不同肠段小肠旷置术对非肥胖型2型糖尿病大鼠的治疗作用

目的 探讨不同肠段小肠旷置术对非肥胖型2型糖尿病大鼠的治疗作用及其可能机制.方法 将40只自发性糖尿病GK大鼠随机分为胃窄肠始端Roux-en-Y吻合组(旷置十二指肠,A组)、胃空肠近端Roux-en-Y吻合组(旷置十二指肠和近端空肠8 cm,B组)、胃回肠始端Roux-en-Y吻合组(旷置十二指肠和全部空肠,C组)、胃回肠中段Roux-en-Y吻合组(旷置次全小肠,D组)和假手术组(SO组)5组,每组8只.观察术前、术后1、3、6、12、24周各组大鼠体质量、日均摄食量和空腹血糖水平;测定术前、术后1、24周各组葡萄糖负荷后胰岛素和胰高血糖素样肽(GLP)-1浓度.结果 各组手术时间无显著性差异(P>0.05),术后1周各组摄食量和体质量显著下降(P<0.01).与术前比较,各手术组术后1～24周空腹血糖明显降低(P<0.05);而SO组空腹血糖术后1、3、6周均未发生明显变化(P>0.05),术后12、24周显著升高(P<0.01).与SO组比较,各手术组术后1～24周空腹血糖均显著下降(P<0.05).各手术组之间比较,B组术后1～24周空腹血糖均显著低于A组(P<0.05),对血糖控制效果优于A组;但与C组和D组相比无显著性差异(P>0.05).与术前比较,各手术组术后1、24周葡萄糖负荷后30 min胰岛素和GLP-1浓度显著增高(P<0.01),SO组未见显著变化(P>0.05).B组术后1、24周葡萄糖负荷后30 min胰岛素和GLP-1浓度显著高于A组(P<0.05),但与C组和D组差异无统计学意义(P>0.05).结论 小肠旷置术对血糖的控制并不依赖于体质量和摄食量的减少,可能与促进GLP-1分泌进而改善第一时相胰岛素分泌有关.从血糖控制和体质最变化方面评估,旷置十二指肠和近端空肠对非肥胖型2型糖尿病大鼠效果最佳.     

Preserve Common Limb in Duodenal–Jejunal Bypass Surgery Benefits Rats with Type 2-Like Diabetes

Background

In order to understand the underlying mechanisms by which weight loss surgeries improve metabolic profiles in type 2 diabetes mellitus (T2DM) patients and to evaluate the relevance of the length of the common limb in modulating various aspects of metabolism, we performed regular duodenal–jejunal bypass (DJB) and long-limb DJB (LL-DJB) surgeries in Goto-Kakizaki (GK) rats and compared their effects on glycemic control.

Methods

Male GK rats at 12 weeks of age were used for this study. Body weight, food intake, fasting glucose, glucagon-like peptide-1 (GLP-1) level, glucose tolerance, insulin sensitivity, cholesterol and triglycerides levels, and fecal energy content were monitored for 26 weeks after the two types of surgeries.

Results

We performed systematic analyses on GK rats after DJB or long-limb surgeries. Both procedures prevented body weight gain, reduced blood glucose and lipid levels, increased GLP-1 levels, and led to better insulin sensitivity. In general, LL-DJB displayed better effects than DJB, except that both surgeries caused similar increase in GLP-1 levels.

Conclusions

Both DJB and LL-DJB surgeries triggered beneficial effects in GK rats. LL-DJB showed better outcomes than DJB, which may be due to reduced food intake and higher fecal energy content. This indicates that the length of the common limb could influence metabolic profiles of surgery recipients.     

Roux-en Y Gastric Bypass Is Superior to Duodeno-Jejunal Bypass in Improving Glycaemic Control in Zucker Diabetic Fatty Rats

Background

Whilst weight loss results in many beneficial metabolic consequences, the immediate improvement in glycaemia after Roux-en-Y Gastric bypass (RYGB) remains intriguing. Duodenal jejunal bypass (DJB) induces similar glycaemic effects, while not affecting calorie intake or weight loss. We studied diabetic ZDF^fa/fa rats to compare the effects of DJB and RYGB operations on glycaemia.

