated in diabetes remission after bariatric surgery. The detailed distribution of incretin cells along the human small gut, so far unknown, is of utmost importance for the understanding of the metabolic changes observed after bariatric surgery because diabetes remission rate varies according to the type of anatomic rearrangement. Objective: To characterize the distribution of incretin producing cells along the human jejunum-ileum. Setting: Academic public institution. Methods: Small intestines (n ¼ 30) from autopsies were sampled every 20 cm along their entire length and tissue microarrays were constructed. The percentage of immunohistochemistry-stained cell areas for GLP-1, GIP, and chromogranin A at each segment length was quantified using a computer-aided analysis tool. Results: The percentage of stained area for GLP-1 immunoreactive cells was found to be significantly higher from 200 cm from Treitz ligament onward compared with the first 80 cm of the small intestine, whereas GIP immunoreactive cells were predominant expressed in the first 80 cm. In contrast, chromogranin A expression was constant along the entire jejunum-ileum. Conclusion: The uneven distribution of GLP-1–expressing cells, with a higher density from 200 cm of the jejunum-ileum, could contribute to explain the improvement of glycemic profile of diabetic patients observed after anatomic rearrangement of the intestinal tract, in particular when subjected to gastric bypass with longer biliopancreatic limbs. (Surg Obes Relat Dis 2015;]:00–00.) r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.

Keywords:

Incretins; Diabetes; L cells; K cells; Small intestine; Human

UMIB is funded by grants from Foundation for Science and Technology (FCT) POCTI/FEDER Portugal (Fcomp-01-0124-FEDER-015896). This work is co-funded by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through the FCT – Foundation for Science and Tecnology under the PROJECT FCOMP-010124-FEDER-027 651 and FCT Project PTDC/SAU-NMC/115700/2009. * Correspondence: Mariana P. Monteiro, Rua Jorge Viterbo Ferreira, 228, 4050-313 PORTO. E-mail: [email protected]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hormones responsible for the incretin effect [1], a phenomenon that consists in amplification of insulin secretion observed after oral glucose administration compared with the insulin excursion perceived after intravenous glucose administration [2–4]. GIP is a peptide produced by K-cells located along the

http://dx.doi.org/10.1016/j.soard.2015.02.011 1550-7289/r 2015 American Society for Metabolic and Bariatric Surgery. All rights reserved.

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small intestine mucosa [5], reported to be preferentially located in the duodenum and proximal jejunum [6], whereas GLP-1 is mainly produced by L-cells that have been found to be mostly located in the ileal and colonic mucosa [7], although likewise reported to be expressed by pancreatic α-cells [8]. In addition, a population of L/K–cells capable of producing both GIP and GLP-1 has also been recently identified [5,9]. GLP-1, besides being insulinotropic, promotes insulin gene expression and biosynthesis [10], suppresses glucagon secretion [11], and was reported to have direct effects on pancreatic β-cells’ growth and survival [12]. On the gastrointestinal (GI) tract, GLP-1 prolongs gastric emptying and slows glucose absorption, known as the ileal-brake phenomenon, which can further contribute to the reduction of postprandial glucose excursions [13,14]. When administered in supra-physiologic doses, GLP-1 also decreases food intake and weight in healthy [15], obese, and diabetic individuals [16,17]. Metabolic improvement and remission of type 2 diabetes after bariatric surgery has been widely reported in the past decades. Among the different hypothesis proposed for this glycemic improvement, the anatomic rearrangement of the GI tract and its putative impact on the incretin cell physiology has been greatly emphasized, by affecting the levels of hormones such as GLP-1, oxyntomodulin, PYY, and ghrelin, which help signal satiety and hunger to the human brain and to improve metabolic control [18–20]. The rearrangement created promotes the early arrival of undigested nutrients to the distal intestine, the so-called hindgut hypothesis, with possible overstimulation of L-cells and GLP-1 secretion [21]. In addition, the exclusion of the duodenum and jejunum from the alimentary flow, known as the foregut hypothesis, could also inhibit the secretion of a still unidentified “antiincretin factor” [22–24]. Although GIP secreting cells have been reported to predominate in the proximal small intestine [6], whereas GLP-1–secreting cells to occur mostly in the distal intestine [25], the detailed anatomy of the incretin system in the human small intestinal tube is yet to be fully defined. Most knowledge of incretin cell distribution derives from studies performed in the 1970s and 1980s, many of which used polyclonal antibodies to perform qualitative or semiquantitative assessment of immune reactive cell distribution [6,26,27] and used animal models, such as rats, pigs, cats, and dogs [5,26]. The very few studies that have used human tissue relied for their conclusions on small numbers of surgical biopsy specimens (n = 2–7) collected from the gastrointestinal tract of different individuals subjected to elective surgery for known neoplasia or chronic inflammatory bowel disease, in which, despite having been performed in microscopically disease-free specimens, the possibility of interference of the underlying medical condition in the incretin system, compared with healthy individuals, could not be completely excluded [5,6,25,27]. The detailed characterization of incretin-secreting cells

