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Glucose Homeostasis Improvement After Single Anastomosis Duodenojejunal Bypass with Sleeve Gastrectomy in Goto-Kakizaki Rats

Glucose Homeostasis Improvement After Single Anastomosis Duodenojejunal Bypass with Sleeve... Background The incidence of type 2 diabetes mellitus (T2DM) is raising with significant associated medical complications and mortality. Bariatric surgery has shown to have beneficial metabolic effects. A model of single anastomosis duodenoje- junal bypass with sleeve gastrectomy (SADJB-SG) was developed in a T2DM animal model without obesity, Goto-Kakizaki (GK) rats, to evaluate the effect of the procedure on glucose homeostasis. Methods Fourteen 12-week old GK rats underwent SADJB-SG, while 11 underwent simulated surgery (Sham). Weight and food intake were recorded comprehensively until sacrifice. Fasting blood glucose data, as well as insulin, fructosamine, and albumin levels were measured both pre-surgically and just before sacrifice. Glucose homeostasis was also monitored by oral glucose tolerance test (OGTT) at different time points. A radiographic study was performed to assess the effect of surgery on gastric emptying. Results Mortality rate was 24% in the SADJB-SG and 4% in Sham rats. Despite similar food intake, the SADJB-SG showed significant weight loss coupled to a decrease in albumin levels. Glucose homeostasis improved in SADJB-SG rats after surgery, reflected in decreased blood glucose, fructosamine levels, and homeostasis model assessment of insulin resistance index (HOMA-IR). OGTT tests, conducted both post-surgery and at follow-up, demonstrated an improvement in glucose metabolism 120 min after glucose administration. However, a peak in glycemia was observed at 30 min, which negatively affected the expected AUC results. Gastric emptying was accelerated in the SADJB-SG, which could contribute to explain the observed glycemia increment, through fast glucose jejunal uptake. Conclusion SADJB-SG surgery improved glucose homeostasis in GK rats. Keywords Metabolic bariatric surgery · Duodenojejunal bypass · Diabetes mellitus · Goto-Kakizaki rats Abbreviations RYGB Roux-en-Y gastric bypass BDP Biliopancreatic diversion SADI-S Single anastomosis duodenoileal bypass DS Duodenal switch with sleeve gastrectomy GERD Gastroesophageal reflux disease SADJB-SG Single anastomosis duodenojejunal bypass GK Goto-Kakizaki with sleeve gastrectomy HOMA-IR Homeostasis model assessment of insulin T2DM Type 2 diabetes mellitus resistance OGTT Oral glucose tolerance test Introduction Key Points Type 2 diabetes mellitus (T2DM) is a very complex and • SADJB-SG improves glycemia in an animal model of T2DM. • Significant weight loss was achieved after SADJB-SG. heterogeneous metabolic disorder associated with a sig- • Faster gastric emptying increases glucose availability in nificant risk for the development of different patholo- jejunum. gies, such as cardiovascular disease, stroke, retinopathy, renal disease, dementia, and even several types of cancer Extended author information available on the last page of the article Vol.:(0123456789) Obesity Surgery [1]. Indeed, the impact of T2DM on associated medical Materials and Methods problems, mortality, quality of life, and healthcare costs have been well described elsewhere [1–4]. Based on the Animals study published by the International Diabetes Federation, there were an estimated 463 million people with DM in All the animal experimental procedures were approved by the world in 2019, and the number of people affected by the Ethical Committee for Animal Welfare of the Uni- the disease is expected to increase to 578 million by 2030 versidad Rey Juan Carlos and Comunidad Autónoma de and to 700 by 2045 [2, 5, 6]. The increase in the incidence Madrid, Spain (PROEX 281/19). The experimental pro- of DM appears to be primarily due to the increment in tocol met European and Spanish (2010/63/EEC and RD type 2 DM (T2DM) [3]. The close relationship between 53/2013) guidelines for the protection of experimental ani- T2DM and obesity has been known since the early twen- mals. Nine-week-old GK rats purchased from the Miguel tieth century, so that an elevated body mass index (BMI) Hernández University (Alicante, Spain) were used. Fol- is considered a risk factor for developing T2DM [7]. The lowing the quarantine period, the animals were housed and mechanisms involved are not yet properly elucidated, bred individually in environmentally controlled conditions although obesity can be linked to the insulin resistance (22 ± 1 °C of temperature, 60% of humidity, and 12 h light/ associated with T2DM. Furthermore, insulin resistance dark cycle), and had access to filtered and sterilized tap could be due to activation of inflammatory cascades, water and food (1320 formula; Altromin International, mitochondrial dysfunction, or hyperinsulinemia associ- Germany) ad libitum. Wood-based aspen bricks were used ated with obesity [8]. for bedding (Sodispan Biotech, Spain). Besides, rats were Potential beneficial metabolic effects of weight reduc- provided with environmental enrichment items for nest tion surgeries have been demonstrated [9], in particular building, chewing, and hiding (Sodispan Biotech, Spain). procedures that surgically bypass the small bowel, such as During the fasting periods, the environmental enrichment Roux-en-Y gastric bypass (RYGB) and duodenal switch elements were removed. (DS). Furthermore, in many cases, this improvement in The animals were subjected to an exhaustive pre- and glycemic control occurs even before significant weight post-operative control, as previously published [16]. Due loss after surgery, raising the hypothesis that there are to sex-based differences in T2DM and, in particular, in GK weight loss independent mechanisms involved in DM rats, only male rats were used to avoid variability in our amelioration [10, 11]. results mainly due to the influence of estrogens in females Single anastomosis duodenojejunal bypass with sleeve [18]. Two experimental groups were established: (1) ani- gastrectomy (SADJB-SG) was first reported in humans mals subjected to surgery (SADJB-SG) and (2) animals by Lee and colleagues [12]. This procedure combines the subjected to simulated surgery (SHAM). The animals were knowledge of Kasama’s sleeve gastrectomy with duo- randomly distributed between the two groups including 11 denojejunal exclusion performing a Roux-en-Y recon- rats in the SHAM group and 14 in the SADJB-SG group. struction [13], and Sanchez-Pernaute’s single anastomo- The timeline and general scheme of the procedures per- sis approach [14]. SADJB-SG achieved significant and formed are shown in Fig. 1. sustained weight loss, as well as T2DM remission rates similar to those of RYGB [15]. The main advantage of this procedure is that performing a single anastomosis Surgical Procedure reduces the operative time as well as surgical complica- tions. Additionally, providing a shorter loop in SADJB- Based on