Methods

Male ZDF^fa/fa rats, aged 12 weeks underwent RYGB, DJB or sham operations. Unoperated ZDF^fa/fa and ZDF^fa/+were used as controls. Body weight, food intake, fasting glucose, insulin and gut hormones were measured at baseline and on postoperative days 2, 10 and 35. An oral glucose tolerance test (OGTT) was performed on days 12 and 26.

Results

DJB had similar food intake and body weight to sham-operated and unoperated control ZDF^fa/fa rats (p?=?NS), but had lower fasting glucose (p?p?fa/fa rats, while RYGB with normalized glycaemia reduced the physiological requirement for raised fasting insulin.

Conclusions

Bypassing the proximal small bowel with the DJB has mild to moderate body weight independent effects on glucose homeostasis and preservation of fasting insulin levels in the medium term. These effects might be further amplified by the additional anatomical and physiological changes after RYGB     

Duodenal�CJejunal Bypass Surgery Does Not Increase Skeletal Muscle Insulin Signal Transduction or Glucose Disposal in Goto�CKakizaki Type 2 Diabetic Rats

Background

Duodenal?Cjejunal bypass (DJB) has been shown to reverse type 2 diabetes (T2DM) in Goto?CKakizaki (GK) rats, a rodent model of non-obese T2DM. Skeletal muscle insulin resistance is a hallmark decrement in T2DM. The aim of the current work was to investigate the effects of DJB on skeletal muscle insulin signal transduction and glucose disposal. It was hypothesized that DJB would increase skeletal muscle insulin signal transduction and glucose disposal in GK rats.

Methods

DJB was performed in GK rats. Sham operations were performed in GK and nondiabetic Wistar?CKyoto (WKY) rats. At 2 weeks post-DJB, oral glucose tolerance (OGTT) was measured. At 3 weeks post-DJB, insulin-induced signal transduction and glucose disposal were measured in skeletal muscle.

Results

In GK rats and compared to sham operation, DJB did not (1) improve fasting glucose or insulin, (2) improve OGTT, or (3) increase skeletal muscle insulin signal transduction or glucose disposal. Interestingly, skeletal muscle glucose disposal was similar between WKY-Sham, GK-Sham, and GK-DJB.

Conclusions

Bypassing of the proximal small intestine does not increase skeletal muscle glucose disposal. The lack of skeletal muscle insulin resistance in GK rats questions whether this animal model is adequate to investigate the etiology and treatments for T2DM. Additionally, bypassing of the foregut may lead to different findings in other animal models of T2DM as well as in T2DM patients.     

Mechanism of gastric bypass-induced body weight loss: One-year follow-up after micro-gastric bypass in rats

Bariatric surgery (Roux-en-Y or mini-gastric bypass) is designed to limit food intake by creating a small gastric pouch and to reduce nutrient absorption by bypassing the long limb of the intestine. We report 1-year follow-up results after micro-gastric bypass in rats. Micro-gastric bypass was performed by anastomosis of the esophagus and the proximal jejunum. Body weight, body composition, bone mineral density, food intake, and serum levels of ghrelin and obestatin were measured. Growing rats had a 40% weight reduction 2 months after micro-gastric bypass surgery compared to 20% after gastrectomy and 30% after stomach bypass (anastomosis of the esophagus and duodenal bulb). Six months after micro-gastric bypass surgery, the rats stopped growing compared to controls that gained continuously due to expansion of the fat compartment. Adult rats (600 g) lost 30% of their body weight 5 months after the micro-gastric bypass, while food intake was not reduced. Serum levels of obestatin (but not ghrelin) were reduced in rats with micro-gastric bypass. The results suggest that micro-gastric bypass efficiently reduced body weight, particularly fat mass; loss of the weight after micro-gastric bypass was not due to reduced food intake; and lean tissue and bone development were impaired in growing subjects after gastric bypass.     

