| Background and Objective：Rapid economic growth, an increase in people’s average life expectancy, and changesin lifestyle have led to a rise in the prevalence of diabetes in China. In the past20years, theprevalence of the disease has increased by four-fold. Today,92.4million adults in Chinasuffer from diabetes, with type2diabetes accounting for93.7%. Chronic complications ofdiabetes include multiple organs, such as diabetic nephropathy, diabetic retinopathy, anddiabetic microvascular disease, all of which contribute to high rates of disability andmortality. In addition to seriously affecting the patient’s quality of life, diabetes places aheavy psychological and economic burden on individuals and families. It also consumeslarge amounts of medical resources. The prevention and treatment of diabetes is a majorsocial health problem that needs to be addressed by the medical profession, the scientificcommunity, and the government.Diet and drug therapy have been the mainstay of type2diabetes therapy for a longtime, but these traditional treatmentshave being only to reduce blood glucose levels, can notfundamentally eliminate the cause of type2diabetes and prevent emerges of chroniccomplications, so the results have been unsatisfactory. In recent years, surgical treatmenthas offered new opportunities to treat the disease. In1965, Mason et al found that the bloodglucose level of morbidly obese patients with type2diabetes who underwent bariatricsurgery begun to decline before major weight loss onset and that the symptoms of type2diabetes were gradually relieved. This suggests that, bariatric surgery has the effect oftreatment of type2diabetes. Thereafter, the clinical effect of bariatric surgery has beenrecognized and accepted by the majority of scholars. At home and abroad in many patientswith type2diabetes, gastric bypass surgery is currently the most widely used surgicalapproach among bariatric surgical approaches. At the2010Global Conference on DiabetesSurgery in Rome, experts agreed that a T2DM patient with a BMI≥35kg/m2may choose gastrointestinal surgery (eg, gastric bypass surgery) if traditional drug treatment provesineffective. The above standards were totally are appropriate in Western populations withBMI≥35kg/m2.However, in China, nonobese type2diabetes patients with an averagebody mass index of around25kg/m2are considered suitable for gastric bypass surgery.Currently, there are insufficient data to determine whether there are other important factorsthat affect the therapeutic effect of bariatric surgery on type2diabetes. In addition, theexact mechanisms of gastric bypass surgery to treat diabetes are not entirely clear, whichlimits the surgical treatment in the clinical application. Many studies have demonstratedthat the remission of insulin resistance after gastric bypass surgery in type2diabetespatients plays an important role in complete diabetes remission. Hepatic insulin resistanceis a driving force in the pathogenesis of type2diabetes mellitus and in insulin resistanceoverall. Research is needed to determine the impact of gastric bypass surgery on the statusof hepatic insulin resistance, the hepatic insulin signaling pathway, and hepatic glucose andlipid metabolism.Therefore, the aim of the present study was to explore the clinical effect of gastricbypass surgery on the treatment of type2diabetes mellitus and the mechanisms underlyingthis effect. An additional aim was to explore the possible mechanisms underlying diabetesremission after gastric bypass surgery.Methods：1. One-year follow-up was carried out on99patients with type2diabetes mellitus whowere treated with gastric bypass surgery at the General Surgery Center of PLA of ChengduMilitary General Hospital from March2009to March2010. During the follow-up, thepatients underwent oral glucose tolerance testing, the insulin release test, and the C-peptiderelease test, and their glycosylated hemoglobin (HbA1c) levels were monitored.2. Goto-Kakizaki (GK) rats were used as an animal model of gastric bypass surgery.The GK rats were randomly divided into2groups: a gastric bypass surgery group (GBP)and a sham-operated control group (CON), with20rats assigned to each group. In the GBPgroup, the gastric stump was cut and closed about3cm above the gastric antrum. Thejejunum was transected at the distal5cm of the Treitz ligament. Stomach-intestinalanastomosis was conducted at the distal bowel using6-0polyester thread sutures.Side-to-side anastomosis of the jejunum and proximal bowel was conducted10cm from theanastomotic site. In the CON group, after the abdominal incision was cut, the jejunum was transected at the distal5cm of the Treitz ligament, and jejunum to jejunum anastomosiswas conducted. Blood glucose and lipids were detected at regular time intervals aftersurgery. Samples were harvested4weeks after surgery, frozen in liquid nitrogen, and fixedto correlated indices.3. Blood glucose was detected by a blood glucose meter, triglyeride (TG) was detectedby an automatic biochemical analyzer, and free fatty acids (FFA) was determined by ELISA(double antibody sandwich method). Insulin signaling pathway key molecules, insulinreceptor substrate-2(IRS-2), Akt, and phospho-Akt expression in liver tissue were detectedby Western blot. The expression of phosphoenolpyruvate carboxykinase (PEPCK) andglucose-6-phosphatase (G-6-Pase), key enzymes involved in gluconeogenesis, in the livertissue were detected by real-time PCR.Results:1. General results of type2diabetes patients who underwent gastric bypass surgeryAmong the99patients,79had a complete response (79.80%),9had to useglucose-lowering drugs (9.09%), and the surgery was ineffective in11(11.11%). One-wayANOVA showed that the body weight, BMI, levels of C-peptide at each time point,0.5hPG,1hPG,0.5hIns, and1hIns