the results of previous work, SADJB-SG was SG could prevent malnutrition, commonly associated performed using the duodenal transection technique for with malabsorptive techniques, such as DS, biliopancre- duodenal exclusion in 12-week-old GK rats [16]. Briefly, atic diversion (BPD), or single anastomosis duodenoileal after 6 h of fasting, the rats were anesthetized, and a 3-cm bypass with sleeve gastrectomy (SADI-S) [15]. midline abdominal incision was made. Then, the liga- Recently, we developed the SADJB-SG technique in ment of Treitz was identified and a side-to-side duodeno- a murine model of T2DM, the Goto-Kakizaki (GK) rat jejunal anastomosis was performed 3–5 mm distal to the [16]. Unlike other animal models of T2DM, GK rats pylorus. Subsequently, the first portion of the duodenum are not animals with obesity, which provides a suitable was excluded by transection, just distal to the anastomosis. model for assessing the effects of SADJB-SG on glucose Finally, a tubular gastrectomy of approximately 70% of the metabolism independently of the effect of obesity [17]. stomach was performed. Sham surgery consisted in lapa- Therefore, the aim of the present study was to evaluate rotomy, gastrotomy, and gastrorrhaphy. The animals were the effect of SADJB-SG technique on glycemic regulation subjected to a weekly control to assess their evolution, in this animal model. Obesity Surgery Fig. 1 Experimental timeline. The animals were subjected to a week to identify and mitigate possible painful symptoms and dehy- weekly control to evaluate their evolution, weight, and food intake. dration. RX, Radiological study; OGTT, oral glucose tolerance test This control was particularly exhaustive during the first postoperative except during the first postoperative week, when the evolu- containing EDTA for insulin preservation. A protease inhibi- tion of the animals was monitored daily. tor (dipeptidyl dipeptidase inhibitor IV; Merck-Millipore, Spain) was immediately added following blood extraction. Body Weight and Food Intake Record The samples were centrifuged at 3000 rpm and 4 °C, for 10 min, and plasma was collected and frozen at − 80 °C. Animal body weight was recorded weekly from 2 weeks Fructosamine and albumin levels were determined on the before surgery until sacrifice. Food intake was also moni - Abbott Alinity analyzer (Abbott; Illinois, USA). An enzyme- tored weekly, except during the 7 days after surgery when linked immunosorbent assay (ELISA) kit was used to meas- the animals received palatable gelatin tablets, prepared as ure blood insulin concentration (Cloud-Clone Corp; USA) previously described [16], until their correct evolution was following the manufacturer’s guidelines. Fasting plasma glu- verified. From the third postsurgery day, the solid diet was cose and insulin levels were used to calculate homeostasis gradually introduced according to their tolerance. From the model assessment of insulin resistance (HOMA-IR) [20]. second week post-surgery, all animals received a solid diet, and the weekly control was reinitiated. Radiographic Study Fasting Glucose and OGTT To analyze the effect of surgery on the stomach size, as well Before blood sampling, the animals were subjected to 6 h as to evaluate a possible alteration in gastric emptying, a of fasting. While fasting, rats had free access to water. Gly- radiographic study was carried out at week 11 (pre-surgery) cemia was measured using a glucometer and reactive strips and 22 (post-surgery), as previously described [21], using (Accu-Chek® Performa; Roche, Spain). Blood drops are the intragastric administration of 1.5 mL of barium sulfate obtained from the tail in conscious rats at different time (Barigraph® AD, Juste SAQF, Spain; 2 g/ml). Image acqui- points (Fig. 1). sition was performed at different time points after barium Oral glucose tolerance test (OGTT) was conducted before administration: immediately (0) and 1, 2, 3, 4, 6, 8, and 24 h surgery (week 11) and after surgery, specifically at week later. Radiographs were taken using a CS2100 digital X-ray 14 (post-surgery) and 21 (follow-up). Fasting glycemia was device (Carestream Dental; 60 kV, 7 mA) and recorded on measured and then a glucose solution (2 mg/kg; Glucoce- a digital plate (Venu1717V, iRay Technologies). The rats min 50%, Braun) was administered orally. Thirty, 60, and did not receive anesthesia and were immobilized in a prone 120 min after glucose administration, glycemia was again position inside transparent, handmade, and adjustable plas- measured. Then, the area under the curve (AUC) was calcu- tic tubes. Exposure time was set to 20 ms (focus distance lated from OGTT data [19]. 50 ± 1 cm), and the rats were returned to their cage immedi- ately after each X-ray shot. A metal block (3 × 1 × 1 cm) was Insulin, Fructosamine, and Albumin Measurements placed aside the animal during X-ray obtention and used as reference for morphometric and densitometric analyses. For Different parameters related to glucose metabolism or nutri- these, the size (measured as area) as well as the density of tional condition of the animals was measured just before the stomach contents (measured as %) were analyzed using surgery and before sacrifice. After 6 h of fasting, blood sam- an image analysis system (ImageJ 1.38, National Institute ples were collected from the tail vein in pre-chilled tubes of Health, USA). Obesity Surgery Histological Study Results Animals were deeply anesthetized with isoflurane and sac- Surgery Evaluation rificed by decapitation. Tissue samples were dissected and fixed in 4% formaldehyde for 24 h before embedding in par - All interventions were successfully performed on 25 rats. affin. Esophageal samples were cut on a Leyca microtome The mean operative time was 29 and 78 min for the Sham (Leyca; Wetzlar, Germany) to obtain 4-μm-thick sections. and SADJB-SG groups, respectively. Anesthetic time was Sections were stained with hematoxylin–eosin for histologi- deliberately prolonged in the Sham group to avoid bias cal evaluation by gastrointestinal pathologist, blinded to the regarding surgical stress and anesthesia effects. Overall, animal group. Representative light microphotographs were mortality rate was 28%; however, 24% corresponded to the acquired with a DMD108 photomicroscope (Leyca; Wetzlar, SADJB-SG group, since only one rat died in the Sham group Germany). (4%), due to duodenal ischemia. In SADJB-SG group, the most common cause of death was anastomosis leakage in 3 cases, gastric leak in one case, and duodenal ischemia in Statistical Analysis one case. STATA 17 statistical software (StataCorp.2021. Stata Sta- Body Weight, Food Intake, and Nutrition Parameters tistical Software: Release 17. StataCorp LLC, USA) was used to perform statistical analyses. Linear mixed models As shown in Fig. 2 a, after surgery, the SADJB-SG group were conducted to analyze longitudinal measures, with an experiences substantial weight loss (average of 21%). unstructured variance matrix to account for