Effect and Mechanism of Sleeve Gastrectomy for Type 2 Diabetes Mellitus in GK Rats_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Shiyun ,  SUN Xuejun , ZHENG Jianbao , WANG Wei , LIU Dong , CHEN Nanzheng , HE Sai , ZHOU Peihua , Wang Xiaolong.

Department of General Surgery， The First Affiliated Hospital， Medical College of Xi’an Jiaotong University， Xi’an 710061， Shaanxi Province， China;

Corresponding author：

SUN Xuejun, Email: sunxy@mail.xjtu.edu.cn

Keywords：

Sleeve gastrectomy; Type 2 diabetes mellitus; Gut hormone; Rat

Video：

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Objective 　To explore the effect and mechanism of sleeve gastrectomy （SG） for type 2 diabetes mellitus （T2DM） in Goto-Kakizaki （GK） rats.
Methods 　Thirteen male GK rats at 12 weeks of age were randomly divided into SG group （n=7） and sham operation group （SO group， n=6）， receiving SG surgery and sham operation respectively.Body weight， food intake in 24hours， fasting plasma glucose， plasma glucagon-like peptide-1 （GLP-1）， and plasma Ghrelin of rats in 2 groups were measured or tested before operation， 1， 4， 10， and 26 weeks after operation. In 10 weeks after operation， fecal energy content of rats in 2 groups was tested， in addition， oral glucose tolerance test （OGTT） and insulin tolerance test （ITT） were performed to investigate the glucose tolerance and insulin sensitivity.　
Results 　①Body weight：there were no significant difference on body weight between the 2 groups （P＞0.05）. Compared with time point of before operation， the body weight of both 2 groups decreased in 1 week after operation （P＜0.01）， but increased in 10 weeks and 26 weeks （P＜0.01）. ②Food intake in 24 hours：compared with SO group， the food intake of SG group were lower in 4 weeks and 10 weeks after operation （P＜0.05）. Compared with time point of before operation， the food intake of SG group were lower in 1， 4， and 10 weeks after operation （P＜0.05）， but lower only in 1 week in SO group （P＜0.05）. ③Value of fasting glucose：compared with SO group， the value of fasting glucose in SG group were lower after operation （P＜0.01）. Compared with time point of before operation， the value of fasting glucose of SG group were lower after operation （P＜0.01）， but decreased in 1 week only in SO group （P＜0.01）. ④Level of serum GLP-1：compared with SO group， the levels of serum GLP-1 in SG group were higher in 4， 10， and 26 weeks after operation （P＜0.05）. Compared with time point of before operation， the levels of serum GLP-1 in SG group were higher in 4， 10， and 26 weeks after operation （P＜0.05）， but levels of serum GLP-1 in SO group didn’t change significantly （P＞0.05）. ⑤Level of serum Ghrelin：compared with SO group， the levels of serum Ghrelin in SG group were lower at all
time points after operation （P＜0.01）. Compared with time point of before operation， the levels of serum Ghrelin in SG
group were lower at all time points after operation （P＜0.001）， but levels of serum Ghrelin in SO group didn’t change significantly （P＞0.05）. ⑥Areas under curves （AUC）：the AUC of OGTT and ITT test in SG group were both lower than those of SO group （P＜0.01）.
Conclusion 　SG surgery can induce the level of fasting plasma glucose， and can
improve glucose tolerance and insulin sensitivity with significant changes of levels of plasma GLP-1 and Ghrelin， sugg-
esting that SG surgery may be a potential strategy to treat patient with T2DM but without obesity or insulin resistance.

Citation： ZHANG Shiyun,SUN Xuejun,ZHENG Jianbao,WANG Wei,LIU Dong,CHEN Nanzheng,HE Sai,ZHOU Peihua,Wang Xiaolong.. Effect and Mechanism of Sleeve Gastrectomy for Type 2 Diabetes Mellitus in GK Rats. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(12): 1363-1368. doi: Copy

