袖状胃切除术对GK大鼠糖代谢及胃肠激素的影响
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摘要
【研究背景及目的】
最新的研究表明,袖状胃切除术用于治疗肥胖症的同时,病态性肥胖患者合并的2型糖尿病也得到了治疗。术后患者血糖得以有效的控制,其原因是手术治疗肥胖症的继发结果,抑或是胃部被切除直接导致的血糖降低,目前尚未定论。袖状胃切除术是否影响了糖代谢及相关胃肠激素,是否对2型糖尿病有独立的治疗作用,值得进一步探讨。本研究旨在探讨袖状胃切除术对非肥胖个体的2型糖尿病的治疗作用及作用机制。
【研究方法】
通过在非肥胖的2型糖尿病动物模型---GK大鼠上,建立2型糖尿病袖状胃切除模型,在特定的时间点对袖状胃切除手术组,限制饮食组,假手术组以及空白对照组大鼠的体重,进食量进行监测,并采集各组大鼠的血液样本,利用酶联免疫法测定血清中血糖、血胰岛素、胃肠激素水平。通过腹腔注射胰岛素的方法行糖耐量试验,比较手术前后以及各组大鼠的不同时间点上血糖调节功能。通过对各组大鼠的体重、进食量和血糖水平的分析,以及手术前后血糖,血胰岛素,胃肠激素的变化比较,探讨袖状胃切除术对2型糖尿病是否有独立的治疗作用。
【实验结果】
1.各观察组于观察期内体重保持增加。SG组与同一时间点的C组比较,于术后第2周始至术后14周,平均体重均明显低于C组(P<0.01/P<0.05);与同时间点的SO组比较,则于第2,10,14周平均体重低于SO组;与RF组比较则无明显差异。SO组和C组体重总增长率达30%,远大于SG组,但SG组和SO组第2周后的体重增长幅度无差异。SG组术后进食量在14周内一直低于术前(P<0.01)。SO组与SG组于术后进食量相近(P>0.05),而在观察的14周内,C组的进食量明显高于SG组(P<0.001)。
2. SG组平均空腹血糖于术后第2周开始降低,第4,第6周SG组空腹血糖波动在5.2±0.8 mmol/L～5.9±0.6 mmol/L之间,明显低于手术前8.7±1.7 mmol/L(P<0.01)。SG组平均空腹血糖于术后第4,第6周明显低于C组和SO组(P<0.01),也低于RF组(SG vs.RF第4周:5.9±0.6 mmol/L vs. 6.6±0.9 mmol/L,第6周:5.2±0.8 mmol/L vs. 7.1±1.6 mmol/L)。SG组餐后1h血糖于术后开始下降,与手术前相比,术后第2,4,6周餐后血糖均明显降低(P<0.01),术后第10及第14周餐后血糖与术前无统计学差异(P>0.05)
3. SG组于术后第2,第4,第6周糖耐量较术前均有明显改善,与术前相比,曲线下面积AUC分别下降了23%,26%及30%(P≈0.02)。于手术后第10周以后,糖耐量与术前相比,无统计学差异(P>0.05)。C组于第6周至第14周糖耐量较前明显变差(P<0.01)。RF组在饮食控制下,糖耐量一直维持稳定(P>0.05)。
4. SG组血清ghrelin于术后2周下降了50%(术前30.38±2.46ng/ml vs.术后2周15.21±3.88ng/ml),于术后4周以后即完全趋近于0。其余3组血清ghrelin水平于观察期间内并无明显变化,与SG组相比,则明显高于SG组(P<0.001)。SG组血清GLP-1于术后一直保持高水平,第2至第14周血清GLP-1水平波动在29.53±3.18ng/ml～42.55±5.45ng/ml vs.术前13.32±2.24ng/ml(P<0.01)。与其余组相比,SG组血清GLP-1也显著高于其余3组(P<0.01)。SG组于观察期内血清胰岛素、血清GIP水平无明显变化。
【结论】
1.本研究首次在非肥胖型2型糖尿病大鼠上成功地建立了袖状胃切除手术模型,并探讨袖状胃切除术对非肥胖型2型糖尿病的作用。研究发现,GK大鼠在行袖状胃切除术后,体重没有出现持续下降反而稳定增长,进食量则维持正常水平。提示袖状胃切除术对非肥胖个体的作用与对肥胖个体不同,不会导致前者消瘦及营养不良。这一研究发现有助于深入理解袖状胃切除术治疗2型糖尿病的作用机制,亦为后续研究奠定了基础。
2.本研究进一步探讨了GK大鼠袖状胃切除术后糖代谢的变化,发现GK大鼠在术后体重增加和进食量无明显降低的情况下,出现了血糖显著下降和糖耐量明显改善。这一研究发现表明袖状胃切除术对非肥胖型2型糖尿病有显著疗效,并且其治疗作用并不是通过减轻体重和减少进食而实现的。
3.本研究进一步探讨了袖状胃切除术后相关激素水平变化,发现袖状胃切除术能显著降低非肥胖型2型糖尿病模型血清ghrelin水平和显著升高血清GLP-1水平,而对血清胰岛素和血清GIP的水平没有影响。这一研究发现提示袖状胃切除术影响了某些胃肠道激素水平,并可能通过影响这些与糖代谢相关的激素的水平而起到了治疗2型糖尿病的作用。
[BACKGROUND&OBJECTIVE] Many current studies indicate that the sleeve gastrectomy (SG) can effectively induce weight loss and control the development of type 2 diabetes in morbidly obese individuals.But it is still obscure whether the control of diabetes is only a secondary outcome from the obesity treatment or is a direct result of the stomapart exclusion.This study try to explore the concrete mechanism on which SG impacts the development of diabetes.
