Novel subtype of obesity influencing the outcomes of sleeve gastrectomy: Familial aggregation of obesity.

BACKGROUND: Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy (SG) between patients with familial aggregation of obesity (FAO) and patients with sporadic obesity (SO) have not been elucidated. AIM: To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO. METHODS: A total of 193 patients with obesity who underwent SG were selected. Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity (1SO vs 1FAO, 2SO vs 2FAO). The baseline characteristics, weight loss outcomes, prevalence of obesity-related comorbidities and incidence of major surgery-related complications were compared between groups. RESULTS: We defined FAO as the presence of two or more first-degree relatives with obesity. Patients with FAO did not initially show significant differences in baseline data, short-term postoperative weight loss, or obesity-related comorbidities when compared to patients with SO preoperatively. However, distinctions between the two groups became evident at the two-year mark, with statistically significant differences in both percentage of total weight loss (P = 0.006) and percentage of excess weight loss (P < 0.001). The FAO group exhibited weaker remission of type 2 diabetes mellitus (T2DM) (P = 0.031), hyperlipidemia (P = 0.012), and non-alcoholic fatty liver disease (NAFLD) (P = 0.003) as well as a lower incidence of acid reflux (P = 0.038). CONCLUSION: FAO patients is associated with decreased mid-to-long-term weight loss outcomes; the alleviation of T2DM, hyperlipidemia and NAFLD; and decreased incidence of acid reflux postoperatively.

Effect of oligofructose on resistance to postoperative high-fat diet-induced damage of metabolism in diabetic rats after sleeve gastrectomy.

BACKGROUND: Sleeve gastrectomy (SG) can induce prominent remission of type 2 diabetes mellitus. However, the long-term remission rate of diabetes usually decreases over time. Oligofructose has been verified to modulate host metabolism. The aim of this study was to explore the protective effect of oligofructose on high-fat diet (HFD)-induced metabolic dysfunction after SG. AIM: To study the effect and mechanism of oligofructose on diabetic remission in diabetic rats after SG. METHODS: SG and SHAM operation were performed on diabetes rats induced with an HFD, nicotinamide, and low-dose streptozotocin. Then the rats in the SHAM and SG groups were continuously provided with the HFD, and the rats in sleeve gastrectomy-oligofructose group were provided with a specific HFD containing 10% oligofructose. Body weight, calorie intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance, lipid profile, serum insulin, glucagon-like peptide 1 (GLP-1), total bile acids, lipopolysaccharide (LPS), and colonic microbiota levels were determined and compared at the designated time points. All statistical analyses were performed using Statistic Package for Social Science version 19.0 (IBM, United States), and the statistically significant difference was considered at P < 0.05. RESULTS: At 2 wk after surgery, rats that underwent SG exhibited improved indexes of glucose and lipid metabolism. Compared with the SG group, the rats from SG-oligofructose group exhibited better parameters of glucose and lipid metabolism, lower body weight (526.86 ± 21.51 vs 469.25 ± 21.84, P < 0.001), calorie intake (152.14 ± 9.48 vs 129.63 ± 8.99, P < 0.001), homeostasis model assessment of insulin resistance (4.32 ± 0.57 vs 3.46 ± 0.52, P < 0.05), and LPS levels (0.19 ± 0.01 vs 0.16 ± 0.01, P < 0.05), and higher levels of insulin (1.17 ± 0.17 vs 1.58 ± 0.16, P < 0.001) and GLP-1 (12.39 ± 1.67 vs 14.94 ± 1.86, P < 0.001), and relative abundances of Bifidobacterium (0.0034 ± 0.0014 vs 0.0343 ± 0.0064, P < 0.001), Lactobacillus (0.0161 ± 0.0037 vs 0.0357 ± 0.0047, P < 0.001), and Akkermansia muciniphila (0.0050 ± 0.0024 vs 0.0507 ± 0.0100, P < 0.001) at the end of the study. However, no difference in total bile acids levels was observed between the two groups. CONCLUSION: Oligofructose partially prevents HFD-induced glucose and lipid metabolism damage after SG, which may be due to the changes of calorie intake, insulin, GLP-1, LPS, and the gut microbiota in rats.

