New Mouse Models of Roux-en Y Gastric Bypass and One Anastomosis Gastric Bypass for Type 2 Diabetes.

BACKGROUND: Current bariatric surgery models primarily utilize mice with obesity, overlooking those with type 2 diabetes (T2DM). These models have limitations in replicating clinical procedures accurately and achieving broad applicability. This study aimed to develop novel mouse models of Roux-en-Y gastric bypass (RYGB) and one anastomosis gastric bypass (OAGB) surgeries specifically designed for T2DM research, utilizing simplified surgical techniques closely resembling clinical procedures. METHODS: Eight-week-old C57/Bl6 mice, except for the Blank-Control group, were induced with T2DM by combining a high-fat diet and streptozotocin injection. RYGB involved creating a 10% gastric pouch, a 4-cm biliopancreatic limb (BL), and a 4-cm Roux limb (RL). Similarly, OAGB maintained a 10% gastric pouch and a 4-cm BL. To assess the efficacy of these models, we measured the body weight and fasting blood glucose (FBG) and conducted intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and liver B-ultrasound, as well as a histopathological analysis of multiple organs 12 weeks post-operation. RESULTS: The survival rates in the Blank-Control, T2DM-Sham, T2DM-RYGB, and T2DM-OAGB groups were 100% (6/6), 100% (6/6), 85.7% (6/7), and 100% (6/6), respectively. Both RYGB and OAGB surgeries similarly led to sustained weight loss, reduced the FBG levels, improved the IPGTT and ITT results, and alleviated the histopathological manifestations in multiple organs. CONCLUSION: The innovative mouse models of RYGB and OAGB surgeries effectively improve T2DM. Both surgeries demonstrate comparable efficacy in ameliorating T2DM, even when utilizing a gastric pouch of the same size and the same length of BL in OAGB.

Corrigendum: ASK1-interacting protein 1 acts as a novel predictor of type 2 diabetes.

[This corrects the article DOI: 10.3389/fendo.2022.896753.].

ASK1-Interacting Protein 1 Acts as a Novel Predictor of Type 2 Diabetes.

Type 2 diabetes (T2D) mellitus is a chronic inflammatory disease characterized with high secretion of tumor necrosis factor (TNF)-α, but the regulatory pathway of TNF-α production in T2D has not been fully elucidated. ASK1-interacting protein 1 (AIP1) is a signaling scaffold protein that modulates several pathways associated with inflammation. In this study, we aimed to investigate the role of AIP1 in T2D development. Our results revealed that AIP1 was downregulated in omental adipose tissue (OAT) of obese patients with T2D compared with that in obese patients. In addition, Pearson's correlation test showed that AIP1 was negatively correlated with the homeostatic model assessment for insulin resistance (HOMA-IR, r = -0.4829) and waist-to-hip ratio (r = -0.2614), which are major clinical indexes of T2D. As revealed by the proteomic analysis, immunohistochemistry, and ELISA, the OAT and the serum of obese patients with T2D presented high inflammatory status. And the increased inflammatory factors TNF-α and C-reactive protein C (CRP) in the serum of obese patients with T2D showed a positive correlation with HOMA-IR (TNF-α, r = 0.4728; CRP, r = 0.5522). Interestingly, AIP1 deficiency in adipocytes facilitated TNF-α secretion and retarded glucose uptake. Mechanistically, AIP1 deletion in human adipocytes activated JNK, p38 MAPK, and ERK1/2 signaling. Furthermore, inhibition of these signaling pathways using specific inhibitors could suppress these signal activation and insulin resistance caused by AIP1 deficiency. In addition, AIP1 and TNF-α expression in the OAT of patients with T2D recovered to normal levels after laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. These findings indicate that AIP1 is negatively correlated with the clinical indexes of T2D. It modulates TNF-α expression in OAT via JNK, p38 MAPK, and ERK1/2 signaling.

[Therapeutic effect of laparoscopic Roux-en-Y gastric bypass in non-obese patients with type 2 diabetes].

OBJECTIVE: To evaluate the effectiveness of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery for treatment of type 2 diabetes (T2D) in patients with a body mass index (BMI) < 27.5 kg/m2. METHODS: We retrospectively analyzed the data of patients who underwent LRYGB surgery from March, 2012 to June, 2018 in the General Hospital of Guangzhou Military Command and Jinshazhou Hospital of Guangzhou University of Chinese Medicine. The changes in the parameters of glucose metabolism and physical indicators of the patients in the first, second and third years after the surgery were analyzed in patients in low BMI group and high BMI group. RESULTS: All the 74 patients underwent LRYGB successfully without conversion to open surgery. One year after the surgery, fasting blood glucose (FBG), HbA1c, postprandial blood glucose, fasting insulin, HOMA-IR, fasting C-peptide, BMI, body weight and waistline were significantly improved compared with their preoperative values in low BMI group (P < 0.05). At 2 years after the operation, FBG, HbA1c, postprandial blood glucose, HOMA-IR, BMI, body weight and waistline were significantly improved compared with the preoperative values in low BMI group (P < 0.05). In the third year, FBG, HOMA-IR, fasting C-peptide, body weight and waistline were significantly improved compared with the preoperative values in low BMI group (P < 0.05). There was no significant difference in the parameters of glucose metabolism and islet function between low BMI group and high BMI group at different stages. No serious complications occurred in these patients after the surgery. CONCLUSIONS: LRYGB is effective for treatment of T2D in Chinese patients with a BMI < 27.5. After the surgery, the patient show reduced waistline without significant weight loss. The long-term results of the surgery still require further investigations with a larger samples and longer follow-up.

Single-Anastomosis Duodenal Jejunal Bypass Improve Glucose Metabolism by Regulating Gut Microbiota and Short-Chain Fatty Acids in Goto-Kakisaki Rats.

In recent years, bariatric surgery has emerged as a promising treatment for type 2 diabetes. Bariatric surgery is known to cause alterations in the relative abundance and composition of gut microbiota, which may lead to alterations in the levels of Short-Chain Fatty Acids (SCFAs) that are produced during fermentation by gut microbes. However, little is known about the mechanism of improved glucose metabolism mediated by gut microbiota following bariatric surgery. The aim of our study was to explore whether changes in gut microbiota and in fecal SCFA could be detected following single-anastomosis duodenal jejunal bypass (DJB-sa) surgery, a type of bariatric surgery, and whether these alterations might be related to the improvement of glucose metabolism. To this end, we performed DJB-sa or SHAM surgery on Goto-Kakisaki (GK) rats. We then compared the glucose metabolism as well as changes in gut microbiota and SCFAs levels between both groups. Our results showed that DJB-sa surgery was associated with a significant decrease in fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and fasting serum insulin (FSI). And, DJB-sa led to a change in the composition of gut microbiota including an increase in the relative abundance of SCFA-producing bacteria (Bifidobacterium and Subdoligranulum). Moreover, the levels of six SCFAs in feces, as well as the intestinal expression of SCFA receptors including G-protein-coupled receptor 41 (GPR41), G-protein-coupled receptor 43 (GPR43), and G-protein-coupled receptor 109A (GPR109A), and the expression of Glucagon-like peptide-1 (GLP-1) displayed a significant increase following DJB-sa compared with the Sham group. Thus, the gut microbiota may contribute to the improvement of glucose metabolism in type 2 diabetes following DJB-sa. In conclusion, our study shows that DJB-sa improves glucose metabolism by modulating gut microbiota and by increasing short-chain fatty acid production.

Overexpression of CENPF correlates with poor prognosis and tumor bone metastasis in breast cancer.

BACKGROUND: Centromere Protein F (CENPF) associates with the centromere-kinetochore complex and influences cell proliferation and metastasis in several cancers. The role of CENPF in breast cancer (BC) bone metastasis remains unclear. METHODS: Using the ONCOMINE database, we compared the expression of CENPF in breast cancer and normal tissues. Findings were confirmed in 60 BC patients through immunohistochemical (IHC) staining. Microarray data from GEO and Kaplan-Meier plots were used analyze the overall survival (OS) and relapse free survival (RFS). Using the GEO databases, we compared the expression of CENPF in primary lesions, lung metastasis lesions and bone metastasis lesions, and validated our findings in BALB/C mouse 4T1 BC models. Based on gene set enrichment analysis (GSEA) and western blot, we predicted the mechanisms by which CENPF regulates BC bone metastasis. RESULTS: The ONCOMINE database and immunohistochemical (IHC) showed higher CENPF expression in BC tissue compared to normal tissue. Kaplan-Meier plots also revealed that high CENPF mRNA expression correlated to poor survival and shorter progression-free survival (RFS). From BALB/C mice 4T1 BC models and the GEO database, CENPF was overexpressed in primary lesions, other target organs, and in bone metastasis. Based on gene set enrichment analysis (GSEA) and western blot, we predicted that CENPF regulates the secretion of parathyroid hormone-related peptide (PTHrP) through its ability to activate PI3K-AKT-mTORC1. CONCLUSION: CENPF promotes BC bone metastasis by activating PI3K-AKT-mTORC1 signaling and represents a novel therapeutic target for BC treatment.

Duodenojejunal Bypass Plus Sleeve Gastrectomy Reduces Infiltration of Macrophages and Secretion of TNF-α in the Visceral White Adipose Tissue of Goto-Kakizaki Rats.

BACKGROUND: Current studies indicate that inflammation of white adipose tissue (WAT) is a pathogenic characteristic of insulin resistance. However, the significance of visceral WAT inflammation after bariatric surgery remains unclear. METHODS: Duodenojejunal bypass plus sleeve gastrectomy (DJB-SG) was performed on Goto-Kakisaki rats. Weight, fasting blood glucose (FBG), and homeostatic model assessment of insulin resistance (HOMA-IR) in the DJB-SG group were compared to those in a sham surgery (SHAM) group every 2 weeks. The results of an oral glucose tolerance test (OGTT) and the volume of visceral adipose tissue (Visc.Fat) were compared before and 8 weeks postsurgery. Eight weeks after surgery, the rats were sacrificed and visceral WAT collected from the greater omentum. Tumor necrosis factor-α (TNF-α) and cluster of differentiation 68 (CD68) expression in the WAT were evaluated in paraffin-embedded sections by immunohistochemistry. RESULTS: Compared with the SHAM group, the DJB-SG group demonstrated a significant reduction in weight, FBG, and HOMA-IR (P < 0.05), with elevation of insulin levels (P < 0.05) from 4 weeks after surgery. OGTT and the quantity of Visc.Fat were significantly reduced (P < 0.05) 8 weeks after surgery. Moreover, the expression of TNF-α and CD68 in the visceral white adipose tissue was significantly lower 8 weeks after surgery (P < 0.05). CONCLUSIONS: The DJB-SG model established in Goto-Kakisaki rats achieved anticipated efficacy. Reduced TNF-α-related inflammation in visceral WAT may result in improved insulin resistance.

Increased Serum IGFBP-1 and Reduced Insulin Resistance After Roux-En-Y Gastric Bypass in Chinese Patients with Type 2 Diabetes: a 6-Month Follow-Up.

OBJECTIVE: This study aimed to measure changes of insulin-like growth factor binding protein-1 (IGFBP-1) in patients with type 2 diabetes mellitus (T2D) following gastric bypass surgery. METHODS: A total of 10 patients with T2D underwent laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. Patient height, weight, waist circumference, and hip circumference were measured pre- and post-operatively at 6 months after surgery. Serum samples were collected at 6 months after surgery to determine fasting blood glucose, glycosylated Hb, fasting insulin, C-peptide, and 2-h postprandial blood glucose, insulin, and C-peptide. Serum was collected at 3 days and 6 months after surgery and IGFBP-1 level determined using ELISA. Serum samples were also collected from 30 healthy weight subjects and 27 overweight control subjects. RESULTS: Body weight, BMI, and waist circumference were significantly improved following RYGB surgery. Blood glucose, fasting blood glucose, 2-h postprandial blood glucose, and HbA1c were also significantly improved. Fasting C-peptide and 2-h postprandial C-peptide were non-significantly reduced. Serum IGFBP-1 significantly increased at 3 days and 6 months after RYGB surgery. Pre-operative serum IGFBP-1 was not significantly different from healthy weight subjects or overweight subjects. CONCLUSION: Increased serum level of IGF-binding proteins after RYGB in 6 months is increased post-surgery compared with overweight and healthy weight controls. IGFBP-1 may serve as part of new supplementary criteria for surgical selection and for defining the success of RYGB.

[Efficacy of two bariatric surgeries in type 2 diabetic patients with a body mass index of 25-27.5].

OBJECTIVE: To evaluate the therapeutic effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic duodenal-jejunal bypass with sleeve gastrectomy (SADJB-SG) in patients with type 2 diabetes mellitus and a low body mass index (BMI) of 25-27.5. METHODS: Thirty-one type 2 diabetic patients with a BMI of 25-27.5 underwent bariatric surgeries in the General Hospital of Guangzhou Military Command between August, 2013 and August, 2015. The patients receiving LRYGB (17 cases) and SADJB-SG (14 cases) were compared for physical indexes, glucose metabolism and of pancreatic islet function at 1 year after the surgeries. RESULTS: No mortality occurred in the patients after the operations. At 1 year after the operation, the patients in LRYGB group showed significant improvements in body weight, BMI, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), oral glucose tolerance test 2 h (OGTT2h), C-peptide, fasting insulin (FINS), and postprandial 2 hour insulin (2 hPINS) (P<0.05); in SADJB-SG group, significant improvements were observed in the body weigh, BMI, HbA1c, FPG, OGTT2h, and FINS after the operation (P<0.05). The postoperative improvements in body weigh, BMI, HbA1c, FPG, OGTT2h, C-peptide, and 2hPINS were comparable between SADJB-SG group and LRYGB group (P>0.05), but the incidence of postoperative anastomotic ulcer was lower in SADJB-SG group. CONCLUSION: SADJB-SG and LRYGB produce similar therapeutic effects in type 2 diabetic patients with a low BMI, but SADJB-SG is associated with a low incidence of postoperative complications and is therefore more suitable in such patients.

B cells present skewed profile and lose the function of supporting T cell inflammation after Roux-en-Y gastric bypass.

Bariatric surgeries, including Roux-en-Y gastric bypass (RYGB) are currently the best treatment for obesity and obesity-related comorbidities, such as type 2 diabetes. However, the underlying mechanism of bariatric surgeries is not entirely understood. Further investigations are needed to improve the success rate and achieve sustained health benefits. Given that B cell dysregulation is a critical component of etiology in inflammatory diseases, whereas obesity and type 2 diabetes represent two major inflammatory disorders, we investigated the effect of RYGB on B cell inflammation. We found that B cells after RYGB presented significantly elevated frequency of interleukin (IL)-10-producing cells and reduced frequency of IL-6-producing cells compared to those before RYGB. When grouping B cell subsets into regulatory (secreting IL-10 and transforming growth factor beta [TGF-ß]) and effector (secreting IL-2, IL-4, IL-6, IL-12, interferon gamma [IFN-γ] and tumor necrosis factor alpha [TNF-α]) types, we found that after RYGB, the regulatory to effector B cell ratio was significantly increased. Function analyses showed that B cells before RYGB supported IL-17 secretion from T cells whereas these cells after RYGB lost such capacity. B cells after RYGB also gained the capacity to suppress T cell IFN-γ production through TGF-ß-mediated effects, a feature not present in B cells before RYGB. Interestingly, the regulatory to effector B cell ratio was directly associated with the reductions in obesity markers following RYGB, such as BMI and fat mass percentage. Together, these results demonstrated a potential mechanism through which RYGB promoted amelioration of obesity and type 2 diabetes.