Gastric volume reduction is essential for the remission of type 2 diabetes mellitus after bariatric surgery in nonobese rats

doi:10.1016/j.soard.2016.04.018

Surgery for Obesity and Related Diseases

Volume 12, Issue 8, September–October 2016, Pages 1569-1576

https://doi.org/10.1016/j.soard.2016.04.018 Get rights and content

Abstract

Background

Roux-en-Y gastric bypass (RYGB) has shown positive outcomes in the remission of type 2 diabetes (T2D) and weight loss in obese patients by inhibiting food intake and nutrient absorption as well as inducing favorable hormonal changes. The purpose of the present study was to investigate whether gastric volume reduction is still required in addition to intestinal bypass for the purpose of T2D remission in nonobese patients.

Setting

University Medical Center.

Methods

Nonobese T2D Goto-Kakizaki rats were employed in the study. All rats were randomized into 3 groups according to the surgical procedure performed, including (1) RYGB, (2) duodeno-jejunal bypass (DJB) without gastric volume reduction, and (3) sham surgery (control). In addition, age-matched Wistar rats were adopted as normal nondiabetic controls. Weight, food intake, fasting plasma glucose, and intraperitoneal glucose tolerance test were measured in vivo before and 2, 4, and 8 weeks after the treatment. Whole body metabolic parameters including respiratory exchange ratio, energy expenditure, and activities were also recorded in all animals at the third week postoperatively.

Results

Compared with DJB and sham animals, the RYGB group had lower weight, less food intake, lower fasting plasma glucose, and improved glucose tolerance at all measuring time points postoperatively. By measuring whole body metabolic parameters, we found that RYGB, but not DJB, increased metabolic rate manifested by increased energy expenditure but less activity at night. In the meantime, respiratory exchange ratio was lower in RYGB group than in the other 3 groups at daytime, meaning adipose tissue became the main source of internal energy production during the resting phase in the group.

Conclusion

For nonobese T2D patients, adding gastric volume reduction to intestine bypass gave better efficacy in remission of T2D by increasing metabolic rate and adipolysis, especially during the resting period.

Section snippets

Animals

The study protocol was reviewed and approved by the Institutional Animal Care and Utilization Committee of Fudan University Pudong Medical Center. A total of 30 male GK rats (a rat model of nonobese T2D)and 10 male Wistar (normal) rats, all aged 8 weeks, were purchased from Shanghai Slyke Laboratory Animal Corp. All animals were housed individually in cages and maintained in a controlled environment with day-night cycles of 12 hours, a relative humidity of 40%–70%, and a temperature of 21–25°C.

Weight and food intake

In this study, weight was measured after 6 hours of fasting. Preoperative and postoperative weight are shown in Fig. 1. DJB had mild weight loss during the postoperative period compared with control animals (P<.01 at the second week, P<.05 at the fourth week with no statistical significance but had trends at the eighth week). Furthermore, compared with DJB and sham animals, the weight of RYGB animals was significantly lower at all measuring time points postoperatively (P<.0001 RYGB versus

Discussion

The present study investigated the effectiveness of gastric volume reduction in addition to intestinal bypass on glycemic control and whole body metabolic changes in nonobese diabetic rats. We found that RYGB preceded DJB in the remission of T2D in these animals. In addition, RYGB animals had elevated energy expenditure and higher adipolysis. RYGB surgery removed about 95% of the stomach volume in these rats, which drastically decreased their food intake and significantly increased weight loss

Conclusion

In the present study, RYGB procedure precedes DJB in remission of T2D in a nonobese T2D GK rat model. In addition, metabolic rate and adipolysis were also increased more in the RYGB group, especially during the resting period. These findings indicated that intestinal bypass was unable to achieve full remission of hyperglycemia. Furthermore, adding gastric volume reduction to intestine bypass gives better efficacy and is essential in the remission of T2D, even in nonobese patients.

Disclosures

The authors have no commercial associations that might be a conflict of interest in relation to this article.

Acknowledgments

Thanks to Yueqian Wang, Lili Gao, and Yongjun Liang for assistance with the experiments and to Tingfeng Wang for a valuable discussion. This study was supported by the Shanghai Bureau of Health and Family Planning Grant (Grant No. 20124443), Shanghai Commission of Science and Technology Grant (Grant No.124119 b1800), and Shanghai Pujiang Telant Project Grant (No. 14 PJ1407800), as well as Pudong Bureau of Health and Family Planning Grants (Grant No. PwRd2013-08, No. PWZxq2014-08). This support