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??Effect of Roux-en-Y gastric bypass on body metabolism in non-obese type 2 diabetes mellitus rates ZHANG Xiong *, YU Bo??WANG Ting-feng, et al. * Center for Metabolic and Bariatric Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
Corresponding author: ZHANG Peng, E-mail??zhangpg@yahoo.com
Abstract Objective To investigate the whole body metabolism in non-obese type 2 diabetes mellitus rats after Roux-en-Y gastric bypass (RYGB) surgery. Methods Non-obese Goto-Kakizaki (GK) rats were randomized into two groups according to the surgical procedure performed including 1) RYGB (n=10), 2) Sham surgery (n=10). In addition, age-matched Wistar rats were employed as normal non-diabetic controls. Fasting plasma glucose and body weight were measured in vivo before and 2, 4, and 8 weeks after the surgery. Activities and metabolic rate of all rats were monitored by metabolic cage system postoperatively. Results Comparing with normal control rats and Sham group, after RYGB surgery, the body weight (P<0.0001), food intake (P<0.0001), fasting plasma glucose (P<0.0001), and free activities at night (P<0.01) were all significantly lower. However the metabolic rate was increased at day (P<0.01) and night (P<0.01). Conclusion RYGB can improve glucose metabolism in non-obese type 2 diabetes mellitus via the mechanism of promoting the overall body metabolism.     

Y型胃旁路术对非肥胖型2型糖尿病大鼠整体代谢水平影响研究

目的 探讨Y型胃旁路术（RYGB）对非肥胖型2型糖尿病（T2DM）大鼠整体代谢水平影响及其意义。方法 将20只非肥胖型T2DM Goto-Kakizaki（GK）大鼠随机分为RYGB手术组和假手术组（Sham）,另取10只健康Wistar大鼠设为正常对照。检测术前以及术后2、4、8周大鼠体重、摄食量和空腹血糖变化,并利用大鼠实时代谢检测系统监测各组大鼠术后整体代谢变化。结果 与正常对照组以及Sham组相比,RYGB术后大鼠体重显著降低（P<0.0001）,摄食量减少（P<0.0001）,空腹血糖明显减低（P<0.0001）,夜间活动量减少（P<0.01）,全天候代谢率均增加（P<0.01）。结论 RYGB手术可改善非肥胖型T2DM的血糖调节,可能与该手术后机体代谢水平提高有关 。     

The effect of selective gut stimulation on glucose metabolism after gastric bypass in the Zucker diabetic fatty rat model

BackgroundPotential mechanisms underlying the antidiabetic effects of Roux-en-Y gastric bypass (RYGB) include altered nutrient exposure in the gut. The aim of this study was to evaluate the effects of selective gut stimulation on glucose metabolism in an obese diabetic rat model.MethodsSixteen male Zucker diabetic fatty rats were randomly assigned to 1 of 2 groups: RYGB with gastrostomy tube (GT) insertion into the excluded stomach or a control group with GT insertion into the stomach. An insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and mixed meal tolerance test (MMTT) were performed before and 14–28 days after surgery. A glucose tolerance test via GT (GTT-GT) and MMTT via GT were performed postoperatively.ResultsPostoperatively, the RYGB group had significant decreases in weight and food intake. Both the ITT and OGTT tests revealed significantly improved glucose tolerance after RYGB. The GTT-GT showed a reversal of the improved glucose tolerance in the RYGB group. In response to meal stimulation, postoperatively, the RYGB group increased glucagon-like peptide 1 (GLP-1) secretion via the oral route and peptide YY secretion by both oral and GT routes.ConclusionWhen foregut exposure to nutrients was reversed after RYGB, the improvement in glucose metabolism was abrogated. This model can be extended to identify the role of gut in glucose homeostasis in type 2 diabetes.     