[METHODS] SG was performed in 13- to 14-week-old Goto-Kakizaki rats,a spontaneous nonobese model of type 2 diabetes .The index about weight, food-intake,fasting glycemia,plasma insulin and plasma levels of gut hormones were respectively measured by ELISA. The SG was challenged against a sham operation,marked food restriction,and control in matched groups of animals.
[RESULTS]
1. Weight and food intake:A progressive increase of weight was observed in all 4 groups.Compared with the group C in the period from week2 to week 14,the average weight of SG group was lower than group C(P<0.01/P<0.05);and at the same time point of week 2,10 and 14,the average weight was lower than the SO group but almost equal to the RF group.Much as the average weight gain reaching 30% in both group of SO and group of C was obviously higher than the average weight gain of SG group in total 14 weeks experimental span, the weight gain of SO had no significant difference with SG group in the experimental span from week 2 to week 14. After the surgical intervention, although the difference of food intake between SG rats and sham-operated animals was insignificant, the food intake of group C was notable higher than the SG group(P<0.001). In addition,food intake in week 14 remains lower than preoperative (P <0.01).
2. FBG and PBG: After SG,.the level of fasting blood glucose was markedly reduced. And mean plasma glucose of 4 weeks and 6 weeks was 5.2±0.8 mmol / L and 5.9±0.6 mmol /L respectively, whereas mean preoperative values were 8.7±1.7 mmol / L (P <0.01). After intervention, SG rats presented a lowest FBG level among 4 groups. Additionally,the level of FBG in SG group was lower than in RF group ( week 4: 5.9±0.6 mmol / L vs. 6.6±0.9 mmol / L, week 6 : 5.2±0.8 mmol / L vs. 7.1±1.6 mmol / L). In 2nd week, the levels of PBG of SG individuals were significantly lower than preoperational(P<0.01)ones,and this trend extended into the 10th week after SG intervention. And there was no significant difference of PBG between week 10 and the preoperative time.