of the79patients in the total remission group showed asignificant difference compared to the other2groups.2. ANOVA of the preoperative-related indicators of type2diabetes patients whounderwent gastric bypass surgeryThe average duration of the complete remission group (4.3±3.8years) was shorterthan that of the other two groups (7.6±3.8years; P<0.05). The weight and BMI in thecomplete remission group showed a significant difference compared to the other2groups(P<0.05or0.01). After gender, age, body weight, and BMI were corrected, the means of theC-peptide levels at each time point, the blood glucose levels at the30min and1h oralglucose tolerance test (OGTT) time points, and the insulin levels at the30min and1hOGTT time points were significantly different between the complete remission group andthe other two groups. The AUC and peak levels of C-peptide, adjusting for gender, age,weight, and BMI, were also significantly different between the complete remission groupcompared with the other2groups (P<0.05or0.01).3. Multivariate analysis of the preoperative-related indicators of type2diabetespatients who underwent gastric bypass surgery A shorter duration of disease, a larger BMI, fasting plasma C-peptide levels, andOGTT1h insulin were independent predictors of postoperative type2diabetes remission.4. Changes in the blood glucose level in the GK rats after gastric bypass surgeryBoth fasting and OGTT2h glucose in the GK rats were significantly decreased afterthe gastric bypass surgery. Fasting blood glucose levels decreased significantly2and4weeks after the gastric bypass surgery compared with preoperative levels (P<0.05). OGTT2h glucose levels were also significantly lower4weeks after the gastric bypass surgerycompared with preoperative levels (P <0.05). Blood glucose levels were significantly lowerin the GBP group2and4weeks after the surgery compared with those of the CON group atthe same time points (P<0.05).5. Changes in the FFA and TG levels in the GK rats after gastric bypass surgerySerum FFA levels were significantly lower4weeks after the gastric bypass surgerythan before the surgery (P<0.05). Serum FFA levels were significantly lower4weeks afterthe surgery in the GBP group than in the CON group at the same time points (P<0.05). Theserum FFA levels of the CON Group did not change significantly4weeks before and afterthe surgery (P>0.05). Four weeks after the gastric bypass surgery, the serum TG levels weresignificantly lower than those before surgery (P<0.05). The serum TG levels of the GBPgroup were also significantly lower4weeks after the surgery compared with those in theCON group at the same time point (P<0.05). In the CON group, the serum TG levels didnot change significantly4weeks before and after the surgery (P>0.05). In addition, theserum TG levels in the CON group showed large fluctuations throughout the4-week period.6. Glycogen staining results in liver tissue after gastric bypass surgeryFour weeks after the surgery, the hepatocellular glycogen content in the GBP groupincreased significantly, showed abundant glycogen granules, and deep staining comparedwith the control group. Quantitative statistical analysis showed that the diabetes glycogenarea percentages in the GBP group were significantly higher than those in the CON group,and the difference was statistically significant (P<0.01).7. Lipid deposition in liver tissue after gastric bypass surgerySlices of liver tissue slices stained with oil red O showed stained areas of lipiddeposition in the CON group4weeks after the surgery that were more numerous and largerthan those in the GBP group at the same time point. Quantitative analysis showed that lipidaccumulation in the liver tissue of the GBP group greatly improved compared to that in the CONgroup(P <0.05).8. Hepatic insulin signaling pathway protein expression in the GK rats after gastricbypass surgeryThe expression of the IRS-2protein decreased significantly in the former comparedwith the CON group (P<0.05). The P-Akt content was significantly increased in the GBPgroup compared with the CON group (P<0.05). However, the total Akt protein content inthe GBP group did not show a significant increase compared to the CON group (P>0.05).9. Gene expression of key enzymes involved in gluconeogenesis in the liver tissueafter gastric bypass surgery in GK ratsThe expression of the liver PEPCK and G-6-Pase enzymes was significantly higher inthe CON group than in the GBP group (P<0.05). Gastric bypass surgery decreased theexpression of the PEPCK and G-6-Pase genes.Conclusion:1. Gastric bypass surgery has a notable effect on patients with type2diabetes mellitus.Gastric bypass surgery may achieve satisfactory results, even for nonobese type2diabetespatients with a BMI≥25kg/m2.2. The duration of diabetes, BMI values, fasting C-peptide values, and1hPG insulinlevels can be used as reliable predictors of the clinical effect of gastric bypass surgery ontype2diabetes.3. Gastric bypass surgery, in addition to effectively alleviating diabetes, can alsoreduce FFA levels and thus improve hepatic insulin signal transduction and relieve hepaticinsulin resistance. Changes in the anatomical intestinal position following bariatric surgerydecreases the absorption of nutrients, and this may be the initiating factor that leads to thedecline in glucose and FFA levels.4. Gastric bypass surgery can decrease the expression of the IRS-2protein, andincrease the expression of phospho-Akt, thereby improving insulin resistance at themolecular level. This, in turn, reduces liver the gene expression of PEPCK and G-6-Pase,inhibits gluconeogenesis, and promotes glycogen synthesis. As a result, glycogendeposition is increased, and hepatic glucose output and blood glucose are reduced. |
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