Duodenal–Jejunal Bypass Improves Glucose Metabolism and Adipokine Expression Independently of Weight Loss in a Diabetic Rat Model

Background

There is accumulating evidence that adipokines lead to a proinflammatory state, which plays crucial roles in insulin resistance and development of type 2 diabetes mellitus (T2DM). Previous studies demonstrated that weight loss after bariatric surgery is accompanied by a suppression of the proinflammatory state. However, the effect of bariatric surgery on adipokine expression beyond weight loss is still elusive. The aim of this study was to investigate the effect of duodenal–jejunal bypass (DJB) on glucose homeostasis and adipokine expression independently of weight loss.

Methods

A T2DM rat model was developed by a high-fat diet and low dose of streptozotocin. Twenty-one diabetic rats and 10 age-matched SD rats were randomly assigned to the DJB group, sham-DJB (S-DJB) group, and control group. For 12 weeks after surgery, their body weight, food intake, glucose homeostasis, lipid parameters, serum adipokine levels, and adipokine gene expression in the mesocolon adipose tissue were measured.

Results

Compared to the S-DJB group, DJB induced significant and sustained glycemic control with improved insulin sensitivity and glucose tolerance independently of weight loss. DJB improved the lipid metabolism by decreasing fasting free fatty acids and triglycerides. Serum leptin and IL-6 significantly decreased 12 weeks after DJB, whereas adiponectin increased and TNF-α remained unchanged. The mRNA expression levels of leptin, TNF-α, and IL-6 decreased, whereas adiponectin increased in the mesocolon adipose tissue.

Conclusion

DJB reduced the proinflammatory adipokines and increased the anti-inflammatory adipokines independently of weight loss, which may contribute to the improvement of insulin sensitivity.     

小肠代谢在十二指肠空肠旁路术对2型糖尿病的治疗作用及机制

目的:观察十二指肠空肠旁路术(DJB)对2型糖尿病(T2DM)大鼠的治疗效果及机制。方法:将高脂饲料联合小剂量链脲佐菌素诱导的T2DM模型大鼠随机分为DJB组和假手术组,每组15只。观察2组大鼠手术前后体质量、空腹血糖及血脂的变化;于术后8周取DJB组大鼠Roux肠袢以及假手术组大鼠相应的肠组织标本,称重并用RT-PCR和Western blot检测参与糖代谢和脂代谢关键酶m RNA和蛋白表达。结果:术前两组空腹血糖、血脂水平、体质量均无统计学差异(均P0.05)。术后DJB组与假手术组比较,空腹血糖水平与各血脂指标均明显降低(均P0.05),但体质量无统计学差异(P0.05);Roux肠袢质量明显增加(2.025 g vs.0.702 g),肠组织参与糖代谢和脂代谢关键酶的m RNA及蛋白水平均明显升高(均P0.05)。结论:DJB能有效降低T2DM大鼠的血糖、血脂水平,该作用可能与术后小肠自身代谢的改变有关。     

Gastrointestinal weight loss surgery for the management of type 2 diabetes: A view from Greece

Several gastrointestinal operations of bariatric surgery, originally designed to achieve and maintain weight loss, can also induce long-term remission of type 2 diabetes mellitus as well as improve other metabolic conditions including hypertension and dyslipidaemia. Moreover, bariatric surgery is increasingly being explored for the treatment of diabetes in moderately obese and non-obese diabetic patients, with positive results. The differences observed amongst the types of bariatric surgery in better control (i.e. sleeve gastrectomy) versus full remission (i.e. Roux-en-Y gastric bypass) of diabetes postoperatively constitute a significant field of study. How surgical gastrointestinal interventions achieve these changes is of a great interest to research, and is evolving rapidly. Several studies have provided evidence that surgical procedures bypassing parts of the small intestine improve glucose homeostasis through mechanisms beyond reduced food intake and body weight. The two major hypotheses put forth to explain these mechanisms are the ‘foregut’ and the ‘hindgut’ hypothesis, focusing on the changes of the secretion pattern of gastrointestinal hormones and neuroendocrine signals observed after surgical manipulation of the gastrointestinal tract. Research to elucidate such weight-independent anti-diabetes mechanisms should facilitate the design of novel anti-diabetic gastrointestinal manipulations, devices and pharmacotherapeutics for obese and non-obese diabetic patients.     