3. IPGTT : After SG, glucose tolerance of the rats was observed a remarkable improvement .Compared with the time of preoperation, the AUC in 2nd,6th and 12th week decreased by 23%, 26% and 30% (P≈0.02) respectively ,and the tendency lasted till week 10.From week 6 to week 14,glucose tolerance got worse in control animals but remained stable in food-restrctived individuals.
4. Hormones: The level of ghrelin decreased 50% in the period of the 14 days after SG(preoperative 30.38±2.46ng/ml vs. After 2 weeks 15.21±3.88ng/ml)and tended to 0 at the 4th week. Among the other three groups, the serum ghrelin levels had no notable change through the entire period.,but the ghrelin level of SG group was significantly lower than the other 3 groups(P <0.001). The GLP-1 level of the SG rates presented a continually high state and was significantly higher than the other three groups (P <0.01) . Serum insulin level and serum GIP level of SG rats presented no remarkable change in 14 weeks.
[CONCLUSION]
1. In this study, we investigated the effect of sleeve gastrectomy in non-obese type 2 diabetic rats. The results reveal that the weight of rats presents a steadily increasing trend and the food intake remains normal after the SG operation. Compared to the obese individuals, the above results infer that the sleeve gastrectomy in non-obese individuals seldom induces emaciation and malnutrition. The findings are beneficial to the further understanding of the mechanism of SG for treating type 2 diabetes.
2. The results show that after SG ,GK rats present a significant decrease in both fasting blood glucose and postprandial blood glucose,an improved trend of glucose tolerance, and a growth of weight. On the other hand, the reduction of food intake is not significant. The study findings suggest that sleeve gastrectomy has a marked therapeutic effect in non-obese type 2 diabetes, and the effect is not the result of weight loss and food-intake reduction.
3. The study reveals that SG can significantly decrease the level of serum ghrelin, increase the level of serum GLP-1 in GK rats, and not influenced the levels of serum insulin and GIP. Therefore, the results infer that SG probably can treat type 2 diabetes through affecting the levels of some gastrointestinal hormones .
最新的研究表明,袖状胃切除术用于治疗肥胖症的同时,病态性肥胖患者合并的2型糖尿病也得到了治疗。术后患者血糖得以有效的控制,其原因是手术治疗肥胖症的继发结果,抑或是胃部被切除直接导致的血糖降低,目前尚未定论。袖状胃切除术是否影响了糖代谢及相关胃肠激素,是否对2型糖尿病有独立的治疗作用,值得进一步探讨。本研究旨在探讨袖状胃切除术对非肥胖个体的2型糖尿病的治疗作用及作用机制。
【研究方法】
