不同区段的胃肠转流术对2型糖尿病大鼠的治疗效果及胰岛素抵抗的影响

An experimental study of gastrointestinal bypass at different sections for the treatment of the type 2 diabetic rats and the effects on insulin resistance

目的探讨胃转流手术对2型糖尿病大鼠(GK大鼠)的治疗效果及手术后大鼠空腹血糖的变化与胰岛素、胰岛血糖素样肽(GLP-1)的分泌以及胰岛素抵抗作用的相关性。方法运用抽签法将32只GK大鼠随机分成四组(n=8),实施保留全胃、不同区段小肠转流的胃肠转流术(GBP)建立起GK大鼠手术动物模型,分别为:对照组;十二指肠转流组;空肠转流组;回肠转流组。分别于术前第1周及术后第1、3、6、12周采取所有大鼠眼眶后静脉血,动态测定各只大鼠体质量和血液中空腹血糖值;应用酶联免疫吸附试验检测各组大鼠手术前后血清胰岛素、GLP-1的水平,最后计算出各只大鼠胰岛素抵抗指数(HOMA-IR)。结果 (1)全组32只大鼠的手术成功率为90%,回肠转流组大鼠术后3~4周时由于严重营养不良相继死亡;(2)与术前和同时间点对照组相比,GBP手术组术后空腹血糖水平均下降,至术后12周时十二指肠转流组由(14.98±2.17)mmol·L^(-1)下降至(5.23±0.70)mmol·L^(-1)(P<0.05);空肠转流组由(15.20±1.92)mmol·L^(-1)下降至(5.29±0.42)mmol·L^(-1)(P<0.05),且比十二指肠转流组降低较显著;(3)与术前相比,术后除回肠转流组外其余各组GK大鼠的体质量均增加,回肠转流组大鼠体质量术后显著降低(P<0.05);(4)与术前和同时间点对照组相比,GBP手术组术后空腹胰岛素先升高后降低,至术后12周时比术前减少;十二指肠转流组由(14.86±1.22)m U·L^(-1)下降至(9.46±1.10)m U·L^(-1)(P<0.05);空肠转流组由(14.71±1.14)m U·L^(-1)下降至(8.93±1.36)m U·L^(-1)(P<0.05),且比十二指肠转流组下降尤为显著;(5)与术前和同时间点对照组相比,GBP手术组术后GLP-1水平均有不同幅度的升高,至12周时达到最高,十二指肠转流组由(9.38±1.88)升高至(18.96±3.42)(P<0.05);空肠转流组由(9.02±2.20)升高至(23.23±4.17)(P<0.05),且比十二指肠转流组上升较为明显;(6)与术前和同时间点对照组相比,GBP手术组术后大鼠HOMA-IR均下降,至12周时下降明显;十二指肠转流组由(9.97±1.95)下降至(2.21±0.38)(P<0.05);空肠转流组由(9.98±1.39)下降至(2.03±0.23)(P<0.05),且比十二指肠转流组下降略为明显。结论保留全胃的胃肠转流手术对非肥胖型GK大鼠有明显的治疗效果,且与大鼠的体质量增减无关;GBP的最佳转流效应区域可能是小肠中段,即空肠与回肠交界处;术后食物提前进入末端回肠,刺激GLP-1的分泌增多,从而达到GBP对2型糖尿病的治疗作用。

Objective To explore the efficacy of gastrointestinal bypass on type 2 diabetic rats(GK rats) and the correlation between change of fasting blood glucose of rats after the surgery and the secretion of insulin and glucagon-like peptide-1(GLP-1) and the function of islet insulin resistance. Methods Gastrointestinal bypass surgery retaining full stomach and small intestine shunt at different sections was performed to establish type 2 diabetic rats(GK rats) model. Thirty-two GK rats were assigned into four groups(n = 8) :control group,duodenal bypass group,jejunal bypass group and ileal bypass group. Posterior orbit venous blood of rats were collected respectively 1 week before operation and postoperative 1,3,6,12 weeks,and body mass and fasting plasma glucose levels in four groups of rats were dynamically determined; enzyme-linked immunosorbent assay(ELISA) was adopted to test the changes of serum insulin and GLP-1 before and after surgery in all rats. Insulin resistance index(HOMA-IR) was finally calculated. Results In all 32 rats the success rate was 90%. Rats in the ileal bypass group died due to severe malnutrition after 3 to 4 weeks. Compared with preoperation and the same time point in the control group,fasting plasma glucose levels in GBP surgery group dropped after surgery. At 12 weeks after the surgery,fasting plasma glucose levels in duodenal bypass group decreased from 14. 98 ± 2. 17mmol·L^(-1)to 5. 23 ± 0. 70mmol·L^(-1),the difference was statistically significant(P < 0. 05). Fasting plasma glucose levels in jejunal bypass group decreased from 15. 20 ±1. 92 mmol·L^(-1)to 5. 29 ± 0. 42 mmol·L^(-1),the difference was statistically significant(P < 0. 05),and it was particularly significant lower than duodenal bypass group. Compared with preoperation,postoperative body mass of GK rats increased in all groups except ileal bypass group,in which body mass of GK rats decreased significantly after surgery(P < 0. 05). Compared with preoperation and the same time point in control group,postoperative fasting insulin(FINS) in GBP surgery group rose at first,then decreased,which was significantly decreased at 12 weeks. In duodenal bypass group FINS decreased from(14. 86 ± 1. 22) m U·L^(-1)to(9. 46 ± 1. 10) m U·L^(-1),the difference was statistically significant(P < 0. 05),in jejunal bypass group FINS decreased from(14. 71 ± 1. 14) m U·L^(-1)to 8. 93 ±1. 36 m U·L^(-1),the difference was statistically significant(P < 0. 05),and it was particularly significant lower than duodenal bypass group. Compared with preoperation and the same time point in control group,postoperative GLP-1 levels in GBP surgery group increased after surgery,which peaked at 12 weeks. GLP-1 in duodenal bypass group increased from(9. 38 ± 1. 88) to(18. 96 ± 3. 42),the difference was statistically significant(P < 0. 05),GLP-1 in jejunal bypass group increased from(9. 02 ± 2. 20) to(23. 23 ± 4. 17),the difference was statistically significant(P < 0. 05),and the increase was more obvious than that in duodenal bypass group. Compared with preoperation and the same time point in control group,postoperative insulin resistance index(HOMA-IR) of rats decreased in GBP surgery group,which decreased significantly at 12 weeks. HOMA-IR in duodenal bypass group decreased from(9. 97 ± 1. 95) to(2. 21 ± 0. 38),the difference was statistically significant(P < 0. 05). HOMA-IR in jejunal bypass group decreased from(9. 98 ±1. 39) to(2. 03 ± 0. 23),the difference was statistically significant(P < 0. 05),and it was slightly significant lower than duodenal bypass group. Conclusions Gastrointestinal bypass surgery by retaining full stomach is effective in the treatment of non-obese diabetic rats,which has nothing to do with increase or decrease in body mass of rats. The gastric bypass may achieve best effect in the middle of the small intestine,that is the junction of the jejunum and ileum. Food advancing earlier into the terminal ileum after surgery results in the increase of GLP-1,so as to achieve the therapeutic effect of GBP on type 2 diabetes mellitus.