[Show abstract][Hide abstract] ABSTRACT: Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.
The FASEB Journal 07/2015; 29(7). DOI:10.1096/fj.15-270496 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eradication of Helicobacter pylori prior to Roux-en-Y gastric bypass (RYGB) has been advocated as a measure to reduce the complications of anastomotic ulceration. However, evidence to support a causal relationship between preoperative H. pylori status and postoperative anastomotic ulceration is weak.
Intraoperative gastric biopsies were obtained on consecutive patients who underwent laparoscopic RYGB at our institution from December 2007 to June 2010. These samples were analyzed by Warthin-Starry stain for H. Pylori organisms. Retrospective chart review was conducted to determine the preoperative presence of acid dyspepsia and acid suppression therapy and to determine postoperative ulcer symptoms, smoking, NSAID or steroid use, and compliance with ulcer prophylaxis. The incidence of ulcer visualization, perforation, and stricture were obtained from a prospectively collected database. Fisher's exact test was used for analyzing associations between discrete groups. Multiple logistic regression was used to assess associations between anastomotic ulcer complications and potential predictors.
Histologic evaluation for H. pylori was available in 708 of the 728 patients who underwent RYGB. Fourteen patients were lost to follow up leaving 694 patients available for review. H. pylori was positive in 66 (9.5 %) patients who did not go on to receive definitive treatment for eradication. Marginal ulcers or related late complications were seen in a total of 113 (16.3 %) patients. In the H. pylori positive group, five patients (7.6 %) developed ulcer complications compared to 108 (17.1 %) in the H. pylori negative group (p = 0.05). Groups were not different in terms of preoperative demographics, postoperative ulcer prophylaxis compliance, steroid, NSAIDs, and cigarette use.
The presence of H. pylori infection at the time of RYGB was found to be associated with a significantly lower incidence of anastomotic ulcer complications postoperatively. This study brings into question efforts and expense allocated to identify and eradicate H. pylori prior to RYGB.
[Show abstract][Hide abstract] ABSTRACT: Background
The purpose of the study is to investigate the association of preoperative glucose optimization prior to a Roux-en-Y gastric bypass (RYGB) and diabetes remission.
The study is a retrospective review of 245 patients with a history of diabetes type II and a RYGB from 2008 to 2012 at UMass Memorial Hospital.
Patients that benefited from glucose optimization prior to RYGB were more likely to achieve diabetes remission 1 year after surgery. The preoperative glucose optimization intervention demonstrated that when patients decreased their HbA1c prior to surgery by 1 %, these individuals were 68 % more likely to remit (p = 0.015). Duration of diabetes (p = 0.005) and insulin use (p
Obesity Surgery 07/2014; 25(1). DOI:10.1007/s11695-014-1339-2 · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Roux-en-Y gastric bypass (RYGB) leads to remission of type 2 diabetes mellitus (T2DM) in a majority of patients. This is prompting investigation of RYGB, and other bariatric operations as interventional therapies for T2DM.
The impact of RYGB is due to an increase in the release of gastrointestinal hormones in response to a meal [glucagon-like peptide, peptide YY, oxyntomodulin]. This effect involves the parasympathetic nervous system. These same hormones are responsible for an early increase in β-cell secretion of insulin, leading to early remission of T2DM following RYGB. Progressive weight loss leads to a later improvement in peripheral insulin sensitivity, which is required for later remissions, and is responsible for re-emergence of T2DM in individuals who regain weight in long-term follow-up. As the success of bariatric surgery has prompted the emergence of the concept that T2DM is reversible, we offer a theory to predict reversibility of diabetes after bariatric surgery that is based on baseline beta cell function.
This review will improve the understanding of the physiology of bariatric surgery and its impact on T2DM, stimulate investigations into new avenues to treat T2DM, and allow better selection of nonobese individuals for interventional therapy of T2DM.
Current opinion in endocrinology, diabetes, and obesity 04/2011; 18(2):119-28. DOI:10.1097/MED.0b013e3283446c1f · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adipose tissue expands in response to excess caloric intake, but individuals prone to deposit visceral instead of subcutaneous adipose tissue have higher risk of metabolic disease. The role of angiogenesis in the expandability of human adipose tissue depots is unknown. The objective of this study was to measure angiogenesis in visceral and subcutaneous adipose tissue and to establish whether there is a relationship between obesity, metabolic status, and the angiogenic properties of these depots.
Angiogenic capacity was determined by quantifying capillary branch formation from human adipose tissue explants embedded in Matrigel, and capillary density was assessed by immunohistochemistry. Subcutaneous adipose tissue had a greater angiogenic capacity than visceral tissue, even after normalization to its higher initial capillary density. Gene array analyses revealed significant differences in expression of angiogenic genes between depots, including an increased subcutaneous expression of angiopoietin-like protein 4, which is proangiogenic in an adipose tissue context. Subcutaneous capillary density and angiogenic capacity decreased with morbid obesity, and subcutaneous, but not visceral, adipose tissue angiogenic capacity correlated negatively with insulin sensitivity.