variability. The Although operated rats gradually gained weight, significant models included treatment group (Sham or SADJB-SG) as differences compared to the Sham group were maintained fixed effect, time as repeated measure, and first level inter - over the time (p < 0.001). The Sham group quickly recov- action time × treatment. Mean and standard error (SE) were ered their initial baseline body weight, which continued to estimated, and pairwise comparisons were adjusted using increase progressively. Regarding food intake, SADJB-SG the Bonferroni method. Statistical significance was defined rats showed a decrease between weeks 12 and 14, just after as *p < 0.05 and **p < 0.001. surgery, as expected due to the post-surgical recovery period Fig. 2 Body weight (a) and food intake (b) were recorded weekly. models were used for repeated measures analysis over time. Esti- Arrowheads indicate the surgical procedure. c Serum albumin lev- mated mean ± SE (standard error) was represented, and Bonferroni els were measured on surgery day and before sacrifice. Linear mixed method was used to calculate adjusted p-values: **p < 0.001 Obesity Surgery (Fig. 2b). Following recovery and introduction of solid diet conducted post-surgically (Fig. 3d). However, the AUC OGTT (weeks 14–16), there was an increase in the food intake in calculated in the follow-up period, decreased in both experi- the operated rats reaching similar values as the Sham group mental groups compared to the pre-surgery values (p < 0.05). until the end of the study. Serum albumin levels in Sham rats revealed a significant Glucose Metabolism Indicators increment at the time of sacrifice compared to basal val- ues (Fig. 2c). On the opposite, SADJB-SG group evidenced Fasting glucose levels in SADJB-SG animals were lower a decrease in albumin levels at the time of sacrifice when 12 weeks after surgery (Fig.  4a). In addition, it was also compared to the basal measurement (p < 0.001). Moreover, observed that in the Sham group, fructosamine levels at sac- SADJB-SG rats had lower albumin blood concentration in rifice were increased compared to the basal measurement, the sample obtained at sacrifice compared to the Sham group whereas the surgery significantly reduced (p < 0.001) long- (p < 0.001), consistent with body weight data. term fructosamine levels in SADJB-SG (Fig. 4b). Regarding fasting insulin levels, a significant increase (p < 0.05) was OGTT observed in SADJB-SG group at sacrifice (Fig. 4 c). On the other hand, HOMA-IR was lower in the SADJB-SG group The OGTT performed before surgery showed a similar (Fig. 4d), indicating a reduced insulin resistance in these profile in both experimental groups (Fig.  3a). In post-sur- animals. gery (Fig. 3b) and follow-up (Fig. 3c) tests, there was an important increase in blood glucose concentration 30 min after glucose overload in SADJB-SG (p < 0.001). Follow- Eec ff ts of SADJB‑SG Surgery on Stomach ing glycemic increment, the glucose concentration declined Size and Gastric Emptying to levels similar to those of the Sham group at 120 min. Moreover, in the follow-up test, glycemia in the SADJB- There was no difference in stomach area in the pre-operative SG group was significantly lower than in Sham at 120 min radiological study. Values were around 5 cm , both in Sham (Fig. 3c). Calculated AUC was higher in SADJB-SG and SADJB-SG animals. Before sacrifice, the radiological OGTT rats (p < 0.05) compared to Sham group in the OGTT test study showed that the mean area of the stomach did not Fig. 3 The OGTT was performed prior to surgery (a), 2  weeks (b), used for repeated measures analysis over time. Estimated mean ± SE and 9  weeks (c) post-surgery. d The OGTT data were used to cal- (standard error) was represented, and Bonferroni method was used to culate the area under the curve (AUC ). Linear mixed models were calculate adjusted p-values: *p < 0.05 and **p < 0.001 Obesity Surgery Fig. 4 Graphical representation of the glycemia-related parameters. model assessment of insulin resistance (HOMA-IR). Data represent a Fasting glucose, b fructosamine, and c insulin blood concentra- estimated mean ± SE (standard error), and Bonferroni method was tions were measured just before surgery and sacrifice. d Homeostasis used to calculate adjusted p-values: *p < 0.05 and **p < 0.001 change in the Sham group compared to pre-surgery values, to those reported both in humans and GK rats [22, 24]. whereas in SADJB-SG, it was 42% smaller than the stomach However, weight loss was higher than we expected, as final in the Sham group (Fig. 5a). Indeed, gastric emptying was stomach size reduction in our surgical modification was 42% accelerated in SADJB-SG rats, and the effect was significant measured on the radiographic study, instead of the usual between 6 and 8 h after barium administration (Fig. 5b); 80% resection in sleeve gastrectomy [24–26]. According to moreover, it was even evident in the radiological images at the analyses we have carried out in this study, we are unable t = 0, where a significant amount of barium could be seen in to determine whether this weight loss is due to a gut rerout- the intestine of the operated rats (Fig. 5c). ing or to a reduction in energy intake as described in other metabolic surgeries in humans [27]. Histological Evaluation of the Esophagus On the other hand, coupled with weight loss, SADJB-SG led to a decrease in serum albumin levels that could indi- Distal esophagus histology was normal in both SADJB-SG cate a poorer nutritional status in SADJB-SG group. Pro- and Sham groups. Specifically, no signs of esophagitis such tein deficiency after metabolic bariatric surgery remains the as mucosal and submucosal eosinophilia were detected in most severe macronutrient complication in bariatric surgery, any experimental group (Fig. 6). especially in derivative procedures such as BPD and RYGB, where protein supplementation might be needed [23]. An improvement in glucose homeostasis following Discussion SADJB-SG was observed. Fasting glycemia and HOMA-IR showed a significant long-term decrease after surgery, indi- Despite promising pharmacotherapies, metabolic surgery cating a lower insulin resistance in these animals [12, 28]. remains the most effective strategy for the treatment of Furthermore, elevated fasting insulin levels were found in obesity and T2DM [22, 23]. In this study, SADJB-SG was the SADJB-SG group. This finding could be correlated with performed in GK rats with similar mortality and associ- improved pancreatic beta-cell function as a consequence of ated medical complications, as previously described [16]. the surgical procedure [26, 29, 30]. Moreover, fructosamine We observed that SADJB-SG led to substantial weight loss was significantly lower in the SADJB-SG group at follow-up despite similar food intake compared to the Sham group supporting the improvement in glucose homeostasis during from the second week post-surgery. These results are similar the preceding 2 weeks before sacrifice [31]. Obesity Surgery Fig. 5 Radiological study and analysis of the images using the SG rats before sacrifice. c Representative images of both experimen- ImageJ software. a Stomach area analysis was performed at T0, right tal groups, before surgery and sacrifice. Linear mixed models were after barium administration, both pre-surgically and pre-sacrifice. The used for repeated measures analysis over time. Estimated mean ± SE reduction observed after surgery was 42% in the SADJB-SG group. b was represented, and Bonferroni method was used to calculate Analysis of the contrast density in the stomach for 24 h after barium adjusted p-values: *p < 0.05 and **p < 0.001 administration showed an increase in gastric emptying in the SADJB- However, post-surgery and follow-up OGTT tests showed of new-onset gastroesophageal reflux disease (GERD), or a significant increase in glycemia 30 min after overload. even a worsening of GERD symptoms prior to surgery There is evidence to support this phenomenon that has also [35]. A meta-analysis showed a significant worsening of been observed after vertical sleeve gastrectomy (VSG) in GERD in 19% of the patients and 23% of de novo GERD mice [32] or following RYGB [30] and sleeve gastrectomy [36]. Moreover, Ser and colleagues reported a 5-year in GK rats [26]. This increase implied a higher post-surgical follow-up study demonstrating de novo GERD in 30.6% AUC in the SADJB-SG animals. AUC is an index of whole of patients after SADJB-SG [15]. GERD has also been glucose excursion after glucose loading that reflects glyce- described in rats after sleeve gastrectomy [37].  Despite mic variability, which is proposed to be harmful for blood GERD was not demonstrated in either the SADJB-SG vessels and affect the development of medical complications or the SHAM group in our study, this procedure cannot [19]. In our model, we can attribute this increase in glycemia be recommended in all types of patients on the sole basis after overloading to a faster gastric emptying as observed of this finding. in previous studies, performing VSG and RYGB [33]. This This study has some limitations. Data concerning other phenomenon could increase glucose availability in the jeju- hormones involved in glucose metabolism (i.e., ghrelin, num, where anastomosis was performed in SADJB-SG, GLP-1, GIP…) would be needed to fully understand the and most of the glucose uptake occurs through the sodium- metabolic effects of SADJB-SG in GK rats. On the other dependent glucose transporter 1 (SGLT1) [34]. hand, the translation of results obtained in animal models to From a clinical point of view, an important issue related humans is complex and the risks/benefits balance must be to sleeve and sleeve-plus procedures is the development carefully evaluated [15, 38]. Obesity Surgery Fig. 6 Representative light microphotographs correspond- ing to hematoxylin–eosin staining in the Sham (a) and in the SADJB-SG (b) groups. Magnification: 40 × , on the left; 100 × , on the right Conclusion Declarations Competing Interests The authors declare no competing interests. SADJB-SG technique in GK rats led to an improvement in glucose homeostasis. Further studies are needed to elucidate Open Access This article is licensed under a Creative Commons Attri- the molecular mechanisms involved in insulin resistance and bution 4.0 International License, which permits use, sharing, adapta- glucose metabolism improvement. tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes Author Contribution The approach and conceptualization of the project were made. The images or other third party material in this article are has been developed by Maria Ruth Pazos (MRP), Sirio Melone (SM) included in the article’s Creative Commons licence, unless indicated and Jose Maria Fernandez (JMF). MRP and SM have developed the otherwise in a credit line to the material. If material is not included in methodology and, together with Mario Amores (MA), have carried the article’s Creative Commons licence and your intended use is not out the surgical procedures, sampling and animal care. Carlos Gui- permitted by statutory regulation or exceeds the permitted use, you will jarro (CG) and Sagrario Martinez Cortijo (SMC) contributed to the need to obtain permission directly from the copyright holder. To view a technical assessment. Raquel Abalo (RA) and Yolanda Lopez-Tofiño copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. (YLT) performed the radiographic study, as well as the analysis of the images and provided assistance in the interpretation of the results. Juan Manuel Acedo (JMA) contributed to measuring biochemical param- eters. Elena Garcia-Garcia (EGG) has carried out the histological study. References Elia Perez-Fernandez (EPF) has conducted statistical analysis. MRP prepared the figures. MRP and SM drafted the manuscript. 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Single-anasto- despite unaffected insulin secretion and beta cell mass. Pep- mosis duodenoileal bypass with sleeve gastrectomy (SADI-S) for tides. 2021;136:170445. https:// doi. org/ 10. 1016/j. pepti des. 2020. obese diabetic patients. Surg Obes Relat Dis. 2015;11(5):1092–8. 170445. https:// doi. org/ 10. 1016/j. soard. 2015. 01. 024. 31. Gounden V, Ngu M, Anastasopoulou C, et al. Fructosamine. In: 15. Ser K-H, Lee W-J, Chen J-C et al. Laparoscopic single-anasto- StatPearls [Internet]. Treasure Island (FL): StatPearls Publish- mosis duodenal-jejunal bypass with sleeve gastrectomy (SADJB- ing; 2023. Available from: https:// www. ncbi. nlm. nih. gov/ books/ SG): surgical risk and long-term results. Surg Obes Relat Dis. NBK47 0185/. 2019;15(2):236–43. https://doi. or g/10. 1016/j. soar d.2018. 11. 020 . 32. Ben-Haroush Schyr R, Al-Kurd A, Moalem B et al. Sleeve gas- 16. Melone S, Fernández-Cebrián JM, Amores M et al. 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Different regulatory mechanisms of stress. Oxid Med Cell Longev. 2019;2019:e6734836. https:// doi. Na+/ glucose transport in mouse ileum and jejunum. 2024. https:// org/ 10. 1155/ 2019/ 67348 36.doi. org/ 10. 21203/ rs.3. rs- 44832 64/ v1. 19. Sakaguchi K, Takeda K, Maeda M et al. Glucose area under the 35. Bernadette C, Lim-Loo M, Huang C-K et al. Sleeve-plus proce- curve during oral glucose tolerance test as an index of glucose dures in asia: duodenojejunal bypass and proximal jejunal bypass. intolerance. Diabetol Int. 2016;7(1):53–8. https://doi. or g/10. 1007/ In: Saiz-Sapena N, Miguel Oviedo J (Eds.), Bariatric surgery - s13340- 015- 0212-4. from the non-surgical approach to the post-surgery individual 20. Aref A-BM, Ahmed OM, Ali LA et al. Maternal rat diabetes mel- care, IntechOpen, 2021. https:// doi. or g/ 10. 5772/ intec hopen. litus deleteriously ae ff cts insulin sensitivity and beta-cell function 96042. Obesity Surgery 36. Yeung KTD, Penney N, Ashrafian L et al. 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Impact of Metabolic Bariatric Surgery on Outcomes and the 10-Year Risk of Major Adverse Authors and Affiliations 1,2 3 2 1 2 Sirio Melone  · Jose Maria Fernandez‑Cebrian  · Mario Amores  · Yolanda Lopez‑Tofiño  · Elia Perez‑Fernandez  · 2 2 1,2 1,2 1 Elena Garcia‑Garcia  · Juan Manuel Acedo  · Carlos Guijarro  · Sagrario Martinez Cortijo  · Raquel Abalo  · 2,4 Maria Ruth Pazos * Sirio Melone Juan Manuel Acedo [email protected] [email protected] * Maria Ruth Pazos Carlos Guijarro [email protected] [email protected] Jose Maria Fernandez-Cebrian Sagrario Martinez Cortijo [email protected] [email protected] Mario Amores Raquel Abalo [email protected] [email protected] Yolanda Lopez-Tofiño Universidad Rey Juan Carlos, Alcorcón, Spain [email protected] Hospital Universitario Fundación Alcorcón, Madrid, Spain Elia Perez-Fernandez [email protected] Hospital Universitario Ramón y Cajal, Madrid, Spain Elena Garcia-Garcia Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain [email protected] http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Obesity Surgery Springer Journals

Glucose Homeostasis Improvement After Single Anastomosis Duodenojejunal Bypass with Sleeve Gastrectomy in Goto-Kakizaki Rats

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Abstract

Background The incidence of type 2 diabetes mellitus (T2DM) is raising with significant associated medical complications and mortality. Bariatric surgery has shown to have beneficial metabolic effects. A model of single anastomosis duodenoje- junal bypass with sleeve gastrectomy (SADJB-SG) was developed in a T2DM animal model without obesity, Goto-Kakizaki (GK) rats, to evaluate the effect of the procedure on glucose homeostasis. Methods Fourteen 12-week old GK rats underwent SADJB-SG, while 11 underwent simulated surgery (Sham). Weight and food intake were recorded comprehensively until sacrifice. Fasting blood glucose data, as well as insulin, fructosamine, and albumin levels were measured both pre-surgically and just before sacrifice. Glucose homeostasis was also monitored by oral glucose tolerance test (OGTT) at different time points. A radiographic study was performed to assess the effect of surgery on gastric emptying. Results Mortality rate was 24% in the SADJB-SG and 4% in Sham rats. Despite similar food intake, the SADJB-SG showed significant weight loss coupled to a decrease in albumin levels. Glucose homeostasis improved in SADJB-SG rats after surgery, reflected in decreased blood glucose, fructosamine levels, and homeostasis model assessment of insulin resistance index (HOMA-IR). OGTT tests, conducted both post-surgery and at follow-up, demonstrated an improvement in glucose metabolism 120 min after glucose administration. However, a peak in glycemia was observed at 30 min, which negatively affected the expected AUC results. Gastric emptying was accelerated in the SADJB-SG, which could contribute to explain the observed glycemia increment, through fast glucose jejunal uptake. Conclusion SADJB-SG surgery improved glucose homeostasis in GK rats. Keywords Metabolic bariatric surgery · Duodenojejunal bypass · Diabetes mellitus · Goto-Kakizaki rats Abbreviations RYGB Roux-en-Y gastric bypass BDP Biliopancreatic diversion SADI-S Single anastomosis duodenoileal bypass DS Duodenal switch with sleeve gastrectomy GERD Gastroesophageal reflux disease SADJB-SG Single anastomosis duodenojejunal bypass GK Goto-Kakizaki with sleeve gastrectomy HOMA-IR Homeostasis model assessment of insulin T2DM Type 2 diabetes mellitus resistance OGTT Oral glucose tolerance test Introduction Key Points Type 2 diabetes mellitus (T2DM) is a very complex and • SADJB-SG improves glycemia in an animal model of T2DM. • Significant weight loss was achieved after SADJB-SG. heterogeneous metabolic disorder associated with a sig- • Faster gastric emptying increases glucose availability in nificant risk for the development of different patholo- jejunum. gies, such as cardiovascular disease, stroke, retinopathy, renal disease, dementia, and even several types of cancer Extended author information available on the last page of the article Vol.:(0123456789) Obesity Surgery [1]. Indeed, the impact of T2DM on associated medical Materials and Methods problems, mortality, quality of life, and healthcare costs have been well described elsewhere [1–4]. Based on the Animals study published by the International Diabetes Federation, there were an estimated 463 million people with DM in All the animal experimental procedures were approved by the world in 2019, and the number of people affected by the Ethical Committee for Animal Welfare of the Uni- the disease is expected to increase to 578 million by 2030 versidad Rey Juan Carlos and Comunidad Autónoma de and to 700 by 2045 [2, 5, 6]. The increase in the incidence Madrid, Spain (PROEX 281/19). The experimental pro- of DM appears to be primarily due to the increment in tocol met European and Spanish (2010/63/EEC and RD type 2 DM (T2DM) [3]. The close relationship between 53/2013) guidelines for the protection of experimental ani- T2DM and obesity has been known since the early twen- mals. Nine-week-old GK rats purchased from the Miguel tieth century, so that an elevated body mass index (BMI) Hernández University (Alicante, Spain) were used. Fol- is considered a risk factor for developing T2DM [7]. The lowing the quarantine period, the animals were housed and mechanisms involved are not yet properly elucidated, bred individually in environmentally controlled conditions although obesity can be linked to the insulin resistance (22 ± 1 °C of temperature, 60% of humidity, and 12 h light/ associated with T2DM. Furthermore, insulin resistance dark cycle), and had access to filtered and sterilized tap could be due to activation of inflammatory cascades, water and food (1320 formula; Altromin International, mitochondrial dysfunction, or hyperinsulinemia associ- Germany) ad libitum. Wood-based aspen bricks were used ated with obesity [8]. for bedding (Sodispan Biotech, Spain). Besides, rats were Potential beneficial metabolic effects of weight reduc- provided with environmental enrichment items for nest tion surgeries have been demonstrated [9], in particular building, chewing, and hiding (Sodispan Biotech, Spain). procedures that surgically bypass the small bowel, such as During the fasting periods, the environmental enrichment Roux-en-Y gastric bypass (RYGB) and duodenal switch elements were removed. (DS). Furthermore, in many cases, this improvement in The animals were subjected to an exhaustive pre- and glycemic control occurs even before significant weight post-operative control, as previously published [16]. Due loss after surgery, raising the hypothesis that there are to sex-based differences in T2DM and, in particular, in GK weight loss independent mechanisms involved in DM rats, only male rats were used to avoid variability in our amelioration [10, 11]. results mainly due to the influence of estrogens in females Single anastomosis duodenojejunal bypass with sleeve [18]. Two experimental groups were established: (1) ani- gastrectomy (SADJB-SG) was first reported in humans mals subjected to surgery (SADJB-SG) and (2) animals by Lee and colleagues [12]. This procedure combines the subjected to simulated surgery (SHAM). The animals were knowledge of Kasama’s sleeve gastrectomy with duo- randomly distributed between the two groups including 11 denojejunal exclusion performing a Roux-en-Y recon- rats in the SHAM group and 14 in the SADJB-SG group. struction [13], and Sanchez-Pernaute’s single anastomo- The timeline and general scheme of the procedures per- sis approach [14]. SADJB-SG achieved significant and formed are shown in Fig. 1. sustained weight loss, as well as T2DM remission rates similar to those of RYGB [15]. The main advantage of this procedure is that performing a single anastomosis Surgical Procedure reduces the operative time as well as surgical complica- tions. Additionally, providing a shorter loop in SADJB- Based on the results of previous work, SADJB-SG was SG could prevent malnutrition, commonly associated performed using the duodenal transection technique for with malabsorptive techniques, such as DS, biliopancre- duodenal exclusion in 12-week-old GK rats [16]. Briefly, atic diversion (BPD), or single anastomosis duodenoileal after 6 h of fasting, the rats were anesthetized, and a 3-cm bypass with sleeve gastrectomy (SADI-S) [15]. midline abdominal incision was made. Then, the liga- Recently, we developed the SADJB-SG technique in ment of Treitz was identified and a side-to-side duodeno- a murine model of T2DM, the Goto-Kakizaki (GK) rat jejunal anastomosis was performed 3–5 mm distal to the [16]. Unlike other animal models of T2DM, GK rats pylorus. Subsequently, the first portion of the duodenum are not animals with obesity, which provides a suitable was excluded by transection, just distal to the anastomosis. model for assessing the effects of SADJB-SG on glucose Finally, a tubular gastrectomy of approximately 70% of the metabolism independently of the effect of obesity [17]. stomach was performed. Sham surgery consisted in lapa- Therefore, the aim of the present study was to evaluate rotomy, gastrotomy, and gastrorrhaphy. The animals were the effect of SADJB-SG technique on glycemic regulation subjected to a weekly control to assess their evolution, in this animal model. Obesity Surgery Fig. 1 Experimental timeline. The animals were subjected to a week to identify and mitigate possible painful symptoms and dehy- weekly control to evaluate their evolution, weight, and food intake. dration. RX, Radiological study; OGTT, oral glucose tolerance test This control was particularly exhaustive during the first postoperative except during the first postoperative week, when the evolu- containing EDTA for insulin preservation. A protease inhibi- tion of the animals was monitored daily. tor (dipeptidyl dipeptidase inhibitor IV; Merck-Millipore, Spain) was immediately added following blood extraction. Body Weight and Food Intake Record The samples were centrifuged at 3000 rpm and 4 °C, for 10 min, and plasma was collected and frozen at − 80 °C. Animal body weight was recorded weekly from 2 weeks Fructosamine and albumin levels were determined on the before surgery until sacrifice. Food intake was also moni - Abbott Alinity analyzer (Abbott; Illinois, USA). An enzyme- tored weekly, except during the 7 days after surgery when linked immunosorbent assay (ELISA) kit was used to meas- the animals received palatable gelatin tablets, prepared as ure blood insulin concentration (Cloud-Clone Corp; USA) previously described [16], until their correct evolution was following the manufacturer’s guidelines. Fasting plasma glu- verified. From the third postsurgery day, the solid diet was cose and insulin levels were used to calculate homeostasis gradually introduced according to their tolerance. From the model assessment of insulin resistance (HOMA-IR) [20]. second week post-surgery, all animals received a solid diet, and the weekly control was reinitiated. Radiographic Study Fasting Glucose and OGTT To analyze the effect of surgery on the stomach size, as well Before blood sampling, the animals were subjected to 6 h as to evaluate a possible alteration in gastric emptying, a of fasting. While fasting, rats had free access to water. Gly- radiographic study was carried out at week 11 (pre-surgery) cemia was measured using a glucometer and reactive strips and 22 (post-surgery), as previously described [21], using (Accu-Chek® Performa; Roche, Spain). Blood drops are the intragastric administration of 1.5 mL of barium sulfate obtained from the tail in conscious rats at different time (Barigraph® AD, Juste SAQF, Spain; 2 g/ml). Image acqui- points (Fig. 1). sition was performed at different time points after barium Oral glucose tolerance test (OGTT) was conducted before administration: immediately (0) and 1, 2, 3, 4, 6, 8, and 24 h surgery (week 11) and after surgery, specifically at week later. Radiographs were taken using a CS2100 digital X-ray 14 (post-surgery) and 21 (follow-up). Fasting glycemia was device (Carestream Dental; 60 kV, 7 mA) and recorded on measured and then a glucose solution (2 mg/kg; Glucoce- a digital plate (Venu1717V, iRay Technologies). The rats min 50%, Braun) was administered orally. Thirty, 60, and did not receive anesthesia and were immobilized in a prone 120 min after glucose administration, glycemia was again position inside transparent, handmade, and adjustable plas- measured. Then, the area under the curve (AUC) was calcu- tic tubes. Exposure time was set to 20 ms (focus distance lated from OGTT data [19]. 50 ± 1 cm), and the rats were returned to their cage immedi- ately after each X-ray shot. A metal block (3 × 1 × 1 cm) was Insulin, Fructosamine, and Albumin Measurements placed aside the animal during X-ray obtention and used as reference for morphometric and densitometric analyses. For Different parameters related to glucose metabolism or nutri- these, the size (measured as area) as well as the density of tional condition of the animals was measured just before the stomach contents (measured as %) were analyzed using surgery and before sacrifice. After 6 h of fasting, blood sam- an image analysis system (ImageJ 1.38, National Institute ples were collected from the tail vein in pre-chilled tubes of Health, USA). Obesity Surgery Histological Study Results Animals were deeply anesthetized with isoflurane and sac- Surgery Evaluation rificed by decapitation. Tissue samples were dissected and fixed in 4% formaldehyde for 24 h before embedding in par - All interventions were successfully performed on 25 rats. affin. Esophageal samples were cut on a Leyca microtome The mean operative time was 29 and 78 min for the Sham (Leyca; Wetzlar, Germany) to obtain 4-μm-thick sections. and SADJB-SG groups, respectively. Anesthetic time was Sections were stained with hematoxylin–eosin for histologi- deliberately prolonged in the Sham group to avoid bias cal evaluation by gastrointestinal pathologist, blinded to the regarding surgical stress