Shaozhuang Liu

The entire small intestine mediates the changes in glucose homeostasis after intestinal surgery in Goto-Kakizaki rats.

Objective:To investigate the potential interaction between excluding foregut and interposing hindgut and the role of different portions of the small intestine in mediating changes in some glucoregulatory mechanisms and glucose homeostasis after intestinal surgery in Goto-Kakizaki (GK) rats. Background:Previous studies have revealed changes in glucoregulatory mechanisms and glucose homeostasis after excluding foregut and interposing hindgut alone and lead to the “foregut hypothesis” and “hindgut hypothesis.” However, these hypotheses are not mutually exclusive. Methods:Duodenal-jejunal bypass (DJB), ileal interposition (IT), duodenal-jejunal bypass with ileal interposition (DJBIT), sub-ileal interposition (sIT), and sham operations were performed on GK rats. Main outcome measures were oral glucose tolerance (studied at 0, 2, 4, 8, and 24 weeks), insulin sensitivity, &bgr;-cell function, and postprandial levels of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and glucose-dependent insulinotropic peptide(GIP) (evaluated at 2 and 24 weeks). Results:Global body weight in the control group was higher than in the operation groups at postoperative week 2, but it was similar among groups at postoperative week 24. The DJBIT procedure induced synergistic improvement in glucose tolerance and insulin sensitivity (P < 0.05). Generalized linear mixed-model analysis confirmed that glucose tolerance in nonsham operation groups improved over time (P < 0.001), with a significant time × treatment interaction (P < 0.001). Fasting C-peptide, postprandial insulin, GLP-1, and PYY levels increased after nonsham operations (P < 0.05); however, they were not significantly different among the DJBIT, DJB, and IT groups (P > 0.05). Compared with sub-IT, IT induced better glucose tolerance (P < 0.05) and higher postprandial insulin, GLP-1 and PYY levels (P < 0.05), and no significant difference in insulin sensitivity and fasting C-peptide was observed (P > 0.05). None of the surgical procedures affected glucose-stimulated GIP levels (P > 0.05). Conclusions:This study provides experimental evidence that excluding foregut and interposing hindgut provided independent and synergistic changes in glucose homeostasis after intestinal surgery in GK rats and that glucose tolerance improved over time.

Duodenal–Jejunal Bypass Surgery Up-Regulates the Expression of the Hepatic Insulin Signaling Proteins and the Key Regulatory Enzymes of Intestinal Gluconeogenesis in Diabetic Goto–Kakizaki Rats

BackgroundDuodenal–jejunal bypass (DJB), which is not routinely applied in metabolic surgery, is an effective surgical procedure in terms of type 2 diabetes mellitus resolution. However, the underlying mechanisms are still undefined. Our aim was to investigate the diabetic improvement by DJB and to explore the changes in hepatic insulin signaling proteins and regulatory enzymes of gluconeogenesis after DJB in a non-obese diabetic rat model.MethodsSixteen adult male Goto–Kakizaki rats were randomly divided into DJB and sham-operated groups. The body weight, food intake, hormone levels, and glucose metabolism were measured. The levels of protein expression and phosphorylation of insulin receptor-beta (IR-β) and insulin receptor substrate 2 (IRS-2) were evaluated in the liver. We also detected the expression of key regulatory enzymes of gluconeogenesis [phosphoenoylpyruvate carboxykinase-1 (PCK1), glucose-6-phosphatase-alpha (G6Pase-α)] in small intestine and liver.ResultsDJB induced significant diabetic improvement with higher postprandial glucagons-like peptide 1, peptide YY, and insulin levels, but without weight loss. The DJB group exhibited increased expression and phosphorylation of IR-β and IRS-2 in liver, up-regulated the expression of PCK1 and G6Pase-α in small intestine, and down-regulated the expression of these enzymes in liver.ConclusionsDJB is effective in up-regulating the expression of the key proteins in the hepatic insulin signaling pathway and the key regulatory enzymes of intestinal gluconeogenesis and down-regulating the expression of the key regulatory enzymes of hepatic gluconeogenesis without weight loss. Our study helps to reveal the potential role of hepatic insulin signaling pathway and intestinal gluconeogenesis in ameliorating insulin resistance after metabolic surgery.