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As a result, food consumption is substantially reduced. Some studies demonstrated that bariatric surgery, including SG and Roux-en-Y gastric bypass, was able to reduce food intake after the operation in rat models [16,17]. Appetite is also an indispensable factor contributing to the loss of food intake.
Obesity is a severe medical problem endangering the health of individuals worldwide. Sleeve gastrectomy (SG), one of the most commonly performed bariatric procedures, has been widely applied to the treatment of such patients. Currently, the potential mechanisms underlying the significant weight loss and metabolic improvement after SG have been well studied. First, and most importantly, by removing a large volume of stomach, the SG directly or indirectly restricts food intake. Then, there are alterations in the absorption and metabolism of both macro- and micronutrients, which may benefit or worsen the patients’ well-being. Another profound change is enhanced secretion of the satiety gut hormone and reduced secretion of the hunger hormone as a consequence of the operation. Additionally, adjustment of gastrointestinal motility, alteration in the gut microbial community, and an inflammatory response were found after surgery. Therefore, the purpose of the present review was focused on such hypotheses and to compile the accumulated facts on the physiologic mechanism of bariatric surgery so that these results can help improve the understanding of how SG produces substantial weight loss and a significant improvement in the metabolism of patients with metabolic syndrome.
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Metabolic and bariatric surgery is effective in ameliorating type 2 diabetes, although its underlying mechanisms are largely unknown. Our previous study indicated that the distinctly expressed duodenal long noncoding RNAs (lncRNAs) induced by the duodenal-jejunal bypass (DJB) might play a role in improving glycemic control via the enteropancreatic axis. Therefore, the physiologic role of the jejunum in metabolic regulation after DJB requires investigation.
To investigate the alterations in the jejunal Roux limb lncRNA expression signatures after DJB and analyze the functional pathways associated with metabolic improvement on a genome-wide scale in high-fat diet–induced diabetic mice.
University medical center.
Diabetic mice induced by high-fat diet were randomly assigned into 2 groups undergoing either DJB or sham surgery. The lncRNA and messenger (m)RNA expression profiles of the Roux limb segment of the jejunum in both groups were investigated using microarray. To identify the functional characteristics of the distinctly expressed lncRNAs, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. The lncRNA-mRNA and lncRNA-transcription factor interaction networks were constructed based on Pearson correlation analysis.
Compared with the sham group, 827 dysregulated (fold change ≥2.0) jejunal lncRNAs were identified in the DJB group. Both Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology enrichment analysis revealed that 601 lncRNA–co-expressed mRNAs (fold change ≥2.0) were associated with neuromodulation-related pathways or biological processes, including serotonergic, glutamatergic, and dopaminergic synapses. In addition, hormonal regulation–related pathways, especially steroid biosynthesis, were also enriched. The results were further confirmed by bioinformatic analysis of target genes or transcription factors predicted on the basis of dysregulated jejunal lncRNAs. Furthermore, the NONMMUT023781 lncRNA may simultaneously target the Adcy8 mRNA both in cis and in trans and participate in neuromodulation and hormonal regulation.
Alterations of jejunal Roux limb lncRNA and mRNA expression profiles trigger both neuromodulation and endocrine-related pathways, which play a critical role in type 2 diabetes remission after metabolic and bariatric surgery via the gut–brain axis. NONMMTU023781 and Adcy8 were identified as potential targets, which warrant further research.
Comparison of the effect by which gastric plication and sleeve gastrectomy procedures alter metabolic and physical parameters in an obese type 2 diabetes rodent model
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Zucker diabetic fatty (ZDF) rats are unable to self-regulate their blood sugar, making them a suitable model for in vivo type 2 diabetes studies [14]. Activity level, energy consumption, food intake, and respiratory exchange ratio (RER) can be monitored in these rats; these parameters reflect the overall metabolism of the individual [15]. Altered levels of ghrelin and glucagon-like peptide (GLP-1) are thought to be involved in the molecular mechanisms by which GP and SG exert their effects [16].
Gastric plication (GP) and sleeve gastrectomy (SG) are 2 restrictive bariatric surgeries that are associated with weight loss and health improvement in patients with obesity. However, differences in how these procedures exert their effects have not been systematically evaluated and compared between techniques.
To investigate the effectiveness of GP and SG surgeries for obese patients with type 2 diabetes based on evaluation of energy metabolism, hormone metabolism, and gastrointestinal dynamics.
University medical center.
Zucker diabetic fatty rats (n = 30) were equally and randomly divided into 3 groups: sham, GP, and SG. Weight, food intake, fasting plasma glucose (FPG), and intraperitoneal glucose tolerance test (IPGTT) were measured in vivo before operation and at 2, 4, and 6 weeks postoperation. Whole-body metabolic parameters including activity, energy expenditure, and respiratory exchange rate (RER) were measured using metabolic cages 3 weeks postoperation. Blood samples were taken 2 weeks before operation and at 2, 4, and 6 weeks postoperation for the purpose of measuring the expression of serum ghrelin and glucagon-like peptide (GLP-1) by enzyme-linked immunosorbent assay. The residual gastric and intestinal propulsive movement were measured at 6 weeks postoperation after all animals were sacrificed.