along the entire small intestine using monoclonal antibodies and computerized morphometric methods of assessment has only been recently performed in rats, indicating that the incretin cell distribution along the gastrointestinal might be different than previously assumed and also influenced by associated medical conditions [28]. In fact, L-cells were reported to be evenly distributed throughout the intestine, with their total numbers significantly increased in the diabetic obese Zucker rat compared with lean controls [28]. Knowledge of incretin cell distribution along the entire human small intestine could contribute to the understanding of the mechanisms underlying the metabolic improvement observed after bariatric surgery and have practical implications in the surgical treatment of obesity and diabetes, allowing the optimization of surgical procedures according to patient co-morbidities. Nonetheless, the evident importance of the incretin cell distribution along the entire human small intestine is so far unknown. The aim of the present investigation was, thus, to characterize in a systematic manner the relative distribution of GLP-1– and GIP-secreting cells along the entire human jejunum-ileum.

Materials and methods Sample selection and histologic procedures Small intestines (n ¼ 30) were harvested from forensic autopsies of adult cadavers. Only cadavers from individuals not registered in the Non-Donor National Register (RENNDA) and with permission granted by the National Institute of Forensic Medicine (INML) to perform the procedures were included, according to the local ethical regulations. Only cadavers without known or recognized oncologic, hepatic, pancreatic, or intestinal disease, previous abdominal surgery, or major macroscopic signs of putrefaction at the time of autopsies were included in the study. The small intestine was detached from the mesentery starting at the Treitz ligament until the ileocecal valve. The entire jejunum-ileum length was measured and 1-cm-wide sections comprising the whole diameter of the gastrointestinal tube were systematically collected at every 20-cm interval. Liver and pancreas fragments were also collected to be used as controls. Tissue sections collected were fixed in 4% buffered formaldehyde (Panreacs, Barcelona, Spain) for 24 hours before being subjected to routine automatic tissue processing procedures for light microscopy. After identifying the small intestinal mucosa in the hematoxilin-eosin–stained slides, paraffin blocks containing sequential 2-mm tissue cores representing all intestinal mucosa samples were created for each cadaver, using tissue microarrays (TMA) [29,30]. In all TMA blocks, liver and pancreatic tissue fragments were included to be used as negative and positive controls, respectively. Histologic 3-mm sections in Superfrost (Thermo Scientific,

Small Gut Incretin Cell Distribution / Surgery for Obesity and Related Diseases ] (2015) 00–00

Waltham, MA) slides were performed to be used for immunohistochemistry (IHC). Immunohistochemistry techniques For IHC detection of the secretory products of K- and L-cells, anti-GIP (ab30679, Abcam, Cambridge, UK) and anti–GLP-1 (ab22625, Abcam) specific antibodies were used, respectively. For the identification of neuroendocrine cells, antichromogranin A (ab17064, Abcam) specific antibody was used. Antigen retrieval of GIP and GLP-1 was performed in the microwave at 900 W in 10 mM citrate buffer (pH 6.0) with .05% Tween 20; whereas for chromogranin A, antigen retrieval was performed by boiling for 3 minutes. The endogenous peroxidase was blocked with a diluted solution of 3% hydrogen peroxide in methanol, followed by incubation in a normal serum for 30 minutes (GIP and chromogranin A) or a commercial blocking solution (Novocastra Leica™, Wetzlar, Germany) for GLP-1. All IHC techniques were performed on Sequenza rack in Coverplates (TermoScientific, Waltham, MA). The incubation with primary antibodies anti–GLP-1 (1:4000 dilution in 5% BSA), anti-GIP (1:100 in 5% BSA), and antichromogranin A (1:100 in 5% BSA) was performed overnight at 41C. Afterward, slides for chromogranin A and GIP detection were incubated for 30 minutes with biotinylated secondary antibody polyclonal swine antirabbit (1:200, EO35301-2, Dako, Glostrup, Denmark) and biotinylated secondary antibody polyclonal rabbit antimouse (EO35401-2, Dako), respectively. For GLP-1 detection, a commercial solution was used for 30 minutes after the primary antibody (Novocastra Leica™, postprimary, ready to use), followed by the avidin-biotin complex (ABC) method (1:100 dilution in 5% BSA; VectorLaboratories, Peterborough, UK) for antichromogranin A and GIP, or polymer ready to use (Leica Novocastra s) for anti–GLP1, both incubated for 30 minutes at room temperature. Diaminobenzidine was used as chromogenic (Dako), followed by nuclear staining with Harris hematoxylin. Data retrieval and analysis Microphotographs were taken of the all intestinal mucosa sections represented in the TMA using a camera and imaging software (Leica; DFC290, Qwin V3, Solms, Germany) attached to the optical microscope (Zeiss, Oberkochen, Germany) with a 200 magnification. The images were analyzed using the image processing software (ImageJ Java Script) and the percentage of stained area (%SA) by IHC was quantified. The data were aggregated in intervals and analyzed in 3 groups: from 0 to 80 cm, from 81 to 200 cm, and from 201 to 700 cm, based on the metrics commonly used in the gastric bypass surgical practice, which includes the creation of biliopancreatic limbs of 70 cm or 200 cm, in the classical Roux-en-Y gastric bypass