通过在非肥胖的2型糖尿病动物模型---GK大鼠上,建立2型糖尿病袖状胃切除模型,在特定的时间点对袖状胃切除手术组,限制饮食组,假手术组以及空白对照组大鼠的体重,进食量进行监测,并采集各组大鼠的血液样本,利用酶联免疫法测定血清中血糖、血胰岛素、胃肠激素水平。通过腹腔注射胰岛素的方法行糖耐量试验,比较手术前后以及各组大鼠的不同时间点上血糖调节功能。通过对各组大鼠的体重、进食量和血糖水平的分析,以及手术前后血糖,血胰岛素,胃肠激素的变化比较,探讨袖状胃切除术对2型糖尿病是否有独立的治疗作用。
【实验结果】
1.各观察组于观察期内体重保持增加。SG组与同一时间点的C组比较,于术后第2周始至术后14周,平均体重均明显低于C组(P<0.01/P<0.05);与同时间点的SO组比较,则于第2,10,14周平均体重低于SO组;与RF组比较则无明显差异。SO组和C组体重总增长率达30%,远大于SG组,但SG组和SO组第2周后的体重增长幅度无差异。SG组术后进食量在14周内一直低于术前(P<0.01)。SO组与SG组于术后进食量相近(P>0.05),而在观察的14周内,C组的进食量明显高于SG组(P<0.001)。
2. SG组平均空腹血糖于术后第2周开始降低,第4,第6周SG组空腹血糖波动在5.2±0.8 mmol/L～5.9±0.6 mmol/L之间,明显低于手术前8.7±1.7 mmol/L(P<0.01)。SG组平均空腹血糖于术后第4,第6周明显低于C组和SO组(P<0.01),也低于RF组(SG vs.RF第4周:5.9±0.6 mmol/L vs. 6.6±0.9 mmol/L,第6周:5.2±0.8 mmol/L vs. 7.1±1.6 mmol/L)。SG组餐后1h血糖于术后开始下降,与手术前相比,术后第2,4,6周餐后血糖均明显降低(P<0.01),术后第10及第14周餐后血糖与术前无统计学差异(P>0.05)
3. SG组于术后第2,第4,第6周糖耐量较术前均有明显改善,与术前相比,曲线下面积AUC分别下降了23%,26%及30%(P≈0.02)。于手术后第10周以后,糖耐量与术前相比,无统计学差异(P>0.05)。C组于第6周至第14周糖耐量较前明显变差(P<0.01)。RF组在饮食控制下,糖耐量一直维持稳定(P>0.05)。
4. SG组血清ghrelin于术后2周下降了50%(术前30.38±2.46ng/ml vs.术后2周15.21±3.88ng/ml),于术后4周以后即完全趋近于0。其余3组血清ghrelin水平于观察期间内并无明显变化,与SG组相比,则明显高于SG组(P<0.001)。SG组血清GLP-1于术后一直保持高水平,第2至第14周血清GLP-1水平波动在29.53±3.18ng/ml～42.55±5.45ng/ml vs.术前13.32±2.24ng/ml(P<0.01)。与其余组相比,SG组血清GLP-1也显著高于其余3组(P<0.01)。SG组于观察期内血清胰岛素、血清GIP水平无明显变化。
【结论】
1.本研究首次在非肥胖型2型糖尿病大鼠上成功地建立了袖状胃切除手术模型,并探讨袖状胃切除术对非肥胖型2型糖尿病的作用。研究发现,GK大鼠在行袖状胃切除术后,体重没有出现持续下降反而稳定增长,进食量则维持正常水平。提示袖状胃切除术对非肥胖个体的作用与对肥胖个体不同,不会导致前者消瘦及营养不良。这一研究发现有助于深入理解袖状胃切除术治疗2型糖尿病的作用机制,亦为后续研究奠定了基础。
2.本研究进一步探讨了GK大鼠袖状胃切除术后糖代谢的变化,发现GK大鼠在术后体重增加和进食量无明显降低的情况下,出现了血糖显著下降和糖耐量明显改善。这一研究发现表明袖状胃切除术对非肥胖型2型糖尿病有显著疗效,并且其治疗作用并不是通过减轻体重和减少进食而实现的。
3.本研究进一步探讨了袖状胃切除术后相关激素水平变化,发现袖状胃切除术能显著降低非肥胖型2型糖尿病模型血清ghrelin水平和显著升高血清GLP-1水平,而对血清胰岛素和血清GIP的水平没有影响。这一研究发现提示袖状胃切除术影响了某些胃肠道激素水平,并可能通过影响这些与糖代谢相关的激素的水平而起到了治疗2型糖尿病的作用。
[BACKGROUND&OBJECTIVE] Many current studies indicate that the sleeve gastrectomy (SG) can effectively induce weight loss and control the development of type 2 diabetes in morbidly obese individuals.But it is still obscure whether the control of diabetes is only a secondary outcome from the obesity treatment or is a direct result of the stomapart exclusion.This study try to explore the concrete mechanism on which SG impacts the development of diabetes.
[METHODS] SG was performed in 13- to 14-week-old Goto-Kakizaki rats,a spontaneous nonobese model of type 2 diabetes .The index about weight, food-intake,fasting glycemia,plasma insulin and plasma levels of gut hormones were respectively measured by ELISA. The SG was challenged against a sham operation,marked food restriction,and control in matched groups of animals.