Gastrostomy tube placement in gastric remnant at gastric bypass: a rat model for selective gut stimulation

BackgroundRoux-en-Y gastric bypass (RYGB) surgery achieves high remission rates of type 2 diabetes mellitus in obese diabetic patients. It has been hypothesized that the changes in bowel nutrient exposure after RYGB results in altered release of gut hormones and improved glucose homeostasis. Our objective was to assess the feasibility of, and report on, our technique and initial experience with selective gut stimulation in a gastric bypass rat model at an academic medical center in the United States.MethodsWe performed RYGB with simultaneous placement of a gastrostomy tube in the excluded gastric remnant in 8 obese Sprague-Dawley rats. A second group of 8 obese Sprague-Dawley rats underwent gastrostomy tube placement without gastric bypass and served as the controls. Each rat was tested for oral glucose tolerance preoperatively. On postoperative days 14 and 28, glucose tolerance was re-evaluated using the oral and gastrostomy tube routes.ResultsThe gastrostomy tubes were successfully inserted in all the rats with no tube-related complications. The area under the curve after oral glucose gavage decreased significantly after gastric bypass (P = .01 at 14 d and P = .003 at 28 d). The gastric remnant glucose gavage after RYGB essentially reversed the effects of surgery on glucose metabolism. The areas under the curve showed no significant differences in the control group between the preoperative and postoperative oral or tube results.ConclusionPlacing a gastrostomy tube into the gastric remnant at RYGB in a rat model is technically feasible. Our initial findings support the role of duodenal exclusion in improving glucose metabolism after RYGB.     

十二指肠空肠旁路术治疗2型糖尿病的作用及机制

2型糖尿病是最常见的威胁公众健康的慢性病之一.传统治疗控制血糖的方法效果较差.胃旁路术在治疗病态性肥胖的同时,可以快速、有效、长期地缓解其并发的2型糖尿病,但其机制目前仍不明确.十二指肠空肠旁路术是胃旁路术的一种改良术式,主要用来研究胃旁路术治疗2型糖尿病的机制,对非病态性肥胖的2型糖尿病患者的临床治疗也取得了一些初步的研究结果.本文对十二指肠空肠旁路术治疗2型糖尿病的效果及机制进行总结,以期对胃旁路术改善糖代谢的机制进行进一步的阐述,并对代谢手术治疗糖尿病的临床应用提供理论依据.     

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

BACKGROUND: The Roux-en-Y gastric bypass and the biliopancreatic diversion effectively induce weight loss and long-term control of type 2 diabetes in morbidly obese individuals. It is unknown whether the control of diabetes is a secondary outcome from the treatment of obesity or a direct result of the duodenal-jejunal exclusion that both operations include. The aim of this study was to investigate whether duodenal-jejunal exclusion can control diabetes independently on resolution of obesity-related abnormalities. METHODS: A gastrojejunal bypass (GJB) with preservation of an intact gastric volume was performed in 10- to 12-week-old Goto-Kakizaki rats, a spontaneous nonobese model of type 2 diabetes. Fasting glycemia, oral glucose tolerance, insulin sensitivity, basal plasma insulin, and glucose-dependent-insulinotropic peptide as well as plasma levels of cholesterol, triglycerides, and free fatty acids were measured. The GJB was challenged against a sham operation, marked food restriction, and medical therapy with rosiglitazone in matched groups of animals. Rats were observed for 36 weeks after surgery. RESULTS: Mean plasma glucose 3 weeks after GJB was 96.3 +/- 10.1 mg/dL (preoperative values were 159 +/- 47 mg/dL; P = 0.01). GJB strikingly improved glucose tolerance, inducing a greater than 40% reduction of the area under blood glucose concentration curve (P < 0.001). These effects were not seen in the sham-operated animals despite similar operative time, same postoperative food intake rates, and no significant difference in weight gain profile. GJB resulted also in better glycemic control than greater weight loss from food restriction and than rosiglitazone therapy. CONCLUSIONS: Results of our study support the hypothesis that the bypass of duodenum and jejunum can directly control type 2 diabetes and not secondarily to weight loss or treatment of obesity. These findings suggest a potential role of the proximal gut in the pathogenesis the disease and put forward the possibility of alternative therapeutic approaches for the management of type 2 diabetes.     