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(RYGB) and the long biliopancreatic limb bypass, also called metabolic gastric bypass, respectively. Because samples were initially selected based on the presence of macroscopic criteria of putrefaction, any tissue fragments with microscopic signs of autolysis were excluded from data analysis. Statistical analysis Results are presented as mean ⫾ standard error of the mean (mean ⫾ SEM) unless otherwise specified. Comparisons among groups were performed with the Kruskal– Wallis test (1-way ANOVA) followed by the Dunn post hoc test. When the comparison involved 2 independent groups, a Mann-Whitney U test was performed. To check whether there was interaction between 2 factors, multifactor ANOVA was used. Statistical significance was assumed with P o .05 for all tests. Data was analyzed using the software GraphPad Prism 5.04 (GraphPad Software Inc., La Jolla, CA) and IBM SPSS Statistics 21.0 (IBM Corp., Armonk, NY). Results The small intestine samples were obtained from adult cadavers (n = 30), which included 57% (n = 17) males and 43% (n = 13) females, with an average age of 65 ⫾ 3.5 years and mean body mass index (BMI) of 25.9 ⫾ .7 kg/m2, with the following distribution: 40% of normal weight individuals (BMI o25 kg/m2, n = 12), 50% with excess weight (BMI Z25 and o30 kg/m2, n = 15), and 10% obese (BMI 430 kg/m2, n = 3), a proportion that reflects the BMI distribution found in the general adult background population [31] (Table 1). The average length of the jejunum-ileum was 533.4 ⫾ 18.1 cm, with an individual variation in length of 320–702 cm. No significant differences or correlations between the length of the small intestine, body mass index, age, and gender were found. Immunoreactive cells to specific antibodies against chromogranin-A, GLP-1, and GIP were found to be present Table 1 Demographic and anthropometric characteristics of the individuals Characteristics

Mean ⫾ standard error of the mean

Age (yr) Male/female Weight (kg) BMI (kg/m2)

65 ⫾ 3.5 17:13 (56.7%:43.3%) 67.5 ⫾ 2.1 25.8 ⫾ .7 26 ⫾ 1.3 25.5 ⫾ .7 12 (40%) 15 (50%) 3 (10%) 533.4 ⫾ 18.1 27.4 ⫾ .9

Total Males Females Normal weight Overweight Obesity Intestinal length (cm) Collected fragments (n) BMI ¼ body mass index.

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along the entire human small intestine mucosa (Fig. 1). The percentage of stained area (%SA) for chromogranin A had no statistically significant differences (P 4 .05) throughout the small intestine length (Fig. 2 A) or particular predominance in the different groups (Fig. 2 B–D). The %SA for GLP-1 had a significant increase (P o .01) throughout the small intestinal length, being significantly higher at the 440-cm fragment compared with the 40-cm fragment (P o .05) (Fig. 3 A). The %SA for GLP-1 was also significantly higher in the distal small intestine intervals compared with the proximal intervals and in particular to the 0–200 cm interval (P o .001) (Fig. 3 B–D). The ratio between the %SA for GLP-1 and chromogranin A, used as a surrogate of relative proportion of GLP-1 cells among the entire enteroendocrine cells population, was also