Sleeve gastrectomy ameliorates endothelial function and prevents lung cancer by normalizing endothelin-1 axis in obese and diabetic rats.

BACKGROUND: Previous evidence has implied that obesity is an independent risk factor for developing cancer. Being closely related to obesity, type 2 diabetes mellitus provides a suitable environment for the formation and metastasis of tumors through multiple pathways. Although bariatric surgeries are effective in preventing and lowering the risk of various types of cancer, the underlying mechanisms of this effect are not clearly elucidated. AIM: To uncover the role and effect of sleeve gastrectomy (SG) in preventing lung cancer in obese and diabetic rats. METHODS: SG was performed on obese and diabetic Wistar rats, and the postoperative transcriptional and translational alterations of the endothelin-1 (ET-1) axis in the lungs were compared to sham-operated obese and diabetic rats and age-matched healthy controls to assess the improvements in endothelial function and risk of developing lung cancer at the postoperative 4th, 8th, and 12th weeks. The risk was also evaluated using nuclear phosphorylation of H2A histone family member X as a marker of DNA damage (double-strand break). RESULTS: Compared to obese and diabetic sham-operated rats, SG brought a significant reduction to body weight, food intake, and fasting blood glucose while improving oral glucose tolerance and insulin sensitivity. In addition, ameliorated levels of gene and protein expression in the ET-1 axis as well as reduced DNA damage indicated improved endothelial function and a lower risk of developing lung cancer after the surgery. CONCLUSION: Apart from eliminating metabolic disorders, SG improves endothelial function and plays a protective role in preventing lung cancer via normalized ET-1 axis and reduced DNA damage.

Warshaw Technique in Laparoscopic Spleen-Preserving Distal Pancreatectomy: Surgical Strategy and Late Outcomes of Splenic Preservation.

Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) can be accomplished with either the preservation or the resection of splenic vessels; the latter is also known as Warshaw technique. Our study is designed to investigate the operation selection strategy when proceeding LSPDP and to evaluate the long-term outcomes of patients undergoing Warshaw surgery. The medical records and follow-up data of patients who underwent LSPDP in Qilu Hospital, Shandong University, were reviewed retrospectively. A total of thirty-five patients were involved in this study, including 17 cases of patients who were treated with Warshaw procedure (WT) while the other 18 cases had splenic vessels preserved (SVP). Compared with the SVP group, the operative time and intraoperative blood loss in WT group were improved significantly. The incidence of early postoperative splenic infarction was higher in WT group. However, there was no report of splenic abscess or second operation. Follow-up data confirmed that there was no significant difference in spleen phagocytosis and immune function compared with normal healthy population. Our study confirms that LSPDP-Warshaw procedure is a safe and efficient treatment for the benign or low grade malignant tumors in distal pancreas in selected patients. The long-term spleen function is normal after Warshaw procedure. Preoperative assessment and intraoperative exploration are recommended for the selection of operation approaches.

Downregulation of lncRNA MALAT1 contributes to renal functional improvement after duodenal-jejunal bypass in a diabetic rat model

Ameliorated renal function has been reported after bariatric surgery, but the mechanisms underlying this phenomenon are not well-studied. To investigate whether the long non-coding RNA (lncRNA) MALAT1 mediates the amelioration of diabetic nephropathy after duodenal-jejunal bypass (DJB) surgery, rats were assigned randomly into four groups: diabetic (DM) group, DM with DJB surgery group, DM with sham surgery group, and healthy control group. Food intake, body weight, oral glucose tolerance test (OGTT), urine albumin excretion rate (UAER), and glomerular filtration rate (GFR) were measured and histological examination of renal sections was performed. For in vitro study, HK-2 cells were cultured under various glucose concentrations following MALAT1 siRNA transfection. Expression levels of MALAT1, SAA3, IL-6, and TNF-α in rat renal tissues or HK-2 cell lines were evaluated by qRT-PCR and/or ELISA. Results showed DJB surgery improved the renal function of diabetic rats, as indicated by ameliorated UAER and GFR and attenuated glomerular hypertrophy. Expression of MALAT1 and its downstream target SAA3 was significantly downregulated in renal tissues after DJB, which in turn decreased the expression of the pro-inflammatory cytokines IL-6 and TNF-α. Knockdown of MALAT1 in HK-2 cell lines further confirmed that expression levels of SAA3, IL-6, and TNF-alfa were regulated by MALAT1 under both low- and high-glucose conditions. Our findings suggest that MALAT1 is implicated in the improvement of renal function after DJB through regulation of its downstream targets SAA3, IL-6, and TNF-alfa

