ORIGINAL CONTRIBUTIONS

The Impacts of Gastroileostomy Rat Model on Glucagon-like Peptide-1:a Promising Model to Control Type 2 Diabetes Mellitus

Behrouz Keleidari1 & Rastin Mohammadi Mofrad2 & Shahab Shahabi Shahmiri1 & Mohammad Hossein Sanei3 &Mohsen Kolahdouzan4 & Erfan Sheikhbahaei5

# Springer Science+Business Media, LLC, part of Springer Nature 2018

AbstractBackground One of the new current treatment options for Diabetes Mellitus is about increasing glucagon-like peptide-1 (GLP-1)activity. GLP-1 with its incretin effect showed major role in glucose homeostasis. Gastroileostomy can increase GLP-1 secretionby rapid delivery of undigested food to the terminal ileum. We studied the early effects of a gastroileostomy on serum levels ofGLP-1, glucose, and insulin in rats.Methods Gastroileostomies with side-to-side anastomosis were performed on 15 male New Zealand rats. Blood samples wereobtained before and 1 week after the gastroileostomy.Results Our results showed that the rats lost a lot of weight from start (330 ± 15 g) to the end (240 ± 25 g) of the experiment (p =0.048). The data analysis showed that the gastroileostomy surgery elevates the level of GLP-1in plasma significantly (89.1852 vs.177.440 respectively; p < 0.001) and caused a significant decrease in plasma glucose as well (92.00 and 66.29 mg/dL respec-tively; p < 0.001). However, the insulin state elevated after the surgery significantly (8.03 vs. 9.89; p < 0.001).Conclusion In this study, we showed the effectiveness of gastroileostomy treatment to decrease body weight and plasma glucosewith increased GLP-1 in rats. This small rat model suggests the potential of this surgery to treat type 2 diabetes mellitus.

Keywords Glucagon-like peptide . Gastroileostomy . Diabetes mellitus . Incretin . Glucose

Introduction

Despite advances in treatment of type 2 diabetes mellitus(T2DM), optimal treatment control is not entirely achievedspecially in obese patients [1]; however, bariatric surgeriesare currently used as new therapeutic approaches [1–3].From which, there are studies on using different methods to

increase glucagon-like peptide-1 (GLP-1) activity; however,these methods have not been well established [2, 3]. GLP-1receptor agonists similarly to exenatide and liraglutide haveshown acceptable effects [1–4]. GLP-1, a gastrointestinal pep-tide with incretin effect, sends postprandial neuroendocrinesignal and has a significant role in glucose homeostasis; it isreleased during a meal and stimulates insulin synthesis and

* Shahab Shahabi Shahmirishshahabi@yahoo.com

Behrouz KeleidariKeleidari@med.mui.ac.ir

Rastin Mohammadi MofradRastinmohammadimofrad@yahoo.com

Mohammad Hossein Saneisanei@med.mui.ac.ir

Mohsen Kolahdouzankolahdouzan@med.mui.ac.ir

Erfan Sheikhbahaeie.shikhbahaei@edc.mui.ac.ir

1 Isfahan Minimally Invasive Surgery and Obesity (IMISO) Center,Department of Surgery, Isfahan University of Medical Sciences,Isfahan, Iran

2 Department of Surgery, Isfahan University of Medical Sciences,Isfahan, Iran

3 Department of Pathology, Al Zahra University Hospital, IsfahanUniversity of Medical Sciences, Isfahan, Iran

4 Department of Thoracic Surgery, Al Zahra University Hospital,Isfahan University of Medical Sciences, Isfahan, Iran

5 Student Research Committee, Cardiovascular Research Institute,Isfahan University of Medical Sciences, Isfahan, Iran

Obesity Surgeryhttps://doi.org/10.1007/s11695-018-3312-y

http://crossmark.crossref.org/dialog/?doi=10.1007/s11695-018-3312-y&domain=pdfhttp://orcid.org/0000-0002-8415-2567mailto:shshahabi@yahoo.com

insulin secretion, which does not occur when carbohydratesare administered intravenously [4]. GLP-1 inhibits post-mealglucagon release [5, 6] and affects the appetite center of thebrain that causes central satiety. Hence, weight loss remains asone of the predictable effect of elevated GLP-1 [5]. AlthoughGLP-1 can stop the progression of beta cell failure, theglucose-lowering effectiveness dissipates rapidly after cessa-tion of GLP-1 agonist medications [7–9]. GLP-1 has a shorthalf-life of about one to 2 min; therefore, continuous infusionof GLP-1 or continuous internal secretion of GLP-1 is neces-sary to achieve a steady state level in the blood [10]. GLP-1 iscurrently being evaluated for the therapy of diabetes.Increased secretion of GLP-1 may help to weight loss andbe responsible for postprandial hypoglycemia [8]. GLP-1 se-cretion can be stimulated by undigested foods containing car-bohydrates from terminal ileum [1–10].

