Mohamed R. Ali

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women

Plasma lipoproteins and glucose homeostasis were evaluated after marked weight loss before and over 12 months following Roux-en-Y gastric-bypass (RYGBP) surgery in 19 morbidly obese women. Standard lipids, remnant-lipoprotein cholesterol (RLP-C); HDL-triglyceride (TG); apolipoproteins (apo) A-I, A-II, E, and A-I-containing HDL subpopulations; lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) mass and activity; plasma glucose and insulin levels were measured before and at 1, 3, 6, and 12 months after GBP surgery. Baseline concentrations of TG, RLP-C, glucose, and insulin were significantly higher in obese than in normal-weight, age-matched women, whereas HDL cholesterol (HDL-C), apoA-I, apoA-II, alpha-1 and alpha-2 levels were significantly lower. Over 1 year, significant decreases of body mass index, glucose, insulin, TG, RLP-C, HDL-TG, and prebeta-1 levels were observed with significant increases of HDL-C and alpha-1 levels (all P < 0.05). Changes of fat mass were correlated with those of LDL cholesterol (P = 0.018) and LCAT mass (P = 0.011), but not with CETP mass (P = 0.265). Changes of fasting plasma glucose concentrations were inversely correlated with those of CETP mass (P = 0.005) and alpha-1 level (P = 0.004). Changes of fasting plasma insulin concentrations were positively correlated with those of LCAT mass (P = 0.043) and inversely with changes of alpha-1 (P = 0.03) and alpha-2 (P = 0.05) concentrations. These results demonstrate beneficial changes in HDL remodeling following substantial weight loss induced by RYGBP surgery and that these changes are associated with improvement of glucose homeostasis in these patients.

Epidemiology and economic impact of obesity and type 2 diabetes.

Obesity has become a major public health concern in the United States and the rest of the world. This disease carries significant health risks that encompass several organ systems. Type 2 diabetes mellitus is a major comorbidity of obesity that predisposes patients to significant end-organ damage. The prevalence of obesity and diabetes is increasing worldwide, and the economic impact of these diseases currently assumes a significant portion of health care expenditure. These factors mandate implementation of therapeutic medical and surgical strategies that target prevention and treatment of obesity and its related medical conditions.

The utility of routine postoperative upper GI series following laparoscopic gastric bypass

BackgroundRoutine upper gastrointestinal (UGI) studies following laparoscopic Roux-en-Y gastric bypass (LRYGBP) have the potential advantage of early identification of anastomotic complications. The aim of our study was to evaluate the efficacy of routine postoperative UGI and its relationship to clinical outcomes.MethodsOver a three-year period, 516 patients underwent LRYGBP followed by routine postoperative UGI studies. Data were collected on the results of the UGI, clinical parameters, and patient outcomes. Study groups were composed of patients with a normal UGI (Group I, n = 455), abnormal UGI not requiring further intervention (Group II, n = 36), and abnormal UGI requiring further intervention (Group III, n =25). Statistical significance was set at α= 0.05 level for all analyses.ResultsThe three study groups were not statistically different in mean age (42 years) or body mass index (BMI) (45) and were predominantly female (90%). Most patients had an uneventful postoperative course. Anastomotic complications (gastrojejunostomy and jejunojejunostomy) were uncommon (1.3%). The sensitivity of the UGI for anastomotic leak in this study was low (33%). However, all patients with alimentary limb obstruction (n = 3) had UGI evidence of this complication. Of the 516 UGI reports, there were only 25 (4.8%, Group III) that were abnormal and required some form of intervention ranging from serial imaging (84%) to reoperation (16%). Of the various clinical parameters examined, the patients in Group III demonstrated a significantly higher prevalence of fever (p < 0.001), tachycardia (p < 0.01), vomiting (p < 0.001), and postoperative day 1 leukocytosis (p < 0.005).ConclusionsOur data suggest that routine UGI after LRYGBP has limited utility as it may result in unnecessary intervention based on false-positive results or a delay in treatment based on false-negative results. We advocate selective UGI imaging following LRYGBP based on the patient’s clinical factors, particularly fever and tachycardia.

Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans

CONTEXT Mouse studies suggest that adropin, a peptide hormone, is required for metabolic homeostasis and prevention of obesity-associated insulin resistance. Whether obesity and insulin resistance are associated with low plasma adropin levels in humans is not known. OBJECTIVES Our objective was to investigate the hypothesis that obesity and indicators of insulin resistance are associated with low adropin levels and determine whether weight loss regulates adropin levels. DESIGN AND PARTICIPANTS Plasma was obtained from 85 female [age 21-67 yr, body mass index (BMI) 19.4-71.5 kg/m2] and 45 male (age 18-70 yr, BMI 19.1-62.6 kg/m2) volunteers for other clinical studies. The impact of Roux-en-Y gastric bypass was investigated in 19 obese females (BMI 37-65 kg/m2) using samples collected at baseline and 1-12 months after surgery. RESULTS Adropin levels correlate negatively with BMI (r=-0.335, P<0.001) and age (r=-0.263, P=0.003). Age-adjusted adropin levels are higher in males [4.1 ng/ml; 95% confidence interval (CI)=3.6-4.6 ng/ml] than females (3.0 ng/ml; 95% CI=2.6-3.4 ng/ml) (P=0.001). In all subjects, lower age-adjusted adropin levels were observed in overweight (3.3 ng/ml; 95% CI=2.8-3.8 ng/ml, P=0.033) and obese (2.7 ng/ml; 95% CI=2.1-3.3 ng/ml, P=0.001) compared with healthy-weight subjects (4.1 ng/ml; 95% CI=3.6-4.5 ng/ml). This effect was gender specific (weight category×gender, P<0.001) and was observed in males only. Aging and diagnosis with two or more metabolic syndrome risk factors was associated with low adropin levels, irrespective of sex. Adropin concentrations increased after Roux-en-Y gastric bypass, peaking 3 months after surgery (P<0.01). CONCLUSIONS Although males exhibit higher adropin levels that are reduced by obesity, aging and markers of insulin resistance are associated with low plasma adropin irrespective of sex.