Glucose Tolerance in the Proximal Versus the Distal Small Bowel in Wistar Rats

Background  Type 2 diabetes is an epidemic and insulin resistance is the central etiology of this disease. Obesity increases insulin resistance and glucose intolerance and also exacerbates metabolic abnormalities present in type 2 diabetes. Bariatric surgery is the most effective treatment for severe obesity. Most reported series show that return to euglycemia and normal insulin levels occur days after gastric bypass and biliopancreatic diversion, long before major weight loss has taken place. The mechanisms underlying this dramatic reversal of type 2 diabetes following these bariatric procedures are not well understood. Methods  Twelve Wistar rats were fed with a palatable hyperlipidic diet for 12 weeks. Body weight, glucose, and intraperitoneal glucose tolerance test were measured regularly. On day 91, they were randomized in two groups (hindgut and controls) and operated. Twenty-one days later, the tests were done again and the hindgut group re-operated. A duodenal exclusion was done. The results of an intraperitoneal glucose tolerance test were compared after the procedures. Results  Body weight increased regularly in all the rats. Some rats developed hyperglycemia 28 days after beginning hyperlipidic diet, but these levels returned to baseline on days 56 and 84. The glucose tolerance test showed an improvement in glycemic levels in the hindgut group 21 days after the first operation (151 ± 21mg/dl). After the second operation, despite weight loss, the glucose tolerance test of the foregut group worsened again (267 ± 53 mg/dl) (p < 0.01). Conclusion  Comparing the “hindgut hypothesis” and the “foregut hypothesis”, our data show an improvement in the 30 min glucose tolerance test in the hindgut group.     

Effects of Diet on Bile Acid Metabolism and Insulin Resistance in Type 2 Diabetic Rats after Roux-en-Y Gastric Bypass

Background

Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear.

Methods

The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism.

Results

GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet.

Conclusion

RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM.

     

Type 2 Diabetes Control in a Nonobese Rat Model Using Sleeve Gastrectomy with Duodenal–Jejunal Bypass (SGDJB)

Background

As a new bariatric procedure, sleeve gastrectomy with duodenal?Cjejunal bypass (SGDJB) needs further assessment. We compared the diabetic control between SGDJB and sleeve gastrectomy (SG) in Goto?CKakizaki (GK) rats, a nonobese rat model of type 2 diabetes. Our aim is firstly to develop a nonobese diabetic rat model for SGDJB and secondly to investigate the feasibility and safety of SGDJB to induce diabetes remission.

Methods

Fifty 11-week-old male GK rats were divided into five groups: sham-operated SG (SOSG), sham-operated SGDJB (SOSGDJB), control, SG, and SGDJB. Rats were observed for 16?weeks after surgery. The body weight, food intake, glycemic control outcomes, ghrelin, peptide YY (PYY), insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide were measured.

Results

The operated groups showed lower food intake since 4?weeks postoperation and significant weight loss since 6?weeks postoperation. SGDJB and SG surgeries induced a decreased fasting ghrelin level and increased levels of glucose-stimulated insulin, GLP-1, and PYY secretion at 2 and 16?weeks postoperation. Compared with the SG group, the SGDJB group showed higher glucose-stimulated GLP-1 levels. Both SGDJB and SG groups exhibited significant improvement in oral glucose tolerance and insulin tolerance compared with sham-operated and control groups, but there was no difference between the operated groups.