[RESULTS]
1. Weight and food intake:A progressive increase of weight was observed in all 4 groups.Compared with the group C in the period from week2 to week 14,the average weight of SG group was lower than group C(P<0.01/P<0.05);and at the same time point of week 2,10 and 14,the average weight was lower than the SO group but almost equal to the RF group.Much as the average weight gain reaching 30% in both group of SO and group of C was obviously higher than the average weight gain of SG group in total 14 weeks experimental span, the weight gain of SO had no significant difference with SG group in the experimental span from week 2 to week 14. After the surgical intervention, although the difference of food intake between SG rats and sham-operated animals was insignificant, the food intake of group C was notable higher than the SG group(P<0.001). In addition,food intake in week 14 remains lower than preoperative (P <0.01).
2. FBG and PBG: After SG,.the level of fasting blood glucose was markedly reduced. And mean plasma glucose of 4 weeks and 6 weeks was 5.2±0.8 mmol / L and 5.9±0.6 mmol /L respectively, whereas mean preoperative values were 8.7±1.7 mmol / L (P <0.01). After intervention, SG rats presented a lowest FBG level among 4 groups. Additionally,the level of FBG in SG group was lower than in RF group ( week 4: 5.9±0.6 mmol / L vs. 6.6±0.9 mmol / L, week 6 : 5.2±0.8 mmol / L vs. 7.1±1.6 mmol / L). In 2nd week, the levels of PBG of SG individuals were significantly lower than preoperational(P<0.01)ones,and this trend extended into the 10th week after SG intervention. And there was no significant difference of PBG between week 10 and the preoperative time.
3. IPGTT : After SG, glucose tolerance of the rats was observed a remarkable improvement .Compared with the time of preoperation, the AUC in 2nd,6th and 12th week decreased by 23%, 26% and 30% (P≈0.02) respectively ,and the tendency lasted till week 10.From week 6 to week 14,glucose tolerance got worse in control animals but remained stable in food-restrctived individuals.
4. Hormones: The level of ghrelin decreased 50% in the period of the 14 days after SG(preoperative 30.38±2.46ng/ml vs. After 2 weeks 15.21±3.88ng/ml)and tended to 0 at the 4th week. Among the other three groups, the serum ghrelin levels had no notable change through the entire period.,but the ghrelin level of SG group was significantly lower than the other 3 groups(P <0.001). The GLP-1 level of the SG rates presented a continually high state and was significantly higher than the other three groups (P <0.01) . Serum insulin level and serum GIP level of SG rats presented no remarkable change in 14 weeks.
[CONCLUSION]
1. In this study, we investigated the effect of sleeve gastrectomy in non-obese type 2 diabetic rats. The results reveal that the weight of rats presents a steadily increasing trend and the food intake remains normal after the SG operation. Compared to the obese individuals, the above results infer that the sleeve gastrectomy in non-obese individuals seldom induces emaciation and malnutrition. The findings are beneficial to the further understanding of the mechanism of SG for treating type 2 diabetes.
2. The results show that after SG ,GK rats present a significant decrease in both fasting blood glucose and postprandial blood glucose,an improved trend of glucose tolerance, and a growth of weight. On the other hand, the reduction of food intake is not significant. The study findings suggest that sleeve gastrectomy has a marked therapeutic effect in non-obese type 2 diabetes, and the effect is not the result of weight loss and food-intake reduction.
3. The study reveals that SG can significantly decrease the level of serum ghrelin, increase the level of serum GLP-1 in GK rats, and not influenced the levels of serum insulin and GIP. Therefore, the results infer that SG probably can treat type 2 diabetes through affecting the levels of some gastrointestinal hormones .
引文
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19. Dezaki K, Hosoda H, Kakei M, et al. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2_ signaling in _-cells: implication in the glycemic control in rodents. Diabetes, 2004,53:3142–3151.
20. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab,2001, 86:5083–5086.
21. Egido EM, Rodriguez-Gallardo J, Silvestre RA, et al.Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol 2002,146:241–244.