Expedited Biliopancreatic Juice Flow to the Distal Gut Benefits the Diabetes Control After Duodenal-Jejunal Bypass.

BackgroundSerum bile acids (BAs) are elevated after metabolic surgeries including Roux-en-Y gastric bypass (RYGB), ileal transposition (IT), and duodenal-jejunal bypass (DJB). Recently, BAs have emerged as a kind of signaling molecules, which can not only promote glucagon-like peptide-1 (GLP-1) secretion but can also regulate multiple enzymes involved in glucose metabolism. The aim of this study was to investigate whether expedited biliopancreatic juice flow to the distal gut contributes to the increased serum GLP-1 and BAs and benefits the diabetes control after DJB.MethodsDJB, long alimentary limb DJB (LDJB), duodenal-jejunal anastomosis (DJA), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ). Body weight, food intake, oral glucose tolerance, insulin tolerance, glucose-stimulated insulin and GLP-1 secretion, fasting serum total bile acids (TBAs), and lipid profiles were measured at indicated time points.ResultsCompared with sham operation, DJA, DJB, and LDJB all achieved rapid and dramatic improvements in glucose tolerance and insulin sensitivity independently of food restriction and weight loss. DJB and LDJB-operated rats exhibited even better glucose tolerance, higher fasting serum TBAs, and higher glucose-stimulated GLP-1 secretion than the DJA group postoperatively. No difference was detected in insulin sensitivity and glucose-stimulated insulin secretion between DJA, DJB, and LDJB groups.ConclusionsExpedited biliopancreatic juice flow to the distal gut was associated with augmented GLP-1 secretion and increased fasting serum TBA concentration, which may partly explain the metabolic benefits of DJB.

The Changes of Pro-opiomelanocortin Neurons in Type 2 Diabetes Mellitus Rats After Ileal Transposition: The Role of POMC Neurons

BackgroundIleal transposition (IT) can effectively resolve obesity and improve type 2 diabetes. IT is associated with increased glucagon-like peptide 1 secretion. The mechanisms mediating the effects of IT on obesity and diabetes remain undefined. Given the role of pro-opiomelanocortin neurons in energy balance, we sought to determine its potential role in these processes.MethodsTwenty non-obese diabetic Goto–Kakizaki rats underwent either IT or sham operation. Various measures including food intake, body weight, fasting plasma glucose, glucagon-like peptide 1 level, activated pro-opiomelanocortin neuron number, and pro-opiomelanocortin mRNA expression were evaluated.ResultsThe IT group demonstrated significantly improved plasma glucose homeostasis with increased glucagon-like peptide 1 secretion. The IT group ate less and demonstrated reduced body weight gain over time. These effects were also associated with increased central neuronal activity with increased pro-opiomelanocortin and derivative gene expression in the hypothalamus and increased protein expression in the pituitary gland.ConclusionsMore pro-opiomelanocortin neurons in the hypothalamus of diabetes rats were activated after ileal transposition. These data suggest a potential important role for pro-opiomelanocortin neurons in the resolution of diabetes after IT.

Exclusion of the Distal Ileum Cannot Reverse the Anti-Diabetic Effects of Duodenal-Jejunal Bypass Surgery

BackgroundDuodenal-jejunal bypass (DJB) has been proven effective in glycemic control in various type 2 diabetes (T2DM) rat models. “Hindgut hypothesis” and “foregut hypothesis” are two prevailing theories to elucidate the weight-independent anti-diabetic mechanisms of DJB, however, which mechanism plays the dominant role that has not been illuminated.ObjectiveThis paper aims to verify that exclusion of the foregut leads to loss of weight and remission of type 2 diabetes without expedited delivery of nutrients to the distal bowel.MethodsThirty-five diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ) were randomly assigned to the control, sham-DJB (S-DJB), DJB, ileal bypass (ILB), and DJB combined with ILB (DJB-ILB) groups. Effects of surgeries on body weight, food intake, blood glucose, glucose-stimulated insulin, and gastrointestinal hormones secretion were evaluated at indicated time points.ResultsCompared to the control and S-DJB groups, the DJB group had significant and sustained glycemic control independent of weight loss. Excluding part of the distal ileum did not reverse the diabetic control that followed DJB surgery. The glucagon-like peptide 1 (GLP-1) and PYY levels were significantly increased after DJB. Although GLP-1 and PYY are mainly secreted by L cells in the distal ileum, excluding part of the ileum did not decrease the levels of GLP-1 and PYY after DJB.ConclusionsThe beneficial effects of DJB in glycemic control could not be reversed by excluding the distal ileum.

Non-invasive diagnosis of papillary thyroid microcarcinoma: a NMR-based metabolomics approach

Papillary thyroid microcarcinoma (PTMC) is a subtype of papillary thyroid carcinoma (PTC). Because its diameter is less than 10 mm, diagnosing it accurately is difficult with traditional methods such as image examinations and FNA (Fine Needle Aspiration). Investigating the metabolic changes induced by PTMC may enhance the understanding of its pathogenesis and provide important information for a new diagnosis method and treatment plan. In this study, high resolution magic angle spin (HRMAS) spectroscopy and 1H-nuclear magnetic resonance (1H-NMR) spectroscopy were used to screen metabolic changes in thyroid tissues and plasma from PTMC patients respectively. The results revealed reduced levels of fatty acids and elevated levels of several amino acids (phenylalanine, tyrosine, lactate, serine, cystine, lysine, glutamine/glutamate, taurine, leucine, alanine, isoleucine and valine) in thyroid tissues, as well as reduced levels of amino acids such as valine, tyrosine, proline, lysine, leucine and elevated levels of glucose, mannose, pyruvate and 3-hydroxybutyrate in plasma, are involved in the metabolic alterations in PTMC. In addition, a receiver operating characteristic (ROC) curve model for PTMC prediction was able to classify cases with good sensitivity and specificity using 9 significant changed metabolites in plasma. This work illustrates that the NMR-based metabolomics approach is capable of providing more sensitive diagnostic results and more systematic therapeutic information for PTMC.

Duodenal–Jejunal Bypass Improves Glucose Homeostasis in Association with Decreased Proinflammatory Response and Activation of JNK in the Liver and Adipose Tissue in a T2DM Rat Model

BackgroundThere is accumulating evidence that obesity leads to a proinflammatory state, which plays crucial roles in insulin resistance and development of type 2 diabetes mellitus (T2DM). Previous studies demonstrated that weight loss after bariatric surgery was accompanied by a suppression of the proinflammatory state. However, the effect of bariatric surgery on the proinflammatory state and associated signaling beyond weight loss is still elusive. The objective of this study was to investigate the effect of duodenal–jejunal bypass (DJB) on glucose homeostasis, the proinflammatory state and the involving signaling independently of weight loss.MethodsA high-fat diet and low-dose streptozotocin administration were used to induce T2DM in male Sprague–Dawley rats. The diabetic rats underwent DJB or sham surgery. The blood glucose, glucose tolerance and insulin resistance were determined to evaluate the glucose homeostasis. Serum insulin, GLP-1 and hsCRP were detected by ELISA. The gene expression of TNF-α, IL-6, IL-1β and MCP-1 in liver and fat was determined by quantitative real-time RT-PCR. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were determined by Western blotting.ResultsCompared to the S-DJB group, DJB induced significant and sustained glycemic control with improved insulin sensitivity and glucose tolerance independently of weight loss. DJB improved the proinflammatory state indicated by decreased circulating hsCRP and proinflammatory gene expression in the liver and adipose tissue. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were significantly reduced after DJB.ConclusionsDJB achieved a rapid and sustainable glycemic control independently of weight loss. The data indicated that the improved proinflammatory state and decreased JNK activity after DJB may contribute to the improved glucose homeostasis.