Conclusions

This nonobese diabetic rat model may be valuable in studying the effect of SGDJB on diabetic control. SGDJB shows similar improvement of glucose metabolism with SG. Our findings do not provide evidence for the foregut-mediated amelioration in glucose homeostasis.     

Restoration of Euglycemia After Duodenal Bypass Surgery Is Reliant on Central and Peripheral Inputs in Zucker fa/fa Rats

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system–derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.Obesity is commonly associated with insulin resistance and type 2 diabetes (1). The most effective therapy for alleviating obesity is bariatric surgery (2). In addition to its long-term impact on body weight, a rapid restoration of euglycemia is observed in diabetic patients preceding substantial weight loss (3,4). Despite widespread appreciation of this phenomenon, little is known regarding the underlying mechanism(s). Because insulin resistance is usually a prerequisite for the development of type 2 diabetes, bariatric surgery likely improves insulin sensitivity. To this end, alterations in hormonal milieu and glucomodulatory effects mediated by the gut-brain axis represent two plausible mechanisms. For evaluation of these mechanisms, glucose clamp studies were undertaken in Zucker fa/fa (ZF) rats after duodenal-jejunal bypass surgery (DJB) with and without total subdiaphragmatic vagotomy (TSV). Furthermore, to determine whether improvement in glucoregulation is in part mediated by changes in intestinally derived hormone peptides, we assessed circulating and tissue concentration of a select set of intestinal factors. Our data indicate that DJB was sufficient to rapidly restore euglycemia in ZF rats. This normalization was attributable to improved lipid metabolism, altered patterning of intestinally derived hormones, and insulin sensitivity but was independent of body weight, food intake, and augmented insulin secretion. Importantly, denervation studies underscored the importance of central nervous system (CNS)-derived vagal inputs with respect to hepatic gluconeogenic capacity and regulation of hepatic glucose production (HGP) after DJB.     

Preserving Duodenal-Jejunal (Foregut) Transit Does Not Impair Glucose Tolerance and Diabetes Remission Following Gastric Bypass in Type 2 Diabetes Sprague-Dawley Rat Model

Background

Possible mechanisms underlying diabetes remission following Roux-en-Y gastric bypass (RYGB) include eradication of putative factor(s) with duodenal-jejunal bypass.

Objective

The objective of this study is to observe the effects of duodenal-jejunal transit on glucose tolerance and diabetes remission in gastric bypass rat model.

Method

In order to verify the effect of duodenal-jejunal transit on glucose tolerance and diabetes remission in gastric bypass, 22 type 2 diabetes Sprague-Dawley rat models established through high-fat diet and low-dose streptozotocin (STZ) administered intraperitoneally were assigned to one of three groups: gastric bypass with duodenal-jejunal transit (GB-DJT n = 8), gastric bypass without duodenal-jejunal transit (RYGB n = 8), and sham (n = 6). Body weight, food intake, blood glucose, as well as meal-stimulated insulin, and incretin hormone responses were assessed to ascertain the effect of surgery in all groups. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were conducted three and 7 weeks after surgery.

Results

Comparing our GB-DJT to the RYGB group, we saw no differences in the mean decline in body weight, food intake, and blood glucose 8 weeks after surgery. GB-DJT group exhibited immediate and sustained glucose control throughout the study. Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were also significantly increased from preoperative level in the GB-DJT group (p < 0.05). Insulin and GLP-1 area under curve (AUC) as well as improved glycemic excursion on OGTT did not differ between GB-DJT and RYGB groups. Outcomes with sham operation did not differ from preoperative level.

Conclusion

Preserving duodenal-jejunal transit does not impede glucose tolerance and diabetes remission after gastric bypass in type-2 diabetes Sprague-Dawley rat model.