Downregulation of lncRNA MALAT1 contributes to renal functional improvement after duodenal-jejunal bypass in a diabetic rat model.

Ameliorated renal function has been reported after bariatric surgery, but the mechanisms underlying this phenomenon are not well-studied. To investigate whether the long non-coding RNA (lncRNA) MALAT1 mediates the amelioration of diabetic nephropathy after duodenal-jejunal bypass (DJB) surgery, rats were assigned randomly into four groups: diabetic (DM) group, DM with DJB surgery group, DM with sham surgery group, and healthy control group. Food intake, body weight, oral glucose tolerance test (OGTT), urine albumin excretion rate (UAER), and glomerular filtration rate (GFR) were measured and histological examination of renal sections was performed. For in vitro study, HK-2 cells were cultured under various glucose concentrations following MALAT1 siRNA transfection. Expression levels of MALAT1, SAA3, IL-6, and TNF-α in rat renal tissues or HK-2 cell lines were evaluated by qRT-PCR and/or ELISA. Results showed DJB surgery improved the renal function of diabetic rats, as indicated by ameliorated UAER and GFR and attenuated glomerular hypertrophy. Expression of MALAT1 and its downstream target SAA3 was significantly downregulated in renal tissues after DJB, which in turn decreased the expression of the pro-inflammatory cytokines IL-6 and TNF-α. Knockdown of MALAT1 in HK-2 cell lines further confirmed that expression levels of SAA3, IL-6, and TNF-α were regulated by MALAT1 under both low- and high-glucose conditions. Our findings suggest that MALAT1 is implicated in the improvement of renal function after DJB through regulation of its downstream targets SAA3, IL-6, and TNF-α.

Immunotherapy for pancreatic cancer: A long and hopeful journey.

Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer.

Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes.

OBJECTIVE: Bariatric surgery could improve pancreatic beta cell function, thereby leading to the remission of the type 2 diabetes mellitus (T2DM). However, the specific mechanism underlying this phenomenon is yet to be revealed. The aim of this study is to test the hypothesis that Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in infiltrating macrophages plays an important role in the modulation of beta cell function after duodenal-jejunal bypass (DJB) surgery. METHODS: DJB and sham surgery were performed in diabetic Sprague-Dawley (SD) rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, and glucose tolerance test (GTT) were measured at indicated time points. Apoptosis of the beta cells was measured by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay. We also assessed the macrophage content and NLRP3 expression in the rat model. Furthermore, macrophage reconstitution was performed after DJB surgery. Beta cell function and NLRP3 inflammasome pathway were re-evaluated in wild-type macrophage reconstitution group and NLRP3-knockdown macrophage reconstitution group. RESULTS: DJB surgery group rats displayed rapid and sustained improvement in glucose tolerance. Decreased apoptosis and improved secretion function of the beta cells were observed in DJB surgery group. NLRP3 inflammasome pathway in infiltrating macrophages was also suppressed after DJB surgery. Moreover, diabetic remission acquired by DJB sustained in NLRP3-knockdown macrophage reconstitution group, while extinguished in group reconstituted with wild-type macrophage. CONCLUSIONS: NLRP3 inflammasome deactivation in infiltrating macrophages is involved in marked beta cell function improvement after DJB surgery.

Effects of sleeve gastrectomy plus trunk vagotomy compared with sleeve gastrectomy on glucose metabolism in diabetic rats.