1.	Olokoba AB， Obateru OA， Olokoba LB. Type 2 diabetes mellitus：a review of current trends[J]. Oman Med J， 2012， 27(4)：269-273.
2.	Pories WJ， Swanson MS， MacDonald KG， et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus[J]. Ann Surg， 1995， 222(3)：339-350.
3.	Salehi M， Prigeon RL， D’Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans[J]. Diabetes， 2011， 60(9)：2308-2314.
4.	Ramos AC， Galvão Neto MP， de Souza YM， et al. Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI＜30 kg/m2 (LBMI)[J]. Obes Surg， 2009， 19(3)：307-312.
5.	Lemanu DP， Srinivasa S， Singh PP， et al. Laparoscopic sleeve gastrectomy：its place in bariatric surgery for the severely obese patient[J]. N Z Med J， 2012， 125(1359)：41-49.
6.	Galli J， Li LS， Glaser A， et al. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat[J]. Nat Genet， 1996， 12(1)：31-37.
7.	Li F， Zhang G， Liang J， et al. Sleeve gastrectomy provides a bettercontrol of diabetes by decreasing ghrelin in the diabetic Goto-Kakizaki rats[J]. J Gastrointest Surg， 2009， 13(12)：2302-2308.
8.	de Bona Castelan J， Bettiol J， d’Acampora AJ， et al. Sleeve gastrectomy model in Wistar rats[J]. Obes Surg， 2007， 17(7)：957-961.
9.	Pruessner JC， Kirschbaum C， Meinlschmid G， et al. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change[J]. Psychoneuroendocrinology， 2003， 28(7)：916-931.
10.	Pata G， Crea N， Di Betta E， et al. Biliopancreatic diversion with transient gastroplasty and duodenal Switch：long-term results of a multicentric study[J]. Surgery， 2013， 153(3)：413-422.
11.	张晓娟，杜涓，杜潇，等. 腹腔镜下胃转流术治疗肥胖型2型糖尿病的疗效分析[J]. 中国普外基础与临床杂志， 2012， 19(12)：1272-1277.
12.	Bradley D， Conte C， Mittendorfer B， et al. Gastric bypass and banding equally improve insulin sensitivity and β cell function[J].J Clin Invest， 2012， 122(12)：4667-4674.
13.	Guidone C， Manco M， Valera-Mora E， et al. Mechanisms ofrecovery from type 2 diabetes after malabsorptive bariatric surgery[J]. Diabetes， 2006， 55(7)：2025-2031.
14.	Jiménez A， Casamitjana R， Flores L， et al. Long-term effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus in morbidly obese subjects[J]. Ann Surg， 2012， 256(6)：1023-1029.
15.	Jørgensen NB， Jacobsen SH， Dirksen C， et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance[J]. Am J Physiol Endocrinol Metab， 2012， 303(1)：122-131.
16.	Nadreau E， Baraboi ED， Samson P， et al. Effects of the biliopan-creatic diversion on energy balance in the rat[J]. Int J Obes， 2006，30(3)：419-429.
17.	Koivisto VA. Insulin therapy in typeⅡ diabetes[J]. Diabetes Care，1993， 16 Suppl 3：29-39.
18.	Knudsen LB. Glucagon-like peptide-1：the basis of a new class of treatment for type 2 diabetes[J]. J Med Chem， 2004， 47(17)：4128-4134.
19.	Chronaiou A， Tsoli M， Kehagias I， et al. Lower ghrelin levels and exaggerated postprandial peptide-YY， glucagon-like peptide-1， and insulin responses， after gastric fundus resection， in patients undergoing Roux-en-Y gastric bypass：a randomized clinical trial[J]. Obes Surg， 2012， 22(11)：1761-1770.
20.	邓治洲，王烈，林忆阳，等. 胃转流术对非肥胖型2型糖尿病的疗效观察及其对胰高血糖素样肽-1的影响[J]. 中国普外基础与临床杂志， 2009， 16(6)：466-469.
21.	Wang TT， Hu SY， Gao HD， et al. Ileal transposition controls diabetes as well as modified duodenal jejunal bypass with betterlipid lowering in a nonobese rat model of type Ⅱ diabetes by incre-asing GLP-1[J]. Ann Surg， 2008， 247(6)：968-975.
22.	Rubino F， Forgione A， Cummings DE， et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes[J]. Ann Surg， 2006， 244(5)：741-749.
23.	Cummings DE， Overduin J. Gastrointestinal regulation of food intake[J]. J Clin Invest， 2007， 117(1)：13-23.
24.	Kageyama H， F unahashi H， Hirayama M， et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas[J]. Regul Pept， 2005， 126(1-2)：67-71.
25.	Dezaki K， Kakei M， Yada T. Ghrelin uses Galphai2 and activatesvoltage-dependent K+ channels to attenuate glucose-induced Ca2+ signaling and insulin release in islet beta-cells：novel signal transduction of ghrelin[J]. Diabetes， 2007， 56(9)：2319-2327.
26.	Dimitriadis E， Daskalakis M， Kampa M， et al. Alterations in gut hormones after laparoscopic sleeve gastrectomy：a prospectiveclinical and laboratory investigational study[J]. Ann Surg， 2013，257(4)：647-654.
27.	朱占永，严玲玲，吴丹，等. 胃袖状切除对GK大鼠血糖、ghrelin和胰高血糖素样肽-1水平的影响[J]. 中国普外基础与临床杂志， 2011， 18(6)：603-609.
28.	Koshy AA， Bobe AM， Brady MJ. Potential mechanisms by which bariatric surgery improves systemic metabolism[J]. Transl Res， 2013， 161(2)：63-72.

1. Olokoba AB， Obateru OA， Olokoba LB. Type 2 diabetes mellitus：a review of current trends[J]. Oman Med J， 2012， 27(4)：269-273.
2. Pories WJ， Swanson MS， MacDonald KG， et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus[J]. Ann Surg， 1995， 222(3)：339-350.
3. Salehi M， Prigeon RL， D’Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans[J]. Diabetes， 2011， 60(9)：2308-2314.
4. Ramos AC， Galvão Neto MP， de Souza YM， et al. Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI＜30 kg/m2 (LBMI)[J]. Obes Surg， 2009， 19(3)：307-312.
5. Lemanu DP， Srinivasa S， Singh PP， et al. Laparoscopic sleeve gastrectomy：its place in bariatric surgery for the severely obese patient[J]. N Z Med J， 2012， 125(1359)：41-49.
6. Galli J， Li LS， Glaser A， et al. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat[J]. Nat Genet， 1996， 12(1)：31-37.
7. Li F， Zhang G， Liang J， et al. Sleeve gastrectomy provides a bettercontrol of diabetes by decreasing ghrelin in the diabetic Goto-Kakizaki rats[J]. J Gastrointest Surg， 2009， 13(12)：2302-2308.
8. de Bona Castelan J， Bettiol J， d’Acampora AJ， et al. Sleeve gastrectomy model in Wistar rats[J]. Obes Surg， 2007， 17(7)：957-961.
9. Pruessner JC， Kirschbaum C， Meinlschmid G， et al. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change[J]. Psychoneuroendocrinology， 2003， 28(7)：916-931.
10. Pata G， Crea N， Di Betta E， et al. Biliopancreatic diversion with transient gastroplasty and duodenal Switch：long-term results of a multicentric study[J]. Surgery， 2013， 153(3)：413-422.
11. 张晓娟，杜涓，杜潇，等. 腹腔镜下胃转流术治疗肥胖型2型糖尿病的疗效分析[J]. 中国普外基础与临床杂志， 2012， 19(12)：1272-1277.
12. Bradley D， Conte C， Mittendorfer B， et al. Gastric bypass and banding equally improve insulin sensitivity and β cell function[J].J Clin Invest， 2012， 122(12)：4667-4674.
13. Guidone C， Manco M， Valera-Mora E， et al. Mechanisms ofrecovery from type 2 diabetes after malabsorptive bariatric surgery[J]. Diabetes， 2006， 55(7)：2025-2031.
14. Jiménez A， Casamitjana R， Flores L， et al. Long-term effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus in morbidly obese subjects[J]. Ann Surg， 2012， 256(6)：1023-1029.
15. Jørgensen NB， Jacobsen SH， Dirksen C， et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance[J]. Am J Physiol Endocrinol Metab， 2012， 303(1)：122-131.
16. Nadreau E， Baraboi ED， Samson P， et al. Effects of the biliopan-creatic diversion on energy balance in the rat[J]. Int J Obes， 2006，30(3)：419-429.
17. Koivisto VA. Insulin therapy in typeⅡ diabetes[J]. Diabetes Care，1993， 16 Suppl 3：29-39.
18. Knudsen LB. Glucagon-like peptide-1：the basis of a new class of treatment for type 2 diabetes[J]. J Med Chem， 2004， 47(17)：4128-4134.
19. Chronaiou A， Tsoli M， Kehagias I， et al. Lower ghrelin levels and exaggerated postprandial peptide-YY， glucagon-like peptide-1， and insulin responses， after gastric fundus resection， in patients undergoing Roux-en-Y gastric bypass：a randomized clinical trial[J]. Obes Surg， 2012， 22(11)：1761-1770.
20. 邓治洲，王烈，林忆阳，等. 胃转流术对非肥胖型2型糖尿病的疗效观察及其对胰高血糖素样肽-1的影响[J]. 中国普外基础与临床杂志， 2009， 16(6)：466-469.
21. Wang TT， Hu SY， Gao HD， et al. Ileal transposition controls diabetes as well as modified duodenal jejunal bypass with betterlipid lowering in a nonobese rat model of type Ⅱ diabetes by incre-asing GLP-1[J]. Ann Surg， 2008， 247(6)：968-975.
22. Rubino F， Forgione A， Cummings DE， et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes[J]. Ann Surg， 2006， 244(5)：741-749.
23. Cummings DE， Overduin J. Gastrointestinal regulation of food intake[J]. J Clin Invest， 2007， 117(1)：13-23.
24. Kageyama H， F unahashi H， Hirayama M， et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas[J]. Regul Pept， 2005， 126(1-2)：67-71.
25. Dezaki K， Kakei M， Yada T. Ghrelin uses Galphai2 and activatesvoltage-dependent K+ channels to attenuate glucose-induced Ca2+ signaling and insulin release in islet beta-cells：novel signal transduction of ghrelin[J]. Diabetes， 2007， 56(9)：2319-2327.
26. Dimitriadis E， Daskalakis M， Kampa M， et al. Alterations in gut hormones after laparoscopic sleeve gastrectomy：a prospectiveclinical and laboratory investigational study[J]. Ann Surg， 2013，257(4)：647-654.
27. 朱占永，严玲玲，吴丹，等. 胃袖状切除对GK大鼠血糖、ghrelin和胰高血糖素样肽-1水平的影响[J]. 中国普外基础与临床杂志， 2011， 18(6)：603-609.
28. Koshy AA， Bobe AM， Brady MJ. Potential mechanisms by which bariatric surgery improves systemic metabolism[J]. Transl Res， 2013， 161(2)：63-72.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect and Mechanism of Sleeve Gastrectomy for Type 2 Diabetes Mellitus in GK Rats

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