Effects of sleeve gastrectomy with jejuno-jejunal or jejuno-ileal loop on glycolipid metabolism in diabetic rats

AIM To explore the effect of sleeve gastrectomy (SG) with jejuno-jejunal or jejuno-ileal loop on glycolipid metabolism in diabetic rats. METHODS Diabetic rats, which were induced by high-fat diet (HFD), nicotinamide and low-dose streptozotocin, underwent sham operations, SG, SG with jejuno-ileal loop (SG-JI) and SG with jejuno-jejunal loop (SG-JJ) followed by postoperative HFD. Then, at the time points of baseline and 2, 12 and 24 wk postoperatively, we determined and compared several variables, including the area under the curve for the results of oral glucose tolerance test (AUCOGTT), serum levels of triglyceride, cholesterol and ghrelin in fasting state, homeostasis model assessment of insulin resistance (HOMA-IR), body weight, calorie intake, glucagon-like peptide (GLP)-1 and insulin secretions after glucose gavage at dose of 1 g/kg. RESULTS At 2 wk postoperatively, rats that underwent SG, SG-JJ and SG-JI, compared with sham-operated (SHAM) rats, demonstrated lower body weight, calorie intake and ghrelin (P < 0.05 vs SHAM), enhanced secretion of insulin and GLP-1 after glucose gavage (P < 0.05 vs SHAM), improved AUCOGTT, HOMA-IR, fasting serum triglyceride and cholesterol (AUCOGTT: 1616.9 ± 83.2, 837.4 ± 83.7, 874.9 ± 97.2 and 812.6 ± 81.9, P < 0.05 vs SHAM; HOMA-IR: 4.31 ± 0.54, 2.94 ± 0.22, 3.17 ± 0.37 and 3.41 ± 0.22, P < 0.05 vs SHAM; Triglyceride: 2.35 ± 0.17, 1.87 ± 0.23, 1.98 ± 0.30 and 2.04 ± 0.21 mmol/L, P < 0.05 vs SHAM; Cholesterol: 1.84 ± 0.21, 1.53 ± 0.20, 1.52 ± 0.20 and 1.46 ± 0.23 mmol/L). At 12 wk postoperatively, rats receiving SG-JJ and SG-JI had lower body weight, reduced levels of triglyceride and cholesterol and elevated level of GLP-1 compared to those receiving SG (P < 0.05 vs SG). At 24 wk after surgery, compared with SG, the advantage of SG-JJ and SG-JI for glucolipid metabolism was still evident (P < 0.05 vs SG). SG-JI had a better performance in lipid metabolism and GLP-1 secretion of rats than did SG-JJ. CONCLUSION SG combined with intestinal loop induces better glycolipid metabolism than simple SG, with the lipid metabolism being more improved with SG-JI compared to SG-JJ.

Comparative Effects of Bile Diversion and Duodenal-Jejunal Bypass on Glucose and Lipid Metabolism in Male Diabetic Rats

BackgroundDuodenal-jejunal bypass (DJB) induces rapid and durable improvement in glucose and lipid metabolism. Besides bypassing the proximal gut, DJB also diverts bile acids (BAs) into the distal gut, increasing luminal and systemic BAs that are essential to metabolic homeostasis. The aim of this study is to evaluate whether bile diversion (BD) alone can recapitulate the effects of DJB on glucose and lipid metabolism.MethodsBD, DJB and SHAM procedures were performed in a diabetic rat model induced by high-fat diet (HFD)/streptozotocin (STZ). Body weight, energy intake, blood glucose, serum hormones, insulin sensitivity, lipid profiles, and luminal and systemic BAs were measured postsurgery.ResultsBD reduced body weight, independently of energy intake, whereas DJB had no effects. Luminal and serum BAs were increased after both DJB and BD, and were higher after BD than DJB. During glucose tolerance test, both fasting and postprandial blood glucose concentrations were reduced with DJB and BD, and were lower after DJB than BD. Insulin sensitivity was improved after DJB, but remained unchanged after BD. Fasting and postprandial GLP-1 were equally increased after DJB and BD. Serum triglyceride and free fatty acids were decreased more after BD than DJB, while hepatic triglyceride storage was reduced more after DJB.ConclusionThese observations indicate that BD, which increases luminal and systemic BAs and postprandial GLP-1, represents an important component of DJB in restoring glucose and lipid homeostasis in diabetic state. However, other mechanisms associated with DJB also appear to make complementary contributions to metabolic regulation.

Jejunum-ileum circuit procedure improves glucose metabolism in diabetic rats independent of weight loss.

To introduce a lower‐risk novel surgical procedure to achieve diabetes reversal along with associated hormonal changes.