and anesthesia effects. Overall, animal group. Representative light microphotographs were mortality rate was 28%; however, 24% corresponded to the acquired with a DMD108 photomicroscope (Leyca; Wetzlar, SADJB-SG group, since only one rat died in the Sham group Germany). (4%), due to duodenal ischemia. In SADJB-SG group, the most common cause of death was anastomosis leakage in 3 cases, gastric leak in one case, and duodenal ischemia in Statistical Analysis one case. STATA 17 statistical software (StataCorp.2021. Stata Sta- Body Weight, Food Intake, and Nutrition Parameters tistical Software: Release 17. StataCorp LLC, USA) was used to perform statistical analyses. Linear mixed models As shown in Fig. 2 a, after surgery, the SADJB-SG group were conducted to analyze longitudinal measures, with an experiences substantial weight loss (average of 21%). unstructured variance matrix to account for variability. The Although operated rats gradually gained weight, significant models included treatment group (Sham or SADJB-SG) as differences compared to the Sham group were maintained fixed effect, time as repeated measure, and first level inter - over the time (p < 0.001). The Sham group quickly recov- action time × treatment. Mean and standard error (SE) were ered their initial baseline body weight, which continued to estimated, and pairwise comparisons were adjusted using increase progressively. Regarding food intake, SADJB-SG the Bonferroni method. Statistical significance was defined rats showed a decrease between weeks 12 and 14, just after as *p < 0.05 and **p < 0.001. surgery, as expected due to the post-surgical recovery period Fig. 2 Body weight (a) and food intake (b) were recorded weekly. models were used for repeated measures analysis over time. Esti- Arrowheads indicate the surgical procedure. c Serum albumin lev- mated mean ± SE (standard error) was represented, and Bonferroni els were measured on surgery day and before sacrifice. Linear mixed method was used to calculate adjusted p-values: **p < 0.001 Obesity Surgery (Fig. 2b). Following recovery and introduction of solid diet conducted post-surgically (Fig. 3d). However, the AUC OGTT (weeks 14–16), there was an increase in the food intake in calculated in the follow-up period, decreased in both experi- the operated rats reaching similar values as the Sham group mental groups compared to the pre-surgery values (p < 0.05). until the end of the study. Serum albumin levels in Sham rats revealed a significant Glucose Metabolism Indicators increment at the time of sacrifice compared to basal val- ues (Fig. 2c). On the opposite, SADJB-SG group evidenced Fasting glucose levels in SADJB-SG animals were lower a decrease in albumin levels at the time of sacrifice when 12 weeks after surgery (Fig.  4a). In addition, it was also compared to the basal measurement (p < 0.001). Moreover, observed that in the Sham group, fructosamine levels at sac- SADJB-SG rats had lower albumin blood concentration in rifice were increased compared to the basal measurement, the sample obtained at sacrifice compared to the Sham group whereas the surgery significantly reduced (p < 0.001) long- (p < 0.001), consistent with body weight data. term fructosamine levels in SADJB-SG (Fig. 4b). Regarding fasting insulin levels, a significant increase (p < 0.05) was OGTT observed in SADJB-SG group at sacrifice (Fig. 4 c). On the other hand, HOMA-IR was lower in the SADJB-SG group The OGTT performed before surgery showed a similar (Fig. 4d), indicating a reduced insulin resistance in these profile in both experimental groups (Fig.  3a). In post-sur- animals. gery (Fig. 3b) and follow-up (Fig. 3c) tests, there was an important increase in blood glucose concentration 30 min after glucose overload in SADJB-SG (p < 0.001). Follow- Eec ff ts of SADJB‑SG Surgery on Stomach ing glycemic increment, the glucose concentration declined Size and Gastric Emptying to levels similar to those of the Sham group at 120 min. Moreover, in the follow-up test, glycemia in the SADJB- There was no difference in stomach area in the pre-operative SG group was significantly lower than in Sham at 120 min radiological study. Values were around 5 cm , both in Sham (Fig. 3c). Calculated AUC was higher in SADJB-SG and SADJB-SG animals. Before sacrifice, the radiological OGTT rats (p < 0.05) compared to Sham group in the OGTT test study showed that the mean area of the stomach did not Fig. 3 The OGTT was performed prior to surgery (a), 2  weeks (b), used for repeated measures analysis over time. Estimated mean ± SE and 9  weeks (c) post-surgery. d The OGTT data were used to cal- (standard error) was represented, and Bonferroni method was used to culate the area under the curve (AUC ). Linear mixed models were calculate adjusted p-values: *p < 0.05 and **p < 0.001 Obesity Surgery Fig. 4 Graphical representation of the glycemia-related parameters. model assessment of insulin resistance (HOMA-IR). Data represent a Fasting glucose, b fructosamine, and c insulin blood concentra- estimated mean ± SE (standard error), and Bonferroni method was tions were measured just before surgery and sacrifice. d Homeostasis used to calculate adjusted p-values: *p < 0.05 and **p < 0.001 change in the Sham group compared to pre-surgery values, to those reported both in humans and GK rats [22, 24]. whereas in SADJB-SG, it was 42% smaller than the stomach However, weight loss was higher than we expected, as final in the Sham group (Fig. 5a). Indeed, gastric emptying was stomach size reduction in our surgical modification was 42% accelerated in SADJB-SG rats, and the effect was significant measured on the radiographic study, instead of the usual between 6 and 8 h after barium administration (Fig. 5b); 80% resection in sleeve gastrectomy [24–26]. According to moreover, it was even evident in the radiological images at the analyses we have carried out in this study, we are unable t = 0, where a significant amount of barium could be seen in to determine whether this weight loss is due to a gut rerout- the intestine of the operated rats (Fig. 5c). ing or to a reduction in energy intake as described in other metabolic surgeries in humans [27]. Histological Evaluation of the Esophagus On the other hand, coupled with weight loss, SADJB-SG led to a decrease in serum albumin levels that could indi- Distal esophagus histology was normal in both SADJB-SG cate a poorer nutritional status in SADJB-SG group. Pro- and Sham groups. Specifically, no signs of esophagitis such tein deficiency after metabolic bariatric surgery remains the as mucosal and submucosal eosinophilia were detected in most severe macronutrient complication in bariatric surgery, any experimental group (Fig. 6). especially in derivative procedures such as BPD and RYGB, where protein supplementation might be needed [23]. An improvement in glucose homeostasis following Discussion SADJB-SG was observed. Fasting glycemia and HOMA-IR showed a significant long-term decrease after surgery, indi- Despite