Main aims of bariatric/metabolic surgeries include provid-ing functional restriction for foods and malabsorption path-ways, which send neuroendocrine signals. Laparoscopicsleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gas-tric bypass (LRYGB) may change intestinal morphology andthe subcellular organization of enterocytes as well as function-al proteins behavior in enterocytes. The later results in in-creased GLP-1 secretion after glucose-rich meals [11–13].Single anastomosis sleeve ileal (SASI) is a new therapeuticapproach introduced by Santoro et al. composed of a sleevegastrectomy with side-to-side gastroileal anastomosis. Recentstudies suggest that SASI has two components: the sleevegastrectomy, the restrictive part, and the gastroileal anastomo-sis sending neuroendocrine signals. Rapid transit of undigest-ed foods elevates GLP-1 and peptide YY (PYY) secretionsfrom terminal ileum, and the sleeve gastrectomy decreasessecretion of ghrelin from gastric fundus. According to modernhuman diet, less undigested foods are delivered to the distalpart of the intestine, resulting in less GLP-1 and PYY secre-tion. Hence, there is more chance for weight gain and diabetesin people [10–17].

Similarly, gastroileostomy can provide intrinsic increasesof GLP-1 secretion in the rapid delivery of undigested foods tothe terminal ileum [8]. Although there are multiple types ofbariatric surgery, there is a lack of evidence to guide the de-velopment of valid and reliable protocols for selection of onetechnique of bariatric surgery [14, 15]. In recent clinical worksreported that SASI was effective for significant weight loss,controlling T2DM, and normalizing lipid profile without anynutrient deficiencies [16, 17]. However, not enough convinc-ing evidence exists on therapeutic effects and complications ofSASI.

Gastrointestinal surgery as a bariatric/metabolic surgerymight be an option for patients with T2DM without adequateclinical control [18, 19]. The underlying mechanisms of bar-iatric surgery to achieve T2DM remission are unclear andmight involve changes in gut hormones such as GLP-1 [20].

To our knowledge, this pre-clinical study is the first exper-imental assessment of the anti-glycemic effect ofgastroileostomy in rat as a promising model to controlT2DM. In this experiment, the gastroileostomy is SASI with-out sleeve procedure; therefore, our study was conducted tocompare and evaluate efficacy of gastroileostomy on plasmalevels of insulin, glucose, and GLP-1.

Materials and Methods

Animals

Fifteen healthy male New Zealand rats with the similar weight(the means and standard deviation (mean ± SD) 330 ± 15 gbody weight), and no history of surgery or other medical in-terventions were included from Central Laboratory of ourUniversity. The animals were maintained under controlledconditions in a pathogen-free environment under constant am-bient temperature and humidity with free access to food andwater at all times, excluding a mandatory overnight fast beforethe surgery (at least 8 h). This research commenced after ful-filling all ethical statements while receiving its approval fromdepartment of ethics in medical research. All procedures wereconducted in agreement with the National Institutes of HealthGuide for Care and Use of Laboratory Animals.

Interventions

Gastroileostomy was performed on 15 male rats after an over-night fast. Surgery for all rats was carried out under the samestandard conditions by one surgeon. Anesthesia was inducedand maintained with 0.1 mg/kg ketamine, (KetamineHydrochloride Rotexmedica, Germany) (Fig. 1), while eachanesthetized rat was laid in the supine position on a surgicaltable (Fig. 2), and the abdominal skin was shaved using hairremoval cream (Veet ®, French) and disinfected with 10%betadine. Under sterile conditions, a 4.5-cm midline incisionwith a No. 10 scalpel was performed on the abdomen. A pieceof peritoneal surface was removed from the abdominal wallwith surgical scissors. Gastroileostomy surgery wasperformed on all animals by anastomosing 1 cm of antrumto terminal ileum (side-to-side). We measured the wholesmall intestine, located the ileum, and create an upward loopfrom its distal one third, about 10 cm from ileocecal part. Aside-to-side 10-mm anastomosis was made to antral part of thestomach. To complete anastomosing, a single layer runningtechnique with absorbable poly-p-dioxanone suture (4/0,Monoplus®) was applied. We tested the opening of theanastomosing with an index finger (Fig. 3). Finally, theincised area of the skin and fascia were repaired with silksutures (4/0 Taft, Yazd, Iran), and the rats were left at asuitable temperature (23–25 °C) to regain consciousness. All

