The effect of ileal interposition surgery on enteroendocrine cell numbers in the UC Davis type 2 diabetes mellitus rat
Introduction
The marked effect of bariatric surgery and gut resection on intestinal morphology has been a matter of intense investigation for more than half a century [1], [2]. The numerous intestinal adaptations include significant alterations in crypt cell proliferation, lengthening of the villi, increases in the crypts-to-villi ratio and an overall increase in the mucosal weight [3]. The responsible factors may be diverse. Peptides, growth factors, cytokines, blood flow and neural influences have all been suggested to play important roles in causing these changes in the intestine [4], [5], [6], [7].
Recently, much attention has been paid to gastrointestinal (GI) peptides such as glucagon-like-peptide-2 (GLP-2) which function as a trophic gut hormone [8], [9]. The intestinotrophic effects of GLP-2 have led to the development and recent approval of a GLP-2 analog for the treatment of short bowel syndrome [10], [11]. GLP-2 is co-secreted with both GLP-1 and oxyntomodulin from the processing of proglucagon in the intestinal L-cells [12], [13] distributed throughout the intestinal tracts with the highest numerical density being in the distal ileum [14], [15]. In addition to proglucagon, L-cells are also known to express peptide tyrosine tyrosine (PYY) which leads to a marked inhibition of food intake in rodents and man [16], [17]. Recently, we demonstrated that Roux-en-Y gastric bypass (RYGB) in Wistar rats is coupled with an increased number of intestinal L-cells, as well as increased preproglucagon and PYY mRNA expression, thereby providing a plausible explanation for the powerful effect of this kind of surgery on body weight and resolution of type 2 diabetes [18]. Elevated post-prandial levels of GLP-1 and PYY are also a general trait of ileal interposition (IT) surgery [19] with associated effects on glucose homeostasis [19], [20], [21], [22]. However, relatively little is known about this kind of surgery on endocrine cell numbers.
Due to their important clinical application for the treatment of type 2 diabetes and potentially also body weight [23], [24] L-cell derived peptides has received increased focus. However, a number of other enteroendocrine (EEC) cell types have important roles in digestive physiology and obesity related diseases (for review, see [25]). It is therefore of potential importance to understand the quantitative and qualitative alterations in those cell types as well to facilitate our understanding of the metabolic benefits and the implications of bariatric surgery. EECs have traditionally been divided into different subtypes based on their hormonal content [26], [27] but although their secretory phenotype may vary, they also share a number of common morphological characteristics. This includes the presence of secretary vesicles, components of which can be exploited as general marker for EECs [28]. Double immunohistochemistry against chromogranin A, a matrix-soluble glycoprotein commonly found in secretary vesicles [28], and a number of different peptidergic hormones have demonstrated that chromogranin A co-localizes not only with serotonin (5-HT positive cells), but also with cholecystokinin, neurotensin and PYY/GLP-1 positive L-cells in the GI tract, thereby supporting the use of chromogranin A as a general marker for EECs [29].
In this study we aimed to examine changes in intestinal volume, intestinal surface area and the total number of chromogranin A immunoreactive EECs, as well as specific subtypes, following IT surgery in the pre-diabetic UCD-T2DM rat model [30], [31]. In this animal model, IT surgery has been shown to improve glucose and lipid metabolism and delay the onset of diabetes potentially associated with increased GLP-1 and PYY secretion, increased circulating bile acid concentrations, decreased endoplasmatic reticulum (ER) stress signaling and improved beta-cell function [31].
However, the effect of IT surgery on gut morphology and EEC numbers has not previously been assessed using stereological methods.
Section snippets
Animals
The present study is based on tissues from a published in vivo study [31].Animals were housed individually in hanging wire cages in the animal facility at the Department of Nutrition at the University of California, Davis (UCD), USA and maintained on a 14:10-hour light–dark cycle. At two months of age rats underwent sham (n = 5) or IT surgery (n = 5) and were terminated 1.5 months later for tissue collection. All animals received ground chow (no. 5012; Ralston Purina, Belmont, CA, USA). Food intake
Body weight and hormone levels
A detailed description of the in vivo data has been published previously [31]. These data showed no significant change in either food intake or bodyweight throughout the 1.5 month duration of this study (Table 1). HbA1c levels were unchanged 1.5 months following IT surgery, and only minor improvements were noted in terminal fasting plasma glucose (Table 1). Hence, no animals developed frank diabetes during the post-surgical period. Fasting insulin levels were significantly lower in the IT group (
Discussion
The present study aimed to investigate the short-term effect of IT surgery on intestinal morphology and EEC numbers in pre-diabetic UCD-T2DM rats. Using mathematically unbiased stereological methods we report that IT surgery led to a marked increase in volume and intraluminal surface area in the transposed and adjacent distal region of the ileum, which was coupled to an increased number of EECs. The increase in the total number of EECs, as well as in individual counts of GLP-2, CCK, 5-HT and
Conflict of interest statement
CFH and EV are currently employed by Gubra. NV and JJ are main shareholders of Gubra. PSA and BPC have no conflict of interest. PH has nothing to declare.
Funding
This research was supported by the Danish Agency for Science, Technology and Innovation by a personal stipend to CFH. This research was also supported by NIH grants 1RC1DK087307-01 and R01DK095960 and the University of California, Davis Veterinary Scientist Training Program to BPC and PJH.
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2021, AppetiteCitation Excerpt :The effects of bariatric surgery on GLP-2 regulation have been explored. A significant increase in GLP-2 levels was observed in rats after ileal interposition surgery (Hansen et al., 2014). Cazzo et al., in a human prospective study, saw an increase in GLP-2 levels 12 months after surgery (Cazzo et al., 2016).
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2017, Molecular Aspects of MedicineCitation Excerpt :Once believed to be apically-expressed, the location of TGR5 within the intestine has been disputed and has been suggested to be present on the basolateral membrane (Brighton et al., 2015); if proven correct, this finding would significantly change the physiological understanding of how bile acids couple to incretin secretion. Another important factor relates to intestinal villous hypertrophy, commonly observed in numerous rodent models of RYGB (le Roux et al., 2010) and ileal interposition (C. F. Hansen et al., 2014; Kohli et al., 2010). Similar findings of hypertrophy in the small intestines were previously described in bariatric patients (Dudrick et al., 1977; Spak et al., 2010).
The endogenous preproglucagon system is not essential for gut growth homeostasis in mice
2017, Molecular MetabolismCitation Excerpt :Thus, it cannot be ruled out that the delivery of macronutrients to the more distal parts of the gut following RYGB may induce higher local release of GLP-1/GLP-2, which could further enhance GLP-1R/GLP-2R trophic signaling to promote hypertrophy of the alimentary and common limb. This notion is also supported by the finding of marked gut hypertrophy following ileal interposition surgery, i.e. in a condition where the ileal segment is transposed to more proximal parts of the gut [83]. Collectively, our data suggest that endogenous GLP-1R signaling does not play an essential role in intestinal growth homeostasis, whereas loss of the GLP-2R produces modest reductions in gut mucosal volume.
Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice
2017, Molecular MetabolismCitation Excerpt :These procedures can also produce a remarkable resolution of type 2 diabetes within days after surgery, long before any significant weight loss takes place, leading some to perform bariatric surgery to treat diabetes even in non-obese individuals [26–28]. The altered flow of nutrients in the gut following bariatric surgery may be associated with adaptive changes in the enteroendocrine cell populations [29–31] and altered production of gastrointestinal hormones, including increases in plasma GIP and GLP-1 levels post surgery [28,32,33]. Changes in basal and/or postprandial release of gut hormones are among the potential mechanisms of improved glucose homeostasis and weight loss following bariatric surgery [34,35].
The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes
2015, Cell MetabolismCitation Excerpt :Moreover, the common limb is also the region in which the greatest morphological changes occur in terms of increased villus height and greater overall surface area (le Roux et al., 2010). A similar effect on increasing enteroendocrine cell numbers is seen after ileal interposition (Hansen et al., 2014). Thus, at least with VSG, but we believe with other surgeries as well, an alternative explanation to the distal gut hypothesis is that chronically high gastric emptying rates drive adaptive enteroplasticity.
Laparoscopic diverted resleeve with ileal transposition for failed laparoscopic sleeve gastrectomy: A case report
2015, Surgery for Obesity and Related DiseasesCitation Excerpt :Beneficial metabolic effects can be observed in addition to long-term weight loss. Ileal transposition may act by mimicking the distal gut peptides response to an oral nutrient load, via peptide YY, glucagon-like peptide-1, and oxyntomodulin, and can be the surgery of choice in selected patients [8–10]. In other words, there is an important modulatory neuroendocrine aspect of the surgical intervention performed.