Renoprotective Effects of Metabolic Surgery Versus GLP1 Receptor Agonists on Progression of Kidney Impairment in Patients with Established Kidney Disease.

OBJECTIVE: To examine the renoprotective effects of metabolic surgery in patients with established chronic kidney disease (CKD). BACKGROUND: The impact of metabolic surgery compared with glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with established CKD has not been fully characterized. METHODS: Patients with obesity (BMI ≥30 kg/m2), type 2 diabetes (T2DM), and baseline estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m² who underwent metabolic bariatric surgery at a large U.S. health system (2010-2017) were compared with nonsurgical patients who continuously received GLP-1RA. The primary end point was CKD progression, defined as decline of eGFR by ≥50% or to <15 mL/min/1.73 m2, initiation of dialysis, or kidney transplant. The secondary end point was the incident kidney failure (eGFR <15 mL/min/1.73 m2, dialysis, or kidney transplant) or all-cause mortality. RESULTS: 425 patients, including 183 patients in the metabolic surgery group and 242 patients in the GLP-1RA group, with a median follow-up of 5.8 years (IQR, 4.4-7.6) were analyzed. The cumulative incidence of the primary end point at 8-years was 21.7% (95% CI, 12.2-30.6) in the surgical group and 45.1% (95% CI, 27.7-58.4) in the nonsurgical group, with an adjusted hazard ratio of 0.40 (95% CI, 0.21-0.76), P=0.006. The cumulative incidence of the secondary composite end point at 8-years was 24.0% (95% CI, 14.1-33.2) in the surgical group and 43.8% (95% CI, 28.1-56.1) in the nonsurgical group, with an adjusted HR of 0.56 (95% CI, 0.31-0.99), P=0.048. CONCLUSIONS: Among patients with T2DM, obesity, and established CKD, metabolic surgery, compared with GLP-1RA, was significantly associated with a 60% lower risk of progression of kidney impairment and a 44% lower risk of kidney failure or death. Metabolic surgery should be considered as a therapeutic option for patients with CKD and obesity.

Can Nonalcoholic Steatohepatitis Be Surgically Cured?: Liver Histologic Comparison After Metabolic Surgery Versus Usual Care.

OBJECTIVE: To compare histologic outcomes in patients with fibrotic nonalcoholic steatohepatitis (NASH) and obesity after metabolic surgery versus nonsurgical care. BACKGROUND: There are no published data comparing the effects of metabolic surgery versus nonsurgical care on histologic progression of NASH. METHODS: Repeat liver biopsies were performed in patients with body mass index >30 kg/m 2 at a US health system whose baseline liver biopsy between 2004 and 2016 confirmed a histologic diagnosis of NASH including the presence of liver fibrosis, but without cirrhosis. Baseline characteristics of liver histology for patients who underwent simultaneous liver biopsy at the time of metabolic surgery were balanced with a nonsurgical control group using overlap weighting methods. The primary composite endpoint required both resolution of NASH and improvement of at least 1 fibrosis stage in the repeat liver biopsy. RESULTS: A total of 133 patients (42 metabolic surgery and 91 nonsurgical controls) had a repeat liver biopsy with a median interval of 2 years. Overlap weighting provided balance for baseline histologic disease activity, fibrosis stage, and time interval between liver biopsies. In overlap-weighted patients, 50.1% in the surgical and 12.1% in the nonsurgical group met the primary endpoint (odds ratio=7.3; 95% CI, 2.8-19.2, P <0.001). NASH resolution and fibrosis improvement occurred in 68.5% and 64.1% of surgical patients, respectively. Surgical and nonsurgical patients who met the primary endpoint lost more weight than their counterparts who did not meet the primary endpoint [mean weight loss difference in the surgical group: 12.2% (95% CI, 7.3%-17.2%) and in the nonsurgical group: 11.6% (95% CI, 6.2%-16.9%)]. CONCLUSIONS: Among patients with fibrotic noncirrhotic NASH, metabolic surgery resulted in simultaneous NASH resolution and fibrosis improvement in half of patients.

Impact of Bariatric Surgery on Left Ventricular Structure and Function.

BACKGROUND: Obesity leads to an increased risk of cardiovascular disease morbidity and death, including heart failure. Bariatric surgery has been proven to be the most effective long-term weight management treatment. This study investigated the changes in cardiac structure and function after bariatric surgery, including left ventricular global longitudinal strain. METHODS AND RESULTS: There were 398 consecutive patients who underwent bariatric surgery with pre- and postoperative transthoracic echocardiographic imaging at a US health system between 2004 and 2019. We compared cardiovascular risk factors and echocardiographic parameters between baseline and follow-up at least 6 months postoperatively. Along with decreases in weight postoperatively, there were significant improvements in cardiovascular risk factors, including reduction in systolic blood pressure levels from 132 mm Hg (25th-75th percentile: 120-148 mm Hg) to 127 mm Hg (115-140 mm Hg; P=0.003), glycated hemoglobin levels from 6.5% (5.9%-7.6%) to 5.7% (5.4%-6.3%; P<0.001), and low-density lipoprotein levels from 97 mg/dL (74-121 mg/dL) to 86 mg/dL (63-106 mg/dL; P<0.001). Left ventricular mass decreased from 205 g (165-261 g) to 190 g (151-236 g; P<0.001), left ventricular ejection fraction increased from 58% (55%-61%) to 60% (55%-64%; P<0.001), and left ventricular global longitudinal strain improved from -15.7% (-14.3% to -17.5%) to -18.6% (-16.0% to -20.3%; P<0.001) postoperatively. CONCLUSIONS: This study has shown the long-term impact of bariatric surgery on cardiac structure and function, with reductions in left ventricular mass and improvement in left ventricular global longitudinal strain. These findings support the cardiovascular benefits of bariatric surgery.

Role of Pellino-1 in Inflammation and Cardioprotection following Severe Sepsis: A Novel Mechanism in a Murine Severe Sepsis Model †.

OBJECTIVES: Intra-abdominal sepsis is commonly diagnosed in the surgical population and remains the second most common cause of sepsis overall. Sepsis-related mortality remains a significant burden in the intensive care unit despite advances in critical care. Nearly a quarter of the deaths in people with heart failure are caused by sepsis. We have observed that overexpression of mammalian Pellino-1 (Peli1), an E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Given these manifold applications, we investigated the role of Peli1 in sepsis using transgenic and knockout mouse models specific to this protein. Therefore, we aimed to explore further the myocardial dysfunction seen in sepsis through its relation to the Peli 1 protein by using the loss of function and gain-of-function strategy. METHODS: A series of genetic animals were created to understand the role of Peli1 in sepsis and the preservation of heart function. Wild-type, global Peli1 knock out (Peli1-/-), cardiomyocyte-specific Peli1 deletion (CP1KO), and cardiomyocyte-specific Peli1 overexpressing (alpha MHC (αMHC) Peli1; AMPEL1Tg/+) animals were divided into sham and cecal ligation and puncture (CLP) surgical procedure groups. Cardiac function was determined by two-dimensional echocardiography pre-surgery and at 6- and 24-h post-surgery. Serum IL-6 and TNF-alpha levels (ELISA) (6 h), cardiac apoptosis (TUNEL assay), and Bax expression (24 h) post-surgery were measured. Results are expressed as mean ± S.E.M. RESULTS: AMPEL1Tg/+ prevents sepsis-induced cardiac dysfunction assessed by echocardiographic analysis, whereas global and cardiomyocyte-specific deletion of Peli1 shows significant deterioration of cardiac functions. Cardiac function was similar across the sham groups in all three genetically modified mice. ELISA assay displayed how Peli 1 overexpression decreased cardo-suppressive circulating inflammatory cytokines (TNF-alpha, IL-6) compared to both the knockout groups. The proportion of TUNEL-positive cells varied according to Peli1 expression, with overexpression (AMPEL1Tg/+) leading to a significant reduction and Peli1 gene knockout (Peli1-/- and CP1KO) leading to a significant increase in their presence. A similar trend was also observed with Bax protein expression. The improved cellular survival associated with Peli1 overexpression was again shown with the reduction of oxidative stress marker 4-Hydroxy-2-Nonenal (4-HNE). CONCLUSION: Our results indicate that overexpression of Peli1 is a novel approach that not only preserved cardiac function but reduced inflammatory markers and apoptosis following severe sepsis in a murine genetic model.

Obesity-associated cancer risk reduction after metabolic surgery: insights from the SPLENDID study and the path forward.

Obesity incidence continues to rise globally along with obesity-associated conditions, which heavily burden individuals' quality of life and healthcare systems. Evidence regarding the power of metabolic and bariatric surgery to treat obesity has, fortunately, brought to light how substantial and sustained weight loss can mitigate adverse clinical outcomes of obesity and metabolic disease. Obesity-associated cancer has been an important focus of studies in recent decades to further elucidate what impact metabolic surgery could have on incidence of cancer and cancer-related mortality. The SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) study is one of the recent large cohort studies that highlights the power of substantial weight loss and the long-term benefits to patients with obesity in preventing cancer. This review of SPLENDID aims to highlight both consistency of results with prior studies and new findings unexplored previously.