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animals were kept on the same diet after surgery. The studytook 7 days after surgery. Silk sutures were removed on day 5of treatment, under general anesthesia.

Blood samples were obtained from the vein in medial can-tus at the base line and 1 week after gastroileostomy (Fig. 4).

Outcome Assessment

The effectiveness was determined by any reduction in bodyweight and plasma glucose level.

Plasma insulin was measured using the LIAISONRAnalyzer. GLP-1 was measured using the human GLP-1ELISA kit (Biotech Co., Germany).

All side effects of the intervention, including adverse ef-fects related to systemic anesthesia, local infection, anasto-mosing leakages, and death, were assessed by the same sur-geon using a questionnaire.

Statistical Analysis

Mean ± SD values were determined for plasma GLP-1, glu-cose, and insulin level as the base line and 1 week after thesurgery. For statistical analysis and to compare two mean ±SD values, paired Student’s t test of IBM SPSS version 21.0(Chicago, USA) was used. p value of < 0.05 was consideredsignificant.

Results

The experiments were performed with 15 male New Zealandrats. One rat died after the operation due to not regainingconsciousness.

One week after the gastroileostomy, the body weight of ratson standard diet decreased significantly compared to baseline(330 ± 15 vs. 240 ± 25 g before and after the surgery respec-tively; p = 0.048).

We detected a similar reduction of plasma glucose levelduring the first week after the gastroileostomy has been re-corded. Blood glucose decreased significantly from 92.00 ±14.21 mg/dL before the surgery to 66.29 ± 16.06 mg/dL afterthat (p < 0.001) (Table 1).

Data shows that gastroileostomy surgery elevates the levelof GLP-1in plasma significantly (89.1852 ± 77.261618 vs.177.440 ± 40.939613; p < 0.001) with simultaneous increasein insulin secretion (8.03 ± 0.01 vs. 9.89 ± 0.36; p < 0.001)(Table 1).

Discussion

A significant reduction of body weight and plasma glu-cose level was achieved in the first week after thegastroileostomy surgery, and simultaneously, the insulinlevel and GLP-1 increased significantly. Weight loss im-proves blood glucose and insulin level, which are

Fig. 1 Anesthesia was induced and maintained with intraperitonealketamine

Fig. 2 Surgical position. Supine position of each rat on a surgical tablebefore the surgery

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independent from increased secretion of GLP-1. Our ratslost one third of their initial weight after 1 week andhad higher level of GLP-1 and insulin, which suggeststhe independent effect of gastroileostomy on neuroendo-crine signals of the intestine leading to increased secre-tion of GLP-1, decreased plasma glucose, and thereforeends with weight reduction. Our results are first exper-imental surgery suggesting the early effects ofgastroileostomy on body weight and glucose homeosta-sis in rat model.

The gastroileostomy resembles the SASI surgery with-out performing the restrictive component, sleeve gastrec-tomy. According to a newly published clinical researchwith limited patients, SASI decreases fasting blood sugar(FBS), glycosylated hemoglobin A (HbA1c), and lipid

profile until 2 years after the surgery continuously andprogressively without nutrient deficiency. C-peptide didnot change significantly in this study suggesting thatSASI improves T2DM by decreasing insulin resistancebut not its secretion level in blood [16, 17]. More com-pelling evidences are required to show the clinical appli-cability of this procedure.

Consistent with the previous results [21, 22], we ob-served that experimental gastroileostomy in rats modelchanged glucose absorption restriction and increasedGLP-1 secretion [23, 24]. We verified that gastroileostomysurgery increases glucose-stimulated GLP-1 secretion inthe rats by measuring GLP-1 in the blood before and afterthe surgery in the same nutritional conditions. GLP-1 in-creases glucose-dependent insulin secretion, exhibits

Fig. 3 Procedure description. aMidline laparotomy andexploration. b Ileum exploration.c Gastroileostomy side-to-sideanastomosis. d Checking theopening of the anastomoses andchecking the leakage

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trophic effects on β cells of the pancreas, inhibits glucagonsecretion from α cells, inhibits glucose production in theliver, increases glucose uptake in the heart, inhibits gastricemptying, decreases postprandial gastrointestinal motility,and reduces appetite [25, 26].