22. Reimer MK, Pacini G, Ahren B: Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinol,2003, 144:916–921.
23. Ikezaki A, Hosoda H, Ito K,et al. Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes,2002 ,51:3408–3411.
24. Poykko SM, Kellokoski E, Horkko S, et al. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes ,2003,52:2546–2553.
25. Dezaki K, Sone H, Koizumi M,et al. Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes, 2006,55:3486–3493.
26. Dezaki K ,Kakei M,Yada T.Ghrelin Uses G_i2 and Activates Voltage-Dependent K_Channels to Attenuate Glucose-Induced Ca2_ Signaling and Insulin Release in Islet _-Cells Novel Signal Transduction of Ghrelin. Diabetes,2007,56:2319–2327.
27. Balks HJ,Holst JJ,Von zur Muhlen A,et al.Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans:cholinergic control of GLP-1 secretion via muscarinic receptors.J Clin Endocrine Metab,1997,82:786-790.
28. Mason EE.Ileal transposition and enteroglucagon/GLP-1 in obesity surgery.Obes Surg,1999,9:223-228.
1. Buchwald H,Avidor Y,Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA, 2004,292:1724–1737.
2. Moo TA, Rubino F. Gastrointestinal surgery as treatment for type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2008 ,15:153-158.
3. Regan JP, Inabnet WB,Ganger M, et al.Early experience with two-stage laparoscopic Roux-en-Y gastric bypass as an alternative in the super-super obese patient.Obes Surg,2003,13:861-4.
4. J.Vidal, A.Ibarzabal, F.Romero,et al.Type 2 diabetes mellitus and the metabolic syndrome following sleeve gastrectomy in severely obese subjects.Obes Surg ,2008,18:1077-1082.
5. Francesco Rubino. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis: Diabetes Care, 2008 ,31: S290-S296.
6. Gnmbs AA, Gagner M, Dakin G,et al.Review article: sleeve gastrectomy for morbid obesity. Obes Surg ,2007,17:962-969.
7. Cohen RV, Schiavon CA, Pinheiro JS,et al. Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with BMI 22–34: a report of two cases. Surg Obes Relat Dis ,2007,3:195–197.
8. Strader AD, Vahl TP, Jandacek RJ,et al.Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab, 2005 ,288:E447–E453.
9. Scopinaro N, Marinari GM, Camerini GB,et al. Specific effects of biliopancreatic diversion on the major components of metabolic syndrome: a long-term follow-up study. Diabetes Care , 2005,28:2406–2411.
10. Sjostrom L, Lindroos AK, Peltonen M,et al.Lifestyle, diabetes, andcardiovascular risk factors 10 years after bariatric surgery. N Engl J Med ,2004 ,351 :2683–2693.
11. MacDonald KG Jr, Long SD, Swanson MS,et al. The gastricbypass operation reduces the Progression and mortality of non-insulin-dependent diabetes mellitus. Journal of Gastrointestinal Surgery ,1997, 1 :213-C220.
12. Sjostrom CD, Lissner L,Wedel H,et al. Reduction in Incidence of diabetes, hypertension and lipid disturbances after Intentional weight loss induced by bariatric surgery :the SOS Intervention study. Obes Res ,1999 ,7: 477-C484.
13. Knowler WC, Barrett-Connor E, Fowler SE,et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med ,2002 ,346 :393–403.
14. Garcia-Fuentes E, Garrido-Sanchez L, Garcia-Almeida JM ,et al. Different effect of laparoscopic Roux-en-Y gastric bypass and open biliopancreatic diversion of scopinaro on serum pyy and ghrelin levels.Obes Surg ,2003,238:467-485.
15. de Paula AL, Macedo AL, Prudente AS,et al. Laparoscopic sleeve gastrectomy with ileal interposition (“neuroendocrine brake”):pilot study of a new operation. Surg Obes Relat Dis, 2006 ,2:464–467.