These data imply that subcutaneous adipose tissue has a higher capacity to expand its capillary network than visceral tissue, but this capacity decreases with morbid obesity. The decrease correlates with insulin resistance, suggesting that impairment of subcutaneous adipose tissue angiogenesis may contribute to metabolic disease pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Obesity is a strong risk factor for resistance to insulin-mediated glucose disposal, a precursor of type 2 diabetes and other disorders. However, not all obese individuals are insulin resistant. We sought to identify the molecular pathways that might cause obesity-associated insulin resistance in humans by studying the morbidly obese who were insulin sensitive versus insulin resistant, thereby eliminating obesity as a variable.
Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental and subcutaneous adipose tissue samples obtained from similarly obese patients undergoing gastric bypass surgery.
Gene sets related to chemokine activity and chemokine receptor binding were identified as most highly expressed in the omental tissue from insulin-resistant compared with insulin-sensitive subjects, independent of the body mass index. These upregulated genes included chemokines (C-C motif) ligand 2, 3, 4, and 18 and interleukin-8/(CC-X motif) ligand 8 and were not differentially expressed in the subcutaneous adipose tissues between the 2 groups of subjects. Insulin resistance, but not the body mass index, was associated with increased macrophage infiltration in the omental adipose tissue, as was adipocyte size, in these morbidly obese subjects.
Our findings have demonstrated that inflammation of the omental adipose tissue is strongly associated with insulin resistance in human obesity even in subjects with similar body mass index values.
Surgery for Obesity and Related Diseases 01/2011; 7(1):60-7. DOI:10.1016/j.soard.2010.05.013 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with a pathologic predominance of sympathetic over parasympathetic tone. With respect to the heart, this autonomic dysfunction presents as a decreased heart rate variability (HRV), which has been associated with increased cardiovascular morbidity. Gastric bypass (GB) reduces cardiovascular mortality, and, thus, could beneficially affect the HRV. We sought to identify the factors predictive of HRV in a severely obese population of undergoing GB at a university hospital in the United States.
The data of all patients presenting for GB were included in a prospective database. The homeostatic model of assessment (HOMA) was used to calculate the insulin resistance and glucose disposition index. A 24-hour Holter monitor was used to assess the HRV. Measurements were repeated at 2 weeks and 6 months postoperatively. The correlations between variables were determined using linear mixed models.
We studied 30 patients undergoing GB. All exhibited some degree of reduced HRV that improved postoperatively. The HOMA-insulin resistance inversely correlated with the HRV, and the HOMA-glucose disposition index directly correlated with the parameters of HRV in our longitudinal models. Weight, body mass index, excess body weight, gender, and age did not correlate with HRV. Improvements in HRV correlated with reductions in the average heart rate, underscoring a postoperative increase in relative vagal tone.
HRV in the severely obese is better predicted by the degree of insulin resistance, than by the degree of obesity, age, or gender. GB led to an improvement in HRV, the magnitude of which correlated with the change in insulin resistance and glucose disposition index, but not with weight loss.
Surgery for Obesity and Related Diseases 09/2009; 6(3):237-41. DOI:10.1016/j.soard.2009.09.012 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to review the etiology and computed tomography (CT) findings of small-bowel obstruction (SBO) in patients who have undergone bariatric laparoscopic Roux-en-Y gastric bypass (LGBP) surgery.
Prospectively entered data from a surgical database of 835 consecutive patients who underwent antecolic-antegastric LGBP for morbid obesity from June 1999 to April 2005 in a single institution were retrospectively reviewed. A total of 42 cases of bowel obstruction were observed in 41 patients. Surgical proof was available in 38 cases, and 4 cases had characteristic imaging features and/or clinical follow-up. Seventeen CT scans were reviewed to determine cause and level of obstruction, and this was correlated with surgical findings and clinical follow-up.
Internal hernia was the most common (13 cases) and also the most frequently missed etiology of SBO on CT scans, with the diagnosis being made prospectively in only 2 of 6 cases, in which CT was done. Adhesions, ventral hernia, postoperative ileus, and jejunojejunal (JJ) anastomotic strictures, in that order, were the other commonly observed etiologies for SBO, with 11, 7, 5, and 4 cases, respectively. Some causes of SBO post-LGBP (JJ anastomotic stricture and postoperative ileus) developed relatively early, whereas others (internal hernia) tended to develop later or had a bimodal distribution (adhesions and ventral hernia). Fifteen (36%) of 42 cases had SBO at or near the level of jejunojejunostomy site; causes included internal hernia (5 cases), adhesions/kinking of small bowel (5 cases), JJ anastomotic stricture (4 cases), and JJ intussusception (1 case).
The time interval between LGBP and development of SBO might provide a useful clinical clue to its etiology. The JJ level is an important location for SBO post-LGBP because of a variety of causes, and special attention must be paid to this site at imaging of post-LGBP patients.
[Show abstract][Hide abstract] ABSTRACT: The traditional therapy for perforated sigmoid diverticulitis with peritonitis is emergency colectomy usually with colostomy. We report laparoscopic exploration with peritoneal lavage as an alternative in seven patients who required emergency surgery for diverticulitis.
Six patients presented with diffuse peritonitis and one with a failure of percutaneous therapy. All patients were explored laparoscopically and the peritoneal cavity was lavaged with saline in addition to receiving intravenous antibiotics. Patient demographics, clinical response, length of stay, and complications were recorded.
Six patients had resolution of peritonitis resolved and patients were discharged from the hospital. One of these patients who developed a pelvic abscess required a percutaneous drainage postoperatively. This patient ultimately returned 3 months later with recurrent symptoms and underwent colectomy with primary anastomosis. One patient failed to improve initially and underwent colectomy with primary anastomosis on the same admission. Five patients subsequently had elective sigmoid resections, four laparoscopic and one open. Mean length of stay was 7.7 days. There was no mortality.
We conclude that laparoscopic exploration and peritoneal lavage can be performed safely in patients with diffuse, purulent peritonitis. Using this approach, most patients with purulent peritonitis can avoid emergent laparotomy with the risk of colostomy, and the need for a second surgery.
International Journal of Colorectal Disease 02/2009; 24(7):797-801. DOI:10.1007/s00384-009-0641-2 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As the number of laparoscopic adjustable gastric bands (LAGBs) placed has increased, the number of patients requiring removal of the device has also increased.
The data from our institution, a U.S. university medical center, were reviewed to determine the feasibility, patient characteristics, and early results of converting patients from LAGB to laparoscopic Roux-en-Y gastric bypass.
A total of 350 patients underwent LAGB placement at our institution from 2001 to 2008. Of these, 26 required conversion to laparoscopic Roux-en-Y gastric bypass for the following reasons: slippage, poor weight loss, LAGB intolerance, esophageal dilation, infection, and gastric ischemia. All conversions were completed laparoscopically. The average operating time and length of stay was 160 minutes and 3 days, respectively. Three complications developed. The average interval to conversion was 29 months. The average follow-up after conversion was 18 months. The average percentage of excess body weight loss at conversion was 23%. At 12 months after conversion, the patients had achieved an average percentage of excess body weight loss of 56% from their pre-LAGB weight.
The increasing popularity of the LAGB has led to a considerable number of revisions of the device. Our early experience has shown that converting patients from LAGB to laparoscopic Roux-en-Y gastric bypass is feasible and safe and can offer patients substantial additional weight loss.
Surgery for Obesity and Related Diseases 12/2008; 5(4):439-43. DOI:10.1016/j.soard.2008.10.012 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Storage of energy as triglyceride in large adipose-specific lipid droplets is a fundamental need in all mammals. Efficient sequestration of fat in adipocytes also prevents fatty acid overload in skeletal muscle and liver, which can impair insulin signaling. Here we report that the Cide domain-containing protein Cidea, previously thought to be a mitochondrial protein, colocalizes around lipid droplets with perilipin, a regulator of lipolysis. Cidea-GFP greatly enhances lipid droplet size when ectopically expressed in preadipocytes or COS cells. These results explain previous findings showing that depletion of Cidea with RNAi markedly elevates lipolysis in human adipocytes. Like perilipin, Cidea and the related lipid droplet protein Cidec/FSP27 are controlled by peroxisome proliferator-activated receptor gamma (PPARgamma). Treatment of lean or obese mice with the PPARgamma agonist rosiglitazone markedly up-regulates Cidea expression in white adipose tissue (WAT), increasing lipid deposition. Strikingly, in both omental and s.c. WAT from BMI-matched obese humans, expression of Cidea, Cidec/FSP27, and perilipin correlates positively with insulin sensitivity (HOMA-IR index). Thus, Cidea and other lipid droplet proteins define a novel, highly regulated pathway of triglyceride deposition in human WAT. The data support a model whereby failure of this pathway results in ectopic lipid accumulation, insulin resistance, and its associated comorbidities in humans.
Proceedings of the National Academy of Sciences 07/2008; 105(22):7833-8. DOI:10.1073/pnas.0802063105 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Use of laparoscopy in penetrating trauma has been well established; however, its application in blunt trauma is evolving. The authors hypothesized that laparoscopy is safe and feasible as a diagnostic and therapeutic modality in both the patients with penetrating and blunt trauma. Trauma registry data and medical records of consecutive patients who underwent laparoscopy for abdominal trauma were reviewed. Over a 4-year period, 43 patients (18 blunt trauma / 25 penetrating trauma) underwent a diagnostic laparoscopy. Conversion to laparotomy occurred in 9 (50%) blunt trauma and 9 (36%) penetrating trauma patients. Diagnostic laparoscopy was negative in 33% of blunt trauma and 52% of penetrating trauma patients. Sensitivity/specificity of laparoscopy in patients with blunt and penetrating trauma was 92%/100% and 90%/100%, respectively. Overall, laparotomy was avoided in 25 (58%) patients. Use of laparoscopy in selected patients with blunt and penetrating abdominal trauma is safe, minimizes nontherapeutic laparotomies, and allows for minimal invasive management of selected intra-abdominal injuries.