How much narcotics are really needed after bariatric surgery: results of a prospective study.

BACKGROUND: To mitigate the opioid crisis, physicians are reevaluating opioid prescribing patterns. OBJECTIVES: To evaluate outcomes of maximal opioid reduction on top of an existing Enhanced Recovery after Surgery (ERAS) pathway in our The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited bariatric surgery program. SETTING: Academic tertiary care hospital, United States. METHODS: Patients undergoing primary bariatric operation were studied from July 2017 to April 2019, (standard ERAS cohort), and compared to patients from April 2019 to February 2021 (standard ERAS with Sparing Opioid Use Postoperatively protocol) (SOUP cohort). The primary endpoint was reduction of perioperative opioid use. RESULTS: Of 367 patients, 212 (57.8%) and 155 (42.2%) were in the ERAS and SOUP cohorts, respectively. Roux-en-Y gastric bypass was 48.6% (n = 103) versus 54.2% (n = 84) and sleeve gastrectomy was 51.4% (n = 109) versus 45.8% (n = 71) for ERAS versus SOUP, respectively (P = .29). The SOUP cohort of patients required a low median inpatient morphine equivalent dose of 4 mg [0-6.2]. The ERAS cohort was discharged on a higher morphine equivalent dose than the SOUP cohort at 186.7 mg ± 92.9 versus 37.6 ± 32.3 (P < .05), and median consumption of the standard 5 mg oxycodone tablet was 1.5 tablets [0-4]. The SOUP cohort patients rated their pain satisfaction score on a scale of 1 to 10 at 9.1 points (standard deviation ± 1.8). The SOUP cohort had a shorter length of stay (P < .05), with comparable readmission rates. CONCLUSIONS: An opioid-sparing protocol can be implemented after bariatric surgery with high overall satisfaction with pain control.

Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity.

Importance: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk. Objective: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity. Design, Setting, and Participants: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021. Exposures: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265). Main Outcomes and Measures: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality. Results: The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01). Conclusions and Relevance: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.

Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.

IMPORTANCE: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH). OBJECTIVE: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021. EXPOSURES: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care. MAIN OUTCOMES AND MEASURES: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework. RESULTS: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2). CONCLUSIONS AND RELEVANCE: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE.

Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity: Comparison of Gastric Bypass, Sleeve Gastrectomy, and Usual Care.

OBJECTIVE: To determine which one of the two most common metabolic surgical procedures is associated with greater reduction in risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) and obesity. RESEARCH DESIGN AND METHODS: A total of 13,490 patients including 1,362 Roux-en-Y gastric bypass (RYGB), 693 sleeve gastrectomy (SG), and 11,435 matched nonsurgical patients with T2DM and obesity who received their care at the Cleveland Clinic (1998-2017) were analyzed, with follow-up through December 2018. With multivariable Cox regression analysis we estimated time to incident extended MACE, defined as first occurrence of coronary artery events, cerebrovascular events, heart failure, nephropathy, atrial fibrillation, and all-cause mortality. RESULTS: The cumulative incidence of the primary end point at 5 years was 13.7% (95% CI 11.4-15.9) in the RYGB groups and 24.7% (95% CI 19.0-30.0) in the SG group, with an adjusted hazard ratio (HR) of 0.77 (95% CI 0.60-0.98, P = 0.04). Of the six individual end points, RYGB was associated with a significantly lower cumulative incidence of nephropathy at 5 years compared with SG (2.8% vs. 8.3%, respectively; HR 0.47 [95% CI 0.28-0.79], P = 0.005). Furthermore, RYGB was associated with a greater reduction in body weight, glycated hemoglobin, and use of medications to treat diabetes and cardiovascular diseases. Five years after RYGB, patients required more upper endoscopy (45.8% vs. 35.6%, P < 0.001) and abdominal surgical procedures (10.8% vs. 5.4%, P = 0.001) compared with SG. CONCLUSIONS: In patients with obesity and T2DM, RYGB may be associated with greater weight loss, better diabetes control, and lower risk of MACE and nephropathy compared with SG.

Metabolic surgery: A clinical update.

Metabolic and bariatric surgery has grown beyond 'experimental' weight-loss surgery. As techniques have advanced over the last few decades, so has the growing body of research and evidence, proving that both weight-loss and metabolic health improvement are induced. Metabolic surgery has become the more appropriate term for weight-loss surgery because of the altered gastrointestinal anatomy and subsequent beneficial metabolic effects. Although the tool of metabolic surgery has been well refined, a large portion of the global population does not have adequate access to it. This clinical update aims to (a) inform healthcare providers from all disciplines about the myriad of benefits of metabolic surgery and (b) equip them with the necessary knowledge to bridge the gap between patients in need of metabolic treatment and the therapies in metabolic surgery available to them.

Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and ß-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery. RESEARCH DESIGN AND METHODS: A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin <6.5% [48 mmol/mol] off medications). RESULTS: Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04-3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. CONCLUSIONS: This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

Metabolic effects of duodenojejunal bypass surgery in a rat model of type 1 diabetes.

BACKGROUND: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. METHODS: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n = 15) or sham (n = 15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. RESULTS: Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g, P = 0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham, P = 0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin-positive cells in the pancreas. DJB rats needed 1.3 ± 0.4 insulin implants vs 1.9 ± 0.5 in sham rats (P = 0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases in Akkermansia and Ruminococcus, while the changes were minimal in sham rats. CONCLUSION: DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome.

A Structured Approach for Safely Reintroducing Bariatric Surgery in a COVID-19 Environment.

Due to the profound effect of novel coronavirus disease 2019 (COVID-19) on healthcare systems, surgical programs across the country have paused surgical operations and have been utilizing virtual visits to help maintain public safety. For those who treat obesity, the importance of bariatric surgery has never been more clear. Emerging studies continue to identify obesity and several other obesity-related comorbid conditions as major risk factors for a more severe COVID-19 disease course. However, this also suggests that patients seeking bariatric surgery are inherently at risk of suffering severe complications if they were to contract COVID-19 in the perioperative period. The aim of this protocol is to utilize careful analysis of existing risk stratification for bariatric patients, novel COVID-19-related data, and consensus opinion from multiple academic bariatric centers within our organization to help guide the reanimation of our programs when appropriate and to use this template to prospectively study this risk-stratified population in real time. The core principles of this protocol can be applied to any surgical specialty.

Does Colectomy Improve Type 2 Diabetes?

Gastrectomy and gastric bypass improve type 2 diabetes (T2DM), potentially through alterations in intestinal hormones and the microbiome. The aim of this study was to analyze whether colorectal resections result in improvement of T2DM. A total of 171 patients with T2DM who underwent colectomy for benign diseases were studied with a median postoperative follow-up of 3 years (interquartile range [IQR] 1-5). The median BMI and glycated hemoglobin (HbA1c) at baseline and post-colectomy were 30.3 kg/m2 (IQR 26.6-34.6) versus 30.4 kg/m2 (IQR 26.2-35) (p = 0.1), and 6.7% (IQR 6.2-7.5) versus 6.5% (IQR 6.5-7.1) (p = 0.5), respectively. The proportion of patients taking diabetes medications at baseline versus post-colectomy did not differ significantly. Changes in BMI, HbA1c, and status of diabetes medications were not statistically different between the subtypes of colorectal resection. Our experience suggests that colectomy for benign colorectal diseases is not associated with long-term changes in body weight or glycemic control.

Thioredoxin-1 augments wound healing and promote angiogenesis in a murine ischemic full-thickness wound model.

BACKGROUND: Nonhealing wounds are a continuing health problem in the United States. Overproduction of reactive oxygen species is a major causative factor behind delayed wound healing. Previously we reported that thioredoxin-1 treatment could alleviate oxidative stress under ischemic conditions, such as myocardial infarction and hindlimb ischemia. In this study, we explored the potential for thioredoxin-1 gene therapy to effectively aid wound healing through improved angiogenesis in a murine ischemic wound model. METHODS: Full-thickness, cutaneous, ischemic wounds were created in the dorsum skin flap of 8- to 12-week-old CD1 mice. Nonischemic wounds created lateral to the ischemic skin flap served as internal controls. Mice with both ischemic wounds and nonischemic wounds were treated with Adeno-LacZ (1 × 109 pfu) or Adeno-thioredoxin-1 (1 × 109 pfu), injected intradermally around the wound. Digital imaging was performed on days 0, 3, 6, and 9 to assess the rate of wound closure. Tissue samples collected at predetermined time intervals were processed for immunohistochemical analysis. RESULTS: No significant differences in wound closure were identified among the nonischemic wounds control, nonischemic wounds-LacZ, and nonischemic wounds-thioredoxin-1 groups. Hence, only mice with ischemic wounds were further analyzed. The ischemic wounds-thioredoxin-1 group had significant improvement in wound closure on days 6 and 9 after surgery compared with the ischemic wounds control and ischemic wounds-LacZ groups. Immunohistochemical analysis indicated increased thioredoxin-1, vascular endothelial cell growth factor, and ß-catenin levels in the ischemic wounds-thioredoxin-1 group compared with the ischemic wounds control and ischemic wounds-LacZ groups, as well as increased capillary density and cell proliferation, as represented by Ki-67 staining. CONCLUSION: Taken together, thioredoxin-1 gene therapy promotes vascular endothelial cell growth factor signaling and re-epithelialization and activates wound closure in mice with ischemic wounds.

Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice.

BACKGROUND: Sepsis is a leading cause of mortality among patients in intensive care units across the USA. Thioredoxin-1 (Trx-1) is an essential 12 kDa cytosolic protein that, apart from maintaining the cellular redox state, possesses multifunctional properties. In this study, we explored the possibility of controlling adverse myocardial depression by overexpression of Trx-1 in a mouse model of severe sepsis. METHODS: Adult C57BL/6J and Trx-1Tg/+ mice were divided into wild-type sham (WTS), wild-type cecal ligation and puncture (WTCLP), Trx-1Tg/+sham (Trx-1Tg/+S), and Trx-1Tg/+CLP groups. Cardiac function was evaluated before surgery, 6 and 24 hours after CLP surgery. Immunohistochemical and Western blot analysis were performed after 24 hours in heart tissue sections. RESULTS: Echocardiography analysis showed preserved cardiac function in the Trx-1Tg/+ CLP group compared with the WTCLP group. Similarly, Western blot analysis revealed increased expression of Trx-1, heme oxygenase-1 (HO-1), survivin (an inhibitor of apoptosis [IAP] protein family), and decreased expression of thioredoxin-interacting protein (TXNIP), caspase-3, and 3- nitrotyrosine in the Trx-1Tg/+CLP group compared with the WTCLP group. Immunohistochemical analysis showed reduced 4-hydroxynonenal, apoptosis, and vascular leakage in the cardiac tissue of Trx-1Tg/+CLP mice compared with mice in the WTCLP group. CONCLUSIONS: Our results indicate that overexpression of Trx-1 attenuates cardiac dysfunction during CLP. The mechanism of action may involve reduction of oxidative stress, apoptosis, and vascular permeability through activation of Trx-1/HO-1 and anti-apoptotic protein survivin.

Increased survivability of ischemic skin flap tissue in Flk-1+/- mice by Pellino-1 intervention.

OBJECTIVE: Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia. METHODS: Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/- mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis. RESULTS: Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/- mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis. CONCLUSION: Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.

Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition.

Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB) often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI). At a cellular level, tight junction proteins (TJPs) between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1) that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1ß (IL-1ß) as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1ß (10 ng/mL; 2 hours)-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 µg/mL; 1 hour), GM6001 (broad spectrum MMP inhibitor; 10 µM; 1 hour), MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour) or MMP-9 siRNA transfection (48 hours) in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1ß-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1ß treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB hyperpermeability in a mouse model of TBI indicating its potential as a therapeutic agent for brain edema when established in humans.

Tumor necrosis factor-alpha-induced microvascular endothelial cell hyperpermeability: role of intrinsic apoptotic signaling

Tumor necrosis factor-alfa (TNF-alfa), a pro-apoptotic cytokine, is involved in vascular hyperpermeability, tissue edema, and inflammation. We hypothesized that TNF-alfa induces microvascular hyperpermeability through the mitochondria-mediated intrinsic apoptotic signaling pathway. Rat lung microvascular endothelial cells grown on Transwell inserts, chamber slides, or dishes were treated with recombinant TNF-alfa (10 ng/ml) in the presence or absence of a caspase-3 inhibitor, Z-DEVD-FMK (100 μM). Fluorescein isothiocyanate (FITC)-albumin (5 mg/ml) was used as a marker of monolayer permeability. Mitochondrial reactive oxygen species (ROS) was determined using dihydrorhodamine 123 and mitochondrial transmembrane potential using JC-1. The adherens junction integrity and actin cytoskeletal organization were studied using β-catenin immunofluorescence and rhodamine phalloidin, respectively. Caspase-3 activity was measured fluorometrically. The pretreatment with Z-DEVD-FMK (100 μM) attenuated TNF-alfa-induced (10 ng/ml) disruption of the adherens junctions, actin stress fiber formation, increased caspase-3 activity, and monolayer hyperpermeability (p < 0.05). TNF-alfa (10 ng/ml) treatment resulted in increased mitochondrial ROS formation and decreased mitochondrial transmembrane potential. Intrinsic apoptotic signaling-mediated caspase-3 activation plays an important role in regulating TNF-α-induced endothelial cell hyperpermeability