16. Mason EE.The mechanism of surgical treatment of type 2 diabetes.Obes Surg,2005,15:459-461.
17. Rubino and Gagner M. Potential of Surgery for Curing Type 2 Diabetes Mellitus Ann Surg 2002,236(5):554-559.
18. Pories WJ, Albrecht RJ. Etiology of type II diabetes mellitus: role of the foregut. World J Surg, 2001,25:527–531.
2.田凤华.中国糖尿病现状及初步分析.中华流行病学杂志,1998,19(6):361-362.
3. J.Vidal, A.Ibarzabal, F.Romero,et al.Type 2 diabetes mellitus and the metabolic syndrome following sleeve gastrectomy in severely obese subjects.Obes Surg ,2008,18:1077-1082.
4. Reimer MK,Pacini G,Ahren B.Dose-dependent inhibition by ghrelin of insulin secretion in the mouse.Endocrinology,2003.144:916-921.
5. Murata M,Okimura Y,Iida K,et al.Ghrelin modulates the downstream moleculates of insulin signaling in hepatoma cells.J Biol Chem,2002,277:5667-5674.
6. Fehmann HC,Goke R,Goke BB.Cell and molecular biology of the incretinhormones glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide.Endocr Rev,1995,16,390-410.
7. Gutniack M,Orskov C,Holst JJ.Antidiabetogenic effect of GLP-1 amide in normal subjects and patients with diabetse mellitus.N Engl J Med,1992,326:1316-1322.
8. Pories WJ, Albrecht RJ. Etiology of type II diabetes mellitus: role of the foregut. World J Surg, 2001,25:527–531.
9. Williamson DF,Thomposon TJ,Thun M,et al.Intentional weight loss and mortality among overweight individuals with diabetes.Diabetes Care.2000,23:1499-1504.
10. Pinkney JH,Sjostrom CD,Gale EA.Should surgeons treat diabetes in severely obese people?Lancet,2001,357:1357-1359.
11. Pories WJ,Swanson MS,Macdonald KG,et al.Who would have thought it?An operation proves to the most effective therapy for adult-onset diabetes mellitus.Ann Surg,1995,222:339-350.
12. Hickey MS, Pories WJ, Macdonald KG,et al.A new paradigm for type 2 diabetes mellitus:could it be a disease of the foregut?Ann Surg,1998,227:637-644.
13. Baltasar A ,Serra C ,Pérez N, et al. Laparoscopic sleeve gastrectomy:a multipurpose bariatric operation. Obes Surg,2005,15:1124-1128.
14.刘冰,秦贞奎,林祥梅等.不同分子量壳寡糖对促胰岛细胞增殖、胰岛素分泌及调节餐后血糖的作用.世界华人消化杂志, 2009, 17(1): 36-42.
15. Francesco Rubino. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable )hypothesis: Diabetes Care, 2008 ,31: S290-S296.
16. Rubino F and Gagner M. Potential of surgery for curing type 2 diabetes mellitus .Ann Surg 2002,236(5):554-559.
17. Kojima M, Hosoda H, Date Y,et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999,402:656–660.
18. Howard AD, Feighner SD, Cully DF, et al.A receptor in pituitary and hypothalamus that functions in growth hormone release. Science, 1996,273:974–977.
19. Dezaki K, Hosoda H, Kakei M, et al. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2_ signaling in _-cells: implication in the glycemic control in rodents. Diabetes, 2004,53:3142–3151.
20. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab,2001, 86:5083–5086.
21. Egido EM, Rodriguez-Gallardo J, Silvestre RA, et al.Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol 2002,146:241–244.