promising pharmacotherapies, metabolic surgery cating a lower insulin resistance in these animals [12, 28]. remains the most effective strategy for the treatment of Furthermore, elevated fasting insulin levels were found in obesity and T2DM [22, 23]. In this study, SADJB-SG was the SADJB-SG group. This finding could be correlated with performed in GK rats with similar mortality and associ- improved pancreatic beta-cell function as a consequence of ated medical complications, as previously described [16]. the surgical procedure [26, 29, 30]. Moreover, fructosamine We observed that SADJB-SG led to substantial weight loss was significantly lower in the SADJB-SG group at follow-up despite similar food intake compared to the Sham group supporting the improvement in glucose homeostasis during from the second week post-surgery. These results are similar the preceding 2 weeks before sacrifice [31]. Obesity Surgery Fig. 5 Radiological study and analysis of the images using the SG rats before sacrifice. c Representative images of both experimen- ImageJ software. a Stomach area analysis was performed at T0, right tal groups, before surgery and sacrifice. Linear mixed models were after barium administration, both pre-surgically and pre-sacrifice. The used for repeated measures analysis over time. Estimated mean ± SE reduction observed after surgery was 42% in the SADJB-SG group. b was represented, and Bonferroni method was used to calculate Analysis of the contrast density in the stomach for 24 h after barium adjusted p-values: *p < 0.05 and **p < 0.001 administration showed an increase in gastric emptying in the SADJB- However, post-surgery and follow-up OGTT tests showed of new-onset gastroesophageal reflux disease (GERD), or a significant increase in glycemia 30 min after overload. even a worsening of GERD symptoms prior to surgery There is evidence to support this phenomenon that has also [35]. A meta-analysis showed a significant worsening of been observed after vertical sleeve gastrectomy (VSG) in GERD in 19% of the patients and 23% of de novo GERD mice [32] or following RYGB [30] and sleeve gastrectomy [36]. Moreover, Ser and colleagues reported a 5-year in GK rats [26]. This increase implied a higher post-surgical follow-up study demonstrating de novo GERD in 30.6% AUC in the SADJB-SG animals. AUC is an index of whole of patients after SADJB-SG [15]. GERD has also been glucose excursion after glucose loading that reflects glyce- described in rats after sleeve gastrectomy [37].  Despite mic variability, which is proposed to be harmful for blood GERD was not demonstrated in either the SADJB-SG vessels and affect the development of medical complications or the SHAM group in our study, this procedure cannot [19]. In our model, we can attribute this increase in glycemia be recommended in all types of patients on the sole basis after overloading to a faster gastric emptying as observed of this finding. in previous studies, performing VSG and RYGB [33]. This This study has some limitations. Data concerning other phenomenon could increase glucose availability in the jeju- hormones involved in glucose metabolism (i.e., ghrelin, num, where anastomosis was performed in SADJB-SG, GLP-1, GIP…) would be needed to fully understand the and most of the glucose uptake occurs through the sodium- metabolic effects of SADJB-SG in GK rats. On the other dependent glucose transporter 1 (SGLT1) [34]. hand, the translation of results obtained in animal models to From a clinical point of view, an important issue related humans is complex and the risks/benefits balance must be to sleeve and sleeve-plus procedures is the development carefully evaluated [15, 38]. Obesity Surgery Fig. 6 Representative light microphotographs correspond- ing to hematoxylin–eosin staining in the Sham (a) and in the SADJB-SG (b) groups. Magnification: 40 × , on the left; 100 × , on the right Conclusion Declarations Competing Interests The authors declare no competing interests. SADJB-SG technique in GK rats led to an improvement in glucose homeostasis. Further studies are needed to elucidate Open Access This article is licensed under a Creative Commons Attri- the molecular mechanisms involved in insulin resistance and bution 4.0 International License, which permits use, sharing, adapta- glucose metabolism improvement. tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes Author Contribution The approach and conceptualization of the project were made. The images or other third party material in this article are has been developed by Maria Ruth Pazos (MRP), Sirio Melone (SM) included in the article’s Creative Commons licence, unless indicated and Jose Maria Fernandez (JMF). MRP and SM have developed the otherwise in a credit line to the material. If material is not included in methodology and, together with Mario Amores (MA), have carried the article’s Creative Commons licence and your intended use is not out the surgical procedures, sampling and animal care. Carlos Gui- permitted by statutory regulation or exceeds the permitted use, you will jarro (CG) and Sagrario Martinez Cortijo (SMC) contributed to the need to obtain permission directly from the copyright holder. To view a technical assessment. Raquel Abalo (RA) and Yolanda Lopez-Tofiño copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. (YLT) performed the radiographic study, as well as the analysis of the images and provided assistance in the interpretation of the results. Juan Manuel Acedo (JMA) contributed to measuring biochemical param- eters. Elena Garcia-Garcia (EGG) has carried out the histological study. References Elia Perez-Fernandez (EPF) has conducted statistical analysis. MRP prepared the figures. MRP and SM drafted the manuscript. 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Impact of Metabolic Bariatric Surgery on Outcomes and the 10-Year Risk of Major Adverse Authors and Affiliations 1,2 3 2 1 2 Sirio Melone  · Jose Maria Fernandez‑Cebrian  · Mario Amores  · Yolanda Lopez‑Tofiño  · Elia Perez‑Fernandez  · 2 2 1,2 1,2 1 Elena Garcia‑Garcia  · Juan Manuel Acedo  · Carlos Guijarro  · Sagrario Martinez Cortijo  · Raquel Abalo  · 2,4 Maria Ruth Pazos * Sirio Melone Juan Manuel Acedo [email protected] [email protected] * Maria Ruth Pazos Carlos Guijarro [email protected] [email protected] Jose Maria Fernandez-Cebrian Sagrario Martinez Cortijo [email protected] [email protected] Mario Amores Raquel Abalo [email protected] [email protected] Yolanda Lopez-Tofiño Universidad Rey Juan Carlos, Alcorcón, Spain [email protected] Hospital Universitario Fundación Alcorcón, Madrid, Spain Elia Perez-Fernandez [email protected] Hospital Universitario Ramón y Cajal, Madrid, Spain Elena Garcia-Garcia Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain [email protected]

Journal

Obesity Surgery – Springer Journals

Published: May 1, 2025

Keywords: Metabolic bariatric surgery; Duodenojejunal bypass; Diabetes mellitus; Goto-Kakizaki rats

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