The Effectiveness And Mechanism Of Gastrointestinal Surgery As A Treatment For Nonobese Type 2 Diabetes In GK Rats

BackgroundType 2 diabetes mellitus presently afflicts more than 170 million people worldwide and is expected to affect about 366 million persons by 2030. The complications of diabetes have rendered the disease a major cause of morbidity and mortality that strains public health care funding. Diet contrrol, exercise, behavior modification, oral hypoglycemic agents and insulin therapy have little efficacy with respect to the return of euglycemia. Because of graft rejection, the side effect of immunosuppression, higher complication rate and other factors, it has restricted the clinical application of the pancreatic gland transplant and the islet cells transplant. Therefore, seeking for a safe, satisfying compliance and long-term effective method of improving the diabetes is a key problem at present which is worth discussing intensively.Early in 1980s, a wide array of investigations has shown bariatric surgery to be an effective means of not only resolving obesity and its co-morbidities, but also well improving the blood sugar, insulin, glycosylated hemoglobin and insulin sensibility, even people can be completely far away from any drug. Because euglycemia often occurs long before significant weight loss after bariatric surgery, the control of diabetes likely stems from direct effects of the operations rather than amelioration of obesity. Moreover, a great amount of retrospective analysis and prospective study were made on the efficacy of other bariatric surgeries, such as gastric bypass (GBP), biliopancreatic diversion (BPD), sleeve gastrectomy (SG), and ileal transposition (IT), it also showed better control of diabetes what most patients in the study were cured or well improved and no recurrence after 10 years. It is put forward if it is possible that the bariatric surgery is effective for non-morbidly obese individuals? And then what are the mechanisms? Researchers have conducted related research and proposed kinds of theory hypotheses, but no comprehensive or systematic theories formed.It supposed that the alteration of gastrointestinal hormone and some endocrine factors plays an important role in the progress of type 2 diabetes. Hormones such as GLP-1 and GIP are related to enteroinsular axis, leptin, resistin and adiponectin are related to adipoinsular axis, insulin-like growth factor-1 (IGF-1) and inflammation mediators also changed and have a synergistic effect.In order to study the effect and mechanism involved in the associations between gastrointestinal intervention and type 2 diabete, and provide the most effective procedure for the treatment of type 2 diabetes, nonobese type 2 diabetic animals were chosen and with respect to the purpose:Firstly, compare and evaluate the efficacy of different kinds of operations to further confirm the resolution of gastrointestinal surgery. Secondly, provide the optimal choice for controlling type 2 diabetes. Finally, study certain factors related to the pathogenesis of diabetes, explore and bring forward the possible mechanisms of gastrointestinal intervention for type 2 diabetes for the purpose of providing supports for the transition of gastrointestinal interventios to clinical application.PartⅠConstruction of animal models of nonobese type 2 diabetesObjectivGK rats, the nonobese spontaneously diabetes rats were randomly divided into the operation groups and the sham operation groups, and all rats underwent different kinds of gastrointestinal operations. The live function and renal function of the GK rats were detected after operations.Methods(1) Selection of type 2 diabetes animalFirst, the 8-10 weeks old GK rats were selected and fasting glycemia, plasma lipid (cholesterol, triglycercide and free fatty acid), liver function (serum total protein and albumin), and renal function (creatinine and blood urea nitrogen) were measured before the intervention in order to evaluated the stability of type 2 diabetes animal models. Then,120 male GK rats were randomly divided into three gastrointestinal operation groups and the corresponding sham operation groups (n=20 in each) that all rats underwent different kinds of gastrointestinal operations. (2) Surgical groups of gastrointestinal operationsGroup A:Sleeve gastrectomy (SG) surgery was conducted in this group. The SG operation was performed as described by de Bona Castelan J, et al. First, define the the line of incision for the longitudinal sleeve gastrectomy which covered the entire gastric fundus and much of the lumen. Then 70% to 80% of total stomach was dissected and removed.Group B:Roux-en-Y gastric bypass (RYGBP) surgery was performed in this group. The RYGBP operation involved (1) a midline abdominal incision was made, (2) distal gastrectomy, (3) the jejunal was divided 30 cm distal to the ligament of Treitz and the distal limb connected to the stomach, (4) small bowel continuity was maintained by an entero-enterostomy between the previously divided proximal jejunum and the distal limb which was so-called Roux limb and at least 50 cm long.Group C:BillrothⅡsurgery was taken in this group. The BillrothⅡoperation was performed as follows:(1) the duodenum was separated from the stomach, (2) distal gastrectomy, (3) an gastrojejunostomy was made with vestige stomach and proximal jejunum.Sham-A,Sham-B and Sham-C group:Sham surgeries involved the same abdominal incisions, transections and re-anastomosis of the gastrointestinal tract at corresponding sites where performed in the SG, RYGBP and BillrothⅡgroups. If necessary, sham operations were prolonged to achieve similar operative times and anesthetic effect as those observed for SG, RYGBP and BillrothⅡ.The surgery time of different groups was strictly recorded, the first defaecation time, serving as an indication of postoperative recovery time, and the occurrence of postoperative complications were observed and recorded carefully.Results(1) Group A:Rate of operative success was 100% of 20 cases and no death occurred in sleeve gastrectomy group. Mean operative time was 47.6±7.5 min, and mean postoperative recovery time (defined to begin at the end of the operation and to end with the first defecation) was 22.4±4.8h.(2) Group B:Rate of operative success was 100% of 20 cases. Mean operative time was 77.8±8.7 min, and mean postoperative recovery time was 49.9±4.9h. Two rats died of intestinal obstruction and one metabolic complication at postoperative 5 day,34 day and 92 day respectively. The postoperative mortality was 15%.(3) Group C:Rate of operative success was 100% of 20 cases. Mean operative time was 53.0±5.1 min, and mean postoperative recovery time was 29.3±4.2h. One rats died of anastomotic leakage on the fourth day. The postoperative mortality was 5%.(4) All the 60 rats of sham surgery groups were performed successfully with no death, and the postoperative survival rate was 100%.(5) Liver function and renal function were gradually recovered during the first week postoperatively and returned to the preoperative level two weeks later. Afterwards, liver function and renal function resumed to normal level and maintained until the end of the 36-week observation period.(6) The operative time, postoperative recovery time and postoperative morbidity were much shorter or lower in group A and there were statistically significant differences between group A and group B or C (P<0.05). The indexes above-mentioned were much longer and higher in group B and there were statistically significant differences between group B and group A or C (P<0.01)Conclusions(1) GK rats exhibit stable as the type 2 diabetes animal models and can meet the requirement for gastrointestinal interventions.(2) Different surgical operations resulted in different effects on the GK rats, and statistically significant differences were observed between groups.PartⅡThe treatment effect of gastrointestinal intervention on nonobese type 2 diabetesObjectivOn the one hand, different kinds of indexes related to type 2 diabetes were measured before and after operation in order to evaluate the efficacy of gastrointestinal surgery, on the other hand, comparisons of the therapeutic effect of different gastrointestinal interventions were made.Methods(1) Weight, fasting glycemia and serum insulin were measured and well documented. In addtion, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were also performed before and at several time points after operation.(2) After the full 36-week observation period ended, all the animals were sacrificed and specific organs were studied by means of pathologic examinations in order to clear the protection of gastrointestinal operation for type 2 diabetes.Results(1) There were statistically significant differences in weight loss of GK rats underwent A, B, and C gastrointestinal surgeries, compared with sham surgery groups and preoperation (P<0.05)(2) It resulted in statistically significant improvement in fasting glucose level, insulin sensibility and serum insulin in GK rats underwent A, B, and C gastrointestinal surgery, compared with sham surgery groups and preoperation (P<0.05). However, there were no statistically significant differences among the three groups (P>0.05).(3) It leaded to significant amelioration on oral glucose tolerance test (OGTT) in GK rats underwent A, B, and C gastrointestinal surgery, compared with sham surgery groups and preoperation (P<0.05).The improvement of OGTT in group A was much better than that in other two groups (P<0.05)(4) The gastrointestinal surgical intervention significantly prevented the aggravation of diabetes in heart, aorta, liver and kidney compared with sham groups by means of pathological examination.Conclusions(1) Remarkably therapeutic effect was observed on type 2 diabetes and sustainable control on glucose metabolism was obtained as a result of gastrointestinal intervention.(2) The surgical procedure played an important and direct role in the improvement of type 2 diabetes which was independent on the weight loss.(3) Different surgical procedure leads to dissimilar effect.PartⅢThe mechanism of gastrointestinal intervention as a treatment for type 2 diabetesObjectivTo further explore the therapeutic mechanism of gastrointestinal intervention as a treatment for type 2 diabetes, gastrointestinal hormones, endocrine factors and inflammation mediators which related to the pathogenesis of type 2 diabetes are selected and measured periodically before and postoperation. Apart from the key goal mentioned above, an optimal surgical procedure should be described and confirmed not only to elucidate the correlation between surgical intervention and type 2 diabetes but to establish and enforce the theoretical basis for the transition to clinical application.Methods(1) Hormones or cytokines related to enteroinsular axis and adipoinsular axis and plasma Ghrelin (growth hormone releasing peptide) were put into study and further to clarify the therapeutic mechanism.(2) The stomach and small intestine were studied in order to explore the compensatory hyperplasia in response to surgical intervention.(3) Data are expressed as mean±SD and trapezoidal integration was applied to calculating areas under curves for OGTT and ITT. Statistical analysis was performed using repeated-measures ANOVA for repeated measures and the Student's t-test as appropriate. All statistical procedures were performed using SPSS version 17.0, P values<0.05 were considered to be statistically significant.Results(1) The result displayed that gastrointestinal intervention significantly increased insulin, GLP-1 and adiponectin (P<0.01), while dramaticlly reduced GIP, FFA and leptin (P＜0.05)(2) Ghrelin levels in group A decreased dramatically after surgery and there were statistically significant differences compared with other groups (P<0.01). GLP-1 levels for group B and group C were statistically significant higher compared with other groups (P＜0.01).(3) The stomach was hyperplastic and hypertrophic after the intervention, and the weight of mucosal in group B and group C was significant higher compared with the sham groups.Conclusions(1) Gastrointestinal intervention is an effective method in the treatment for type 2 diabetes that result in significant and durable glycemic control, and lead to improvement or resolution of diabetes related co-morbidities.(2) The enteroinsular axis performs an important function in the mechanism of diabetes pathogenesis which is related to the short-term effect of gastrointestinal intervention.(3) GLP-1 and GIP play an important role in the improvement of glycometabolism and treatment of diabetes after gastrointestinal intervention via the regulation of enteroinsular axis.(4) Leptin,FFA and adiponectin contribute to the management of diabetes by means of adipoinsular axis which is responsible for the long-term resolution of type 2 diabetes.(5) Due to the decrease of plasma Ghrelin, the inhibition of insulin secretion is released, as a result, the glucose levels, insulin sensitivity and insulin resistance were improved. Therefore the lower level of Ghrelin is considered playing a therapeutic role in type 2 diabetes.(6) SG surgery is the optimal procedure with advantages of acceptably low morbidity and mortality, reliable and durable therapeutic effect on type 2 diabetes.