22. Reimer MK, Pacini G, Ahren B: Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinol,2003, 144:916–921.
23. Ikezaki A, Hosoda H, Ito K,et al. Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes,2002 ,51:3408–3411.
24. Poykko SM, Kellokoski E, Horkko S, et al. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes ,2003,52:2546–2553.
25. Dezaki K, Sone H, Koizumi M,et al. Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes, 2006,55:3486–3493.
26. Dezaki K ,Kakei M,Yada T.Ghrelin Uses G_i2 and Activates Voltage-Dependent K_Channels to Attenuate Glucose-Induced Ca2_ Signaling and Insulin Release in Islet _-Cells Novel Signal Transduction of Ghrelin. Diabetes,2007,56:2319–2327.
27. Balks HJ,Holst JJ,Von zur Muhlen A,et al.Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans:cholinergic control of GLP-1 secretion via muscarinic receptors.J Clin Endocrine Metab,1997,82:786-790.
28. Mason EE.Ileal transposition and enteroglucagon/GLP-1 in obesity surgery.Obes Surg,1999,9:223-228.
1. Buchwald H,Avidor Y,Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA, 2004,292:1724–1737.
2. Moo TA, Rubino F. Gastrointestinal surgery as treatment for type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2008 ,15:153-158.
3. Regan JP, Inabnet WB,Ganger M, et al.Early experience with two-stage laparoscopic Roux-en-Y gastric bypass as an alternative in the super-super obese patient.Obes Surg,2003,13:861-4.
4. J.Vidal, A.Ibarzabal, F.Romero,et al.Type 2 diabetes mellitus and the metabolic syndrome following sleeve gastrectomy in severely obese subjects.Obes Surg ,2008,18:1077-1082.
5. Francesco Rubino. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis: Diabetes Care, 2008 ,31: S290-S296.
6. Gnmbs AA, Gagner M, Dakin G,et al.Review article: sleeve gastrectomy for morbid obesity. Obes Surg ,2007,17:962-969.
7. Cohen RV, Schiavon CA, Pinheiro JS,et al. Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with BMI 22–34: a report of two cases. Surg Obes Relat Dis ,2007,3:195–197.
8. Strader AD, Vahl TP, Jandacek RJ,et al.Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab, 2005 ,288:E447–E453.
9. Scopinaro N, Marinari GM, Camerini GB,et al. Specific effects of biliopancreatic diversion on the major components of metabolic syndrome: a long-term follow-up study. Diabetes Care , 2005,28:2406–2411.
10. Sjostrom L, Lindroos AK, Peltonen M,et al.Lifestyle, diabetes, andcardiovascular risk factors 10 years after bariatric surgery. N Engl J Med ,2004 ,351 :2683–2693.
11. MacDonald KG Jr, Long SD, Swanson MS,et al. The gastricbypass operation reduces the Progression and mortality of non-insulin-dependent diabetes mellitus. Journal of Gastrointestinal Surgery ,1997, 1 :213-C220.
12. Sjostrom CD, Lissner L,Wedel H,et al. Reduction in Incidence of diabetes, hypertension and lipid disturbances after Intentional weight loss induced by bariatric surgery :the SOS Intervention study. Obes Res ,1999 ,7: 477-C484.
13. Knowler WC, Barrett-Connor E, Fowler SE,et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med ,2002 ,346 :393–403.
14. Garcia-Fuentes E, Garrido-Sanchez L, Garcia-Almeida JM ,et al. Different effect of laparoscopic Roux-en-Y gastric bypass and open biliopancreatic diversion of scopinaro on serum pyy and ghrelin levels.Obes Surg ,2003,238:467-485.
15. de Paula AL, Macedo AL, Prudente AS,et al. Laparoscopic sleeve gastrectomy with ileal interposition (“neuroendocrine brake”):pilot study of a new operation. Surg Obes Relat Dis, 2006 ,2:464–467.
16. Mason EE.The mechanism of surgical treatment of type 2 diabetes.Obes Surg,2005,15:459-461.
17. Rubino and Gagner M. Potential of Surgery for Curing Type 2 Diabetes Mellitus Ann Surg 2002,236(5):554-559.
18. Pories WJ, Albrecht RJ. Etiology of type II diabetes mellitus: role of the foregut. World J Surg, 2001,25:527–531.