Bariatric procedures send glucose-rich meals to theterminal ileum and lead activation of L-cells by theseglucose, which may explain the glucose-induced GLP-1secretion after gastroileostomy surgery [27, 28]. The in-creased glucose-induced release of GLP-1 from L-cellsobserved in animals after bariatric surgery, includingIleal Interposition surgery, can be due to an increasedstimulation of L cells because of contact with higherintraluminal glucose concentrations after surgery [22].In gastroileostomies, the duodenum and the jejunum areremoved to increase the amount of glucose reaching theileum after a glucose-rich meal is increased [11, 22, 27].

Shortening of the food retention time in the GI tract aftergastroileostomy is also thought to increase the glucose con-centration in the ileum after glucose-rich meals.Gastroileostomy forces more than half of the meal to passfrom the anastomosis and the remaining from pyloricsphincter.

It is unclear which one of the two major types of bariatricsurgery achieves the greatest and the most durable remissionof T2DM and induced weight loss [29].

There are limited randomized clinical trials in this topic[15, 30]. Each technique has some advantages and disadvan-tage. LRYGB is fully reversible; however, the irreversibleLSG is a faster and simpler procedure with potentially lessdumping [29–31].

Technical difficulties are involved in performing LRYGBin severely obese patients; therefore, these patients may havelimited success from LRYGB attributed to pouch dilation andloss of restriction at the gastrojejunal anastomosis over time[29–31].

Therefore, a simple technique with fast efficacy and mini-mal complications is desirable.

We chose gastroileostomy over other glycemic con-trols by bariatric surgery and anti-metabolic procedures,since it causes a rapid and continuous elevation in thelevel of GLP-1.

This procedure may change intestinal morphology and anincreased number of GLP-1-secreting L cells per cross sec-tion, as shown in previous studies [22, 23].

Gastroileostomy leads to increased GLP-1 secretion af-ter glucose-rich meals and can be considered as a prom-ising option for control of hyperglycemia in type 2 diabe-tes mellitus.

The limitations of our study include the relatively smallsample size and the lack of control rats in our study de-sign. Therefore, side effects related to general anesthesiaand midline laparotomy were not studied. This study re-vealed the early outcomes of gastroileostomy. The au-thors recommend further clinical studies evaluating theefficacy and safety of this surgery to find the mostefficient and safe surgical technique that can be usedin a human model. Like other researches in this field,long-term results of this surgery should be evaluatedtoo.

Fig. 4 Blood sampling from periorbital vein in a rat before theexperimental surgery

Table 1 Effect of experimentalgastroileostomy on blood glucoselevel, glucagon-like peptide-1,and insulin level of operated rats

Variables Intervention Minimum Maximum Mean Std. deviation p value

Blood glucose level Before 71 131 92.00 14.21 < 0.001After 45 90 66.29 16.06

Glucagon-like peptide-1 Before 10.34 183.26 89.18 77.26 < 0.001After 96.72 255.17 177.44 40.93

Insulin level Before 8.01 8.07 8.03 0.01 < 0.001After 9.02 10.09 9.89 0.36

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Conclusion

Based on the results of this study, gastroileostomy is an effec-tive way of improving metabolism of glucose in rats and willhelp to decrease body weight and to treat type 2 diabetesmellitus.

Acknowledgments The authors acknowledge Mr. Amirsalar MoazenSafaei and Mr. Aria Azarshahi for their help in proofreading thismanuscript.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Funding Resource No fund received for this research.

Ethics Statements This research commenced after fulfilling all of theethical statements and receiving its approval from department of ethics inmedical research. All procedures were conducted in agreement with theNational Institutes of Health Guide for Care and Use of LaboratoryAnimals.

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The Impacts of Gastroileostomy Rat Model on Glucagon-like Peptide-1: a Promising Model to Control Type 2 Diabetes MellitusAbstractAbstractAbstractAbstractAbstractIntroductionMaterials and MethodsAnimalsInterventionsOutcome AssessmentStatistical Analysis

ResultsDiscussionConclusionReferences