significantly higher in the distal small intestine (201–700 cm) compared with proximal intestine (0–200 cm) (P o .001) (Fig. 4 A). The same pattern was found to be present in the grouped analysis by intervals comparing proximal and distal small intestine intervals (Fig. 4 B–D). The %SA for GIP had no statistically significant difference throughout the small intestine (P 4 .05) (Fig. 5 A), as well as the ratio between the %SA of GIP and chromogranin A (Fig. 5 B). However, the ratio of the %SA of GIP to GLP-1 was significantly higher in the proximal intestine (0–200 cm interval) compared with the distal intestine (201–700 cm interval) (Fig. 5 C) (P o .05), as well the ratio between the %SA of GLP-1 and GIP was found to be higher in the 0–80 cm interval compared with the 201–700 cm interval (P o .05) (Fig. 5 D).

Fig. 1. Small intestinal mucosa sample (A) stained with hematoxylin-eosin; (B) stained immunohistochemistry anti–chromogranin A; (C) anti–glucagon-like peptide-1 (anti–GLP-1); (D) anti–glucose-dependent insulinotropic polypeptide (anti-GIP) (200).

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Fig. 2. Percentage of stained area for chromogranin A in the different fragments of intestine at (A) 20-cm intervals; (B) grouped data at 100-cm intervals; (C) grouped data in 3 intervals from 0 to 80 cm, from 81 to 200 cm, and from 201 to 700 cm; (D) grouped data from 0 to 200 cm and 201 cm to 700 cm.

No significant differences or correlations were found in the expression of the different markers between the 2 genders as well as with the cadavers’ BMI or age. Discussion The fact that GIP-producing K-cells are predominant in the proximal small intestine, whereas GLP-1–producing L-cells are mainly located in the distal small intestine, has been known since the early 1970s. This knowledge, mostly derived from studies that used small intestinal biopsies obtained from duodenum and terminal ileum [5–7], has led to the assumption, not confirmed, that the L-cell density increased gradually from the duodenum to the distal ileum. It was the aim of this study to bring new data from a more detailed and systematic analysis of the incretin-producing neuroendocrine cells distribution along the entire human small intestine using samples of the human small intestine obtained from autopsies and not from surgical biopsy sampling from living individuals with known medical conditions, such as neoplasia and chronic inflammatory bowel disease, that could interfere with the results. Otherwise, the thoroughness of this work would not have been possible.

Using computerized morphometric methods to assess the cell distribution normalized for the mucosal area of the small intestine, which allowed an unbiased, accurate, and reliable quantification of the immune staining, the relative distribution of incretin-expressing cells along the small intestine has been characterized in detail. This work has revealed that the distribution of chromogranin A immunoreactive neuroendocrine cells presents no differences from the ligament of Treitz, at the beginning of jejunum, until the ileocecal valve at the end of the small intestine. This suggests that neuroendocrine cells have a constant and homogeneous distribution along the small intestine. In contrast, GLP-1 immunoreactive L-cells distribution was found to be higher in the distal small intestine, as previously described [25]. In addition, the present study documents for the first time that GLP-1 and GLP-1/chromogranin A ratio expressions, in the human small intestine of individuals without neoplastic or inflammatory bowel disease, are particularly increased from the 200-cm length of the small intestine onward. The distribution of GIP-immunoreactive K-cells was also found to be constant along the small intestine. Nevertheless, the ratio between GIP and GLP-1, an indicator of the

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Fig. 3. Percentage of stained area for glucagon-like peptide-1 (GLP-1) in the different segments of small intestine (A) at 20-cm intervals (*P o .05 versus 40 cm); (B) grouped data in 100-cm intervals (***P o .01 versus 0–100 cm); (C) grouped data from 0 to 80 cm, from 81 to 200 cm, and from 201 to 700 cm (*P o .05 and ***P o .001 versus 0–80 cm); (D) grouped data from 0 to 200 cm and from 201 cm to 700 cm (***P o .001).

relative proportion of the different incretin-secreting cells, had a predominance of GIP-secreting cells over GLP-1– secreting cells in the proximal region because of the increased GIP expression in the 0–80 cm interval compared with the 201–700 cm interval. These data reinforce the previously known relative location of GLP-1 cells in the distal small intestine and bring a new cutoff point at the length of small intestine at which the expression of GLP-1 is more pronounced, which has been reported to be at 200 cm from the Treitz ligament. Incretin hormones are known for their antidiabetic effects in increasing insulin secretion by pancreatic β-cells (GIP and GLP-1) [32,33] and decreasing glucagon secretion by pancreatic α-cells (GLP-1) [11,34], as well as other extrapancreatic effects that include the interaction with the pathways of appetite and satiety regulation [35] and the ability to alter gastrointestinal motility [14]. Bariatric surgery leads to rapid weight loss and an overall improvement of glycemic control or even clinical remission of diabetes in the short and long term [19,36]. Diabetes remission rate varies with the type of surgical procedure,

ranging from 48% after purely restrictive procedures to 95% after malabsorptive procedures, and 84% after mixed procedures, such as RYGB [19]. In addition, diabetes remission rates observed in patients undergoing RYGB variations using long biliopancreatic limbs, compared with the classic procedure, have been reported to be greater than those previously described [18–20,37,38]. Although β-cell status/function has a major contribution to the long-term metabolic results after bariatric surgery [39], the knowledge of the anatomy of the incretin system in the human small intestine, in particular the distribution of GLP-1–secreting cells herein defined, can contribute to explain some of the metabolic effects observed after anatomic modification of the GI tract in diabetic patients subjected to bariatric surgery, in particular, after gastric bypass procedures. It might also help to explain the potential differences observed between classic RYGB technique and variations to this technique in the magnitude of the antidiabetic effects [18,20]. Taking into account the data herein reported, the improvement of the glycemic profile observed after RYGB

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Fig. 4. Ratio between the percentage of area of marked of glucagon-like peptide-1 (GLP-1) to chromogranin A: (A) in the different segments of small intestine at 20-cm intervals (Kruskal-Wallis test, **P o .01); (B) grouped data in 100-cm intervals (*P o .05, ***P o .001 versus 0–100 cm); (C) grouped data from 0 to 80 cm, from 81 to 200 cm, and from 201 to 700 cm (*P o .05, ***P o .001 versus 0–80 cm); (D) grouped data from 0 to 200 cm and from 201 to 700 cm (***P o .001).

could probably be partially explained by the anatomic modification of the GI tract, leading to earlier exposure of L-cells to the nutrients and overstimulation, with increased secretion of GLP-1 and other anorexigenic peptides, such as PYY also secreted by the same cell population [21]. The relative distribution of GLP-1–immunoreactive cells in the small intestine found in the present study is consistent with the hindgut hypothesis [20]. The role of GLP-1 in the improvement of glucose metabolism after intestinal anatomy rearrangement has been recently reinforced by studies in rats submitted to duodenojejunal bypass and small bowel resection with the preservation of the terminal ileum, which displayed increased GLP-1 and improved glucose control [40,41]. Furthermore, the metabolic improvement after duodenojejunal bypass was found to be prevented by GLP-1 antagonism [41]. The knowledge of the detailed anatomy of the incretin system described in this study could contribute to optimize the bariatric surgical techniques according to patient comorbidities to maximize the possible metabolic benefits

derived from the anatomic rearrangement of the GI tract [42]. In addition, this information regarding the distribution of incretin-producing cells along the human small intestine could also provide possible targets for new pharmacologic agents capable of selective stimulation of the enteroendocrine cells on the intestinal segments with higher cell density, mimetizing the anatomic rearrangement of the intestinal tract. In conclusion, GLP-1–immunoreactive cells have a significantly increased expression distally to the 200 cm from Treitz ligament cutoff, which could contribute to explain the improvement of the glycemic profile and remission of type 2 diabetes observed after anatomic rearrangement of the gastrointestinal tract, in particular of patients who undergo RYGB with longer biliopancreatic limbs.

Disclosures The authors have no interests to disclose.

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Fig. 5. (A) Percentage of stained area for glucose-dependent insulinotropic polypeptide (GIP); (B) ratio between the percentage of area stained of GIP to chromogranin A in 20-cm intervals; (C) ratio between the percentage of area stained of marked GIP to glucagon-like peptide-1 (GLP-1) grouped from 0 to 80 cm, from 81 to 200 cm, and 201 to 700 cm (*P o .05 versus 0–80 cm); (D) ratio between the percentage of stained area between GLP-1 and GIP grouped from 0 to 200 cm and from 201 to 700 cm (*P o .05).

Acknowledgments The authors would like to acknowledge Prof. Regina Silva for providing the equipment required to perform the tissue microarrays, and Angela Moreira and Ana Pinto for providing technical support to the histology studies.

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Detailed characterization of incretin cell distribution along the human small intestine.

Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are physiologic stimulants of insulin relea...
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