Compared with sham, the GP and SG procedures achieved near equivalent levels of efficacy as far as weight loss, reduced food intake, and decreased FBG and IPGTT in our rodent model. The GP and SG procedures also provided the same effectiveness as far as altering serum ghrelin and GLP-1 hormones. In addition, results showed that the GP and SG procedures can increase metabolic rate by consuming more energy and reducing activity. RERs in GP and SG animals were lower than in sham animals, which indicates that the energy mainly comes from adipose tissue. Moreover, the GP procedure showed lower gastric residual compared to sham, while the SG procedure did not appear to have this affect; the SG procedure resulted in deficiencies in intestinal propulsion function.
The GP and SG procedures have the same effectiveness and can help improve diabetes control by regulating weight, glucose tolerance, and metabolic hormones and augmenting gastrointestinal dynamics. Therefore, these procedures have great potential as therapies for obesity and type 2 diabetes.
Duodenal long noncoding RNAs are associated with glycemic control after bariatric surgery in high-fat diet-induced diabetic mice
2017, Surgery for Obesity and Related Diseases
Citation Excerpt :
After a 20% (w/v) glucose solution challenge at a dose of 2 g/kg weight, blood glucose levels were measured at 0, 30, 60, 90, 120, 150, and 180 minutes. The area under curve of the glucose excursions during OGTT was calculated using the trapezoidal method [24]. The DJB and sham procedures in mice were adopted from the same operations in rats [24].
The duodenum plays a role in the mechanism of type 2 diabetes remission after bariatric surgery. Roux-en-Y gastric bypass (RYGB) may change gene expression in the duodenum and metabolism. Long noncoding RNAs (lncRNAs) constitute a novel class of RNAs that regulate gene expression. Little is known about how duodenal lncRNAs respond to RYGB. Logically, studies on the changes of duodenal lncRNAs potentially can lead to an understanding of the mechanisms of bariatric surgery, as well as discovery of antidiabetic drug targets and biomarkers predicting postoperative outcome.
To investigate the expression signature of duodenal lncRNAs associated with glycemic improvement by duodenal-jejunal bypass (DJB), a component of RYGB, on a genome-wide scale in high-fat diet–induced diabetic mice.
University medical center.
High fat diet–induced diabetic mice were randomized into 2 groups receiving either the DJB or a sham procedure. Microarray was applied to screen the differentially expressed lncRNAs and messenger RNAs (mRNAs) in the duodenum between the DJB and sham groups, and the result was validated by quantitative real-time polymerase chain reaction in another cohort of animals. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential lncRNA functions. Based on Pearson correlation analysis, the lncRNA-mRNA and lncRNA-transcription factor (TF) interaction networks were constructed to identify and rank core regulatory lncRNAs and transcription factors.
A total of 301 lncRNAs, including 232 that were upregulated and 69 downregulated (fold change≥2.0), were differentially expressed in the duodenum between the DJB and sham groups. GO enrichment indicated that these lncRNA-coexpressed mRNAs were correlated with biological processes including cell proliferation, digestion, and catabolic and biosynthetic processes. KEGG pathway analysis revealed that in addition to the digestion and absorption signaling pathways, pancreatic secretion– and inflammatory process–related signaling pathways were mostly enriched in the DJB group. In addition, the lncRNA-mRNA interaction network combined with GO and KEGG pathway analysis suggested that as a top-ranked gene, NONMMUG021726 may play an important role in the mechanism of type 2 diabetes remission after DJB.
DJB leads to drastic changes in lncRNA and mRNA expressions in the duodenum. The majority of top-ranked lncRNAs and mRNAs have roles in pancreatic secretion and inflammatory processes, implying that bypass of the duodenum may initiate insulin secretion and attenuate inflammation. In addition, modulators of such lncRNAs, most likely NONMMUG021726, have potential to become therapeutic targets or biomarkers for prediction of the outcomes of bariatric surgery.
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Original articleGastric volume reduction is essential for the remission of type 2 diabetes mellitus after bariatric surgery in nonobese rats

Abstract

Background

Setting

Methods

Results

Conclusion

Section snippets

Animals

Weight and food intake

Discussion

Conclusion

Disclosures

Acknowledgments

Diabetes Res Clin Pract

Neuropeptides

Surg Obes Relat Dis

J Urol

Cell Metab

Surg Obes Relat Dis

Surg Obes Relat Dis

J Biol Chem

Mol Cell Endocrinol

Excess mortality among persons with type 2 diabetes

N Engl J Med

Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes

N Engl J Med

Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity

JAMA

Bariatric surgery versus conventional medical therapy for type 2 diabetes

N Engl J Med

Link between increased satiety gut hormones and reduced food reward following gastric bypass surgery for obesity

J Clin Endocrinol Metab

Equivalent increases in circulating GLP-1 following jejunal delivery of intact and hydrolysed casein: relevance to satiety induction following bariatric surgery

Obes Surg. Epub

Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease

Ann Surg

Original article
Gastric volume reduction is essential for the remission of type 2 diabetes mellitus after bariatric surgery in nonobese rats