AIM: To investigate the effects of sleeve gastrectomy plus trunk vagotomy (SGTV) compared with sleeve gastrectomy (SG) in a diabetic rat model. METHODS: SGTV, SG, TV and Sham operations were performed on rats with diabetes induced by high-fat diet and streptozotocin. Body weight, food intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin signaling (IR, IRS1, IRS2, PI3K and AKT), oral glucose stimulated insulin secretion, GLP-1 and ghrelin were compared at various postoperative times. RESULTS: Both SG and SGTV resulted in better glucose tolerance, lower HOMA-IR, up-regulated hepatic insulin signaling, higher levels of oral glucose-stimulated insulin secretion, higher postprandial GLP-1 and lower fasting ghrelin levels than the TV and Sham groups. No significant differences were observed between the SG and SGTV groups. In addition, no significant differences were found between the TV and Sham groups in terms of glucose tolerance, HOMA-IR, hepatic insulin signaling, oral glucose-stimulated insulin secretion, postprandial GLP-1 and fasting ghrelin levels. No differences in body weight and food intake were noted between the four groups. CONCLUSION: SGTV is feasible for diabetes control and is independent of weight loss. However, SGTV did not result in a better improvement in diabetes than SG alone.

Diabetes recurrence after metabolic surgeries correlates with re-impaired insulin sensitivity rather than beta-cell function.

AIM: To investigate factors causing diabetes recurrence after sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB). METHODS: SG and DJB were performed on rats with diabetes induced by high-fat diet (HFD) and streptozotocin (STZ). HFD was used to induce diabetes recurrence at 4 wk postoperatively. Body weight, oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), insulin signaling [IR, insulin receptor substrate (IRS)1, IRS2, phosphatidylinositol 3-kinase and AKT in liver and skeletal muscle], oral glucose stimulated insulin secretion, beta-cell morphology (mass, apoptosis and insulin secretion), glucagon-like peptide (GLP)-1, PYY and ghrelin were compared among SG rats with common low-fat diet (SG-LFD), SG with HFD (SG-HFD), DJB rats with LFD (DJB-LFD), DJB with HFD (DJB-HFD) and sham-operation with LFD (Sham) at targeted postoperative times. RESULTS: SG and DJB resulted in significant improvement in glucose tolerance, lower HOMA-IR, up-regulated hepatic and muscular insulin signaling, higher levels of oral glucose-stimulated insulin secretion, bigger beta-cell mass, higher immunofluorescence intensity of insulin, fewer transferase-mediated dUTP-biotin 3' nick end-labeling (TUNEL)-positive beta cells and higher postprandial GLP-1 and PYY levels than in the Sham group. The improvement in glucose tolerance was reversed at 12 wk postoperatively. Compared with the SG-LFD and DJB-LFD groups, the SG-HFD and DJB-HFD groups showed higher HOMA-IR, down-regulated hepatic and muscular insulin signaling, and more TUNEL-positive beta cells. No significant difference was detected between HFD and LFD groups for body weight, glucose-stimulated insulin secretion, beta-cell mass, immunofluorescence intensity of insulin, and postprandial GLP-1 and PYY levels. Fasting serum ghrelin decreased in SG groups, and there was no difference between HFD-SG and LFD-SG groups. CONCLUSION: HFD reverses the improvement in glucose homeostasis after SG and DJB. Diabetes recurrence may correlate with re-impaired insulin sensitivity, but not with alterations of beta-cell function and body weight.

Early detection of pancreatic cancer: Where are we now and where are we going?

Pancreatic cancer (PC) is one of the most lethal malignancies. Recent studies indicate that patients with incidentally diagnosed PC have better prognosis than those with symptoms and that there is a sufficient window for early detection. However, effective early diagnosis remains difficult and depends mainly on imaging modalities and the development of screening methodologies with highly sensitive and specific biomarkers. This review summarizes recent advances in effective screening for early diagnosis of PC using imaging modalities and novel molecular biomarkers discovered from various "omics" studies including genomics, epigenomics, non-coding RNA, metabonomics, liquid biopsy (CTC, ctDNA and exosomes) and microbiomes, and their use in body fluids (feces, urine and saliva). Although many biomarkers for early detection of PC have been discovered through various methods, larger scale and rigorous validation is required before their application in the clinic. In addition, more effective and specific biomarkers of PC are urgently needed.

Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology.

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease.