Mechanism Of Surgical Treatment Of Obesity And Type 2 Diabetes Mellitus

BackgroundBariatric surgery (gastrointestinal surgery) is the most effective weight loss treatment resulting in significant weight loss that is sustained for many years. Most patients with morbid obesity undergoing bariatric surgery achieve excellent weight control and are able to reap the clinical benefits of improving metabolic syndrome such as dyslipidemia, hyperglycaemia, hypercholesteremia. But the mechanism of bariatric surgery for treatment of obesity is not fully understood until now.Type 2 diabetes mellitus(T2DM) is a public health problem, affecting more than 150million people worldwide. This number is expected to double in 15 years Recently, evidence for reduction of complications of T2DM with tight control of hyperglycemia has been reported, but current therapies, including diet, exercise, behavior modification, oral hypoglycemic agents and insulin, rarely return patients to euglycemia. There is enough evidence to say that bariatric surgery is an effective form of therapy for T2DM, including non-obese diabetes. But the mechanism of bariatric surgery for treatment of T2DM is not so clear until recently. Some factors that have roles both in obesity and T2DM, such as some hormones and enzymes, have been the focus of considerable attention.Neuropeptide Y(NPY) is a potent stimulator of food intake. It is widely distributed in the central nervous system and circulating blood. NPY not only stimulates feeding behavior, but also decreases energy expenditure. Some studies have shown that chronic intracerebroventricular administration of NPY in normal rats increases food intake and produces a syndrome characterized by obesity, hyperinsulinaemia, increased adipose tissue deposit and muscle insulin resistance. NPY is a major neuromodulator with a role in nutrient partitioning.Peptide YY (PYY) is released postprandially from the L cells in the distal intestinal tract, especially from the terminal ileum and the ascending colon and has been shown to inhibit food intake. Recent reports indicate that intraperitoneal administration of PYY reduces food intake via inhibition of NPY expression in the arcuate nucleus and induces weight loss in rodents.Previous studies showed that PYY acutely reinforced insulin action on glucose disposal in insulin resistant mice and tissue specific glucose uptake was significantly increased in adipose tissue.Leptin is a peptide predominantly produced by adipocytes, plays an important role in regulating appetite and energy expenditure by acting on specific receptors in the hypothalamus to reduce hypothalamic NPY expression. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Plasma leptin levels strongly correlate with the degree of adiposity and diabetes, with greater levels found in overweight and diabetes individuals. Leptin resistance has been suggested as an explanation for why increased plasma leptin concentrations do not have the expected weight reducing and improving hyperglycaemia effect.Type 2 diabetes mellitus is reaching epidemic proportions all over the world. Obesity is a major factor in this disease, since about most of obese individuals will develop type 2 diabetes. The insulin receptor consists of two ligand-binding a-subunits and two tyrosine kinase (3-subunits. When insulin binds to its receptor, the intrinsic tyrosine kinase activity of theβ-subunit of the receptor is activated. This is followed by autophosphorylation of the receptor. The counterpart of the process is the protein tyrosine phosphatase-1B (PTP-1B), which removes the phosphate. PTP-1B has been shown to be a negative regulator of the insulin signaling pathway. Previous study verified elevated expression and activity of PTP-1B in skeletal muscle of insulin-resistant T2DM GK Rats. PTP-1B negatively regulates leptin signaling, and provides one mechanism by which it regulates obesity, suggesting that inhibitors of this enzyme may be beneficial in the treatment of T2DM and obesity. Mice lacking PTP-1B are resistant to both diabetes and obesity.To the best of our knowledge, the effect of NPY, PYY, leptin and PTP-1B on surgical treatment of obesity and T2DM has not been systematically studied. Therefore, we are intent to investigate the mechanism of bariatric surgeries (Gastric Banding, GB; Sleeve Gastrectomy, SG; Mini-Gastric Bypass, MGBP; Roux-en-Y Gastric Bypass, RYGB) in treatment of obesity and type 2 diabetes mellitus by measure NPY, PYY, leptin, PTP-1B levels pro and/or post operations.PartⅠLaboratory Animal and Animal Experiment1. study on surgical treatment of obesity Eighty 5-week-old male Sprague-Dawley rats were housed in our laboratory. Seventy rats were fed ad libitum a high-fat diet,10 rats were fed ad libitum a common low-fat diet as normal control rats. After 12 weeks,52 rats kept on the high-fat diet developed obesity (their weight exceeded that of the normal control rats by 20%), named diet-induced obesity rats; 18 rats kept on the high-fat diet remained lean, named diet-induced obesity resist rats. The obesity rats exhibited higher Lee's index, higher plasma NPY, leptin, insulin, glucose, triglyceride, cholesterol levels, lower plasma PYY level compared with the normal control rats. Forty four obesity rats comparable in terms of weight were randomly divided into 6 groups:No operation group (NO, n=6), Sham Operation group(SO, n=6), Gastric Banding group(GB, n=8), Sleeve Gastrectomy group (SG, n=8),Mini-Gastric Bypass group (MGBP, n=8),Roux-en-Y Gastric Bypass group(RYGB, n=8). Age matched SD rats fed with the low-fat diet rats were also randomly selected as normal control group (NC, n=6). SO,GB,SG, MGBP and RYGB group rats underwent SO,GB,SG, MGBP and RYGB respectively.2. study on surgical treatment of diabetesNon-obese, insulin-resistan Goto-Kakizaki (GK) rats are a highly inbred strain of Wistar rats that spontaneously developed T2DM. This genetic rat model is particularly relevant to understanding human type T2DM. We purchased 45 eight-week-old GK rats and 10 age matched Wistar rats as normal control rats. GK rats exhibited higher plasma NPY, leptin, glucose, insulin, triglyceride, cholesterol levels and lower plasma PYY level, insulin sensitivity index compared with the normal control rats. Forty four GK rats comparable in terms of weight and plasma glucose were randomly divided into 6 groups:No operation group (NO, n=6), Sham Operation group(SO, n=6), Gastric Banding group(GB, n=8), Sleeve Gastrectomy group (SG, n=8), Mini-Gastric Bypass group (MGBP,n=8),Roux-en-Y Gastric Bypass group(RYGB, n=8). Age and weight matched Wistar rats were also randomly selected as normal control group (NC, n=6).SO, GB, SG, MGBP and RYGB group rats underwent SO, GB, SG, MGBP and RYGB respectively.PartⅡMechanism of surgical treatment of ObesityObjective:To observe the therapeutic effects of surgical treatment of obesity.To investigate the mechanism of surgical treatment of obesity. Methods:Thirty eight obesity rats underwent SO, GB, SG, MGBP and RYGB respectively. Plasma NPY, PYY, leptin and insulin levels were measured by ELISA before and 12 weeks after bariatric surgeries. Plasma glucose, triglyceride and cholesterol levels were measured by biochemical analyzer before and 12 weeks after operations. The expression of NPY, PTP-1B in the hypothalamus and the expression of PYY in the terminal ileum were detected by Western-Blot 12 weeks after operations.NPYmRNA level in the hypothalamus and PYY mRNA level in the terminal ileum were measured by RT-PCR 12 weeks after operations. Lee's index and insulin sensitivity index (ISI) were calculated by plasma glucose, insulin levels and weight, body length levels. Food intake and weight were recorded post operations.Results:Five obesity rats died after bariatric surgeries:1 of SG group,2 of MGBP group,2 of RYGB group. Obesity and relative metabolism syndrome were all improved in obesity rats undergoing bariatric surgeries. RYGB group had better weigh loss, lower Lee's index compared with MGBP, SG, GB groups in turn 12 weeks after operations. GB group had lower food- intake compared with MGBP, RYGB, SG groups in turn. RYGB group had similar improved plasma glucose, insulin levels and ISI compared with MGBP group, and better than SG,GB group. RYGB, MGBP group had lower plasma triglyceride and cholesterol levels than SG,GB group. RYGB group had lower plasma NPY, leptin levels; lower PTP-1B,NPY,NPY mRNA levels in the hypothalamus; higher plasma PYY levels, higher PYY mRNA levels in the terminal ileum compared with MGBP,SG,GB group. NPY was positively correlated with leptin, Lee's index; was inversely correlated with PYY and ISI. PYY was positively correlated with ISI; was inversely correlated with NPY, Lee's index. Leptin was positively correlated with NPY, Lee's index; was inversely correlated with ISI.Conclusion:Decreasing of postoperative circulating NPY, leptin levels and PTP-1B, NPYmRNA levels in the hypothalamus were supposed to be reasons of improved obesity and relative metabolic syndrome after bariatric surgeries. Increasing postoperative circulating PYY level and PYYmRNA level in the terminal ileum may be other reasons of improved obesity and relative metabolic syndrome after bariatric surgeries.PartⅢMechanism of surgical treatment for Tape 2 Diabetes Objective:To observe the therapeutic effects of surgical treatment of tape 2 diabetes.To investigate the mechanism of surgical treatment of tape 2 diabetes.Methods:Thirty eight GK rats underwent SO, GB, SG, MGBP and RYGB respectively. Plasma NPY, PYY, leptin and insulin levels were measured by ELISA before and 10 weeks after bariatric surgeries. Plasma glucose, triglyceride and cholesterol levels were measured by biochemical analyzer before and 10 weeks after operations. The expression of PTP-1B in the pancreas and skeletal muscle were detected by Western-Blot. PTP-1B level and distribution in the pancreas and skeletal muscle were observed by immunol histochemistry 10 weeks after operations. PTP-1B activity level in the pancreas and skeletal muscle was judged by colorimetric method 10 weeks after operations. Food intake and weight were recorded post operations. ISI was calculated by plasma glucose and insulin levels. Apoptosis of the pancreas was measured by tunel method.Results:Four GK rats died after bariatric surgeries:1 of SG group,1 of MGBP group, 2 of RYGB group. Diabetes and relative metabolism syndrome were all improved in GK rats undergoing bariatric surgeryies. RYGB group had more weight reduction, better improved ISI, plasma glucose and insulin levels compared with MGBP,SG and GB group. GB group had lower food-intake compared with MGBP, RYGB and SG group in turn. RYGB, MGBP group had lower plasma triglyceride and cholesterol levels compared with SG,GB group. RYGB group had lower plasma NPY and leptin levels; lower PTP-1B and PTP-1B activity levels in the pancreas and skeletal muscle; higher Plasma PYY level compared with MGBP,SG and GB group. NPY was positively correlated with glucose, insulin and leptin, was positively correlated with ISI. PYY was positively correlated with ISI, was positively correlated with NPY, glucose, insulin. Leptin was positively correlated with NPY, glucose and insulin, was positively correlated with PYY and ISI. RYGB group had lower apoptosis level of the pancreas compared with MGBP, SG and GB group in turn.Conclusion:Decreasing of postoperative circulating NPY, leptin levels and PTP-1B, PTP-1B activity levels in the pancreas and skeletal muscle were supposed to be reasons of improved diabetes and relative metabolic syndrome after bariatric surgeries. Increasing postoperative circulating PYY level may be the other reason of improved diabetes and relative metabolic syndrome after bariatric surgeries.