Validation that a 1-year fellowship in minimally invasive and bariatric surgery can eliminate the learning curve for laparoscopic gastric bypass

BackgroundThe concept that advanced surgical training can reduce or eliminate the learning curve for complex procedures makes logical sense but is difficult to verify and has not been tested for laparoscopic Roux-en-Y gastric bypass (LRYGB). We sought to determine if minimally invasive/bariatric surgery fellowship graduates (FGs) would demonstrate complication-related outcomes (CRO) equivalent to the outcomes achieved during their training experience under the supervision of experienced bariatric surgeons.MethodsWe compared CRO for the first 100 consecutive LRYGBs performed in practice by five consecutive minimally invasive/bariatric fellows at new institutions (total 500 cases) to CRO for the 611 consecutive LRYGBs performed during their fellowship training experience under the supervision of three experienced bariatric surgeons at the host training institution.ResultsThe two patient groups did not differ demographically. The 18 types of major and minor complications identified after LRYGB did not differ among the five fellowship graduates. The mentors’ CRO were compatible with published benchmark data. As compared with the training institution data, the overall incidence of complications for the combined experience of fellowship graduates did not differ statistically from that of the mentors. The fellowship graduates’ early experience included zero nongastrojejunostomy leaks (0% versus 1.5%) and a low rate of anastomotic stricture (0.8% versus 3.0%), incisional hernia (1% versus 4.4%), bowel obstruction (0% versus 3%), wound infection (0.3% versus 3.1%), and gastrointestinal hemorrhage (0.2% versus 1.6%). The rate of gastrojejunostomy leak (1.8% versus 2.6%) and, most importantly, mortality (0.8% versus 0.7%) did not differ between the two groups.ConclusionsFellowship graduates achieved high-quality surgical outcomes from the very beginning of their postfellowship practices, which are comparable to those of their experienced mentors. These data validate the concept that advanced surgical training can eliminate the learning curve often associated with complex minimally invasive procedures, specifically LRYGB.

Robot-assisted laparoscopic Roux-en-Y gastric bypass

BackgroundRobotic surgery promises to extend the capabilities of the minimally invasive surgeon. The aim of this study was to examine the feasibility of robotic surgery in the setting of laparoscopic gastric bypass.MethodsThe Zeus robotic surgical system was used in 50 laparoscopic gastric bypass procedures. The learning curve was staged to add complexity to the robotic tasks as experience grew. Robotic setup time, robotic operative time, total operative time, and operative outcomes were tracked prospectively.ResultsWe observed a significant decrease in the robotic setup time. Our robotic learning curve demonstrated decreased operative time, even as more complex tasks were accomplished. Total operative time also decreased significantly over the series. There were no complications in our series that could be attributed to the robotic technique.ConclusionsRobot-assisted laparoscopic Roux-en-Y gastric bypass is safe. The steadiness and extra degrees of freedom of surgical robotic systems may improve the accuracy of laparoscopic tasks. The learning curve for robot-assisted laparoscopic Roux-en-Y gastric bypass is significant but manageable.

Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity.

The extracellular matrix (ECM) plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accommodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weight-matched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECM-related factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship.

Teaching robotic surgery: a stepwise approach

BackgroundAfter an initial institutional experience with 50 robot-assisted laparoscopic Roux-en-Y gastric bypass procedures, a curriculum was developed for fellowship training in robotic surgery.MethodsThirty consecutive robotic gastric bypasses were performed using the Zeus robotic surgical system to fashion a two-layer gastrojejunostomy. For teaching purposes, performance of the anastomosis was divided into three discrete tasks. Robotic suturing tasks were assigned to the trainee in cumulative order in ten-case increments. Our patient population averaged 44 years of age and 47 kg/m2 in BMI. Patients were predominantly female (87%).ResultsThe robotic training experience of the fellow defines the increases in surgical responsibility over the series of cases. Statistical analysis revealed no significant differences in task times or total robotic operative time as participation of the trainee in performing the gastrojejunostomy increased. No adverse robotic events or surgical complications occurred throughout this series. The learning curve of the fellow compared favorably with the initial experience of the institution.ConclusionRobotic surgery training may be safely implemented in a minimally invasive surgery training program. A gradual introduction of robotic technique appears to maximize the learning experience and minimize the potential for adverse outcomes.

Single-site robotic cholecystectomy in a broadly inclusive patient population: A prospective study

Objectives:To describe our initial experience with single-site robotic cholecystectomy (SSRC) and its applicability to a broad segment of patients. Background:At the initiation of our study, there were only 3 published reports on SSRC. These initial studies had limited inclusion criteria. We present our experience with the technical aspects and patient outcomes of SSRC in a broadly inclusive patient population. Methods:Prospective cohort study from January 2012 to January 2013, in which 95 patients underwent SSRC. Procedural times, postoperative complications, delayed hospital discharges, and re-admissions were evaluated. Results:Patients were predominantly female (71.6%) had mean age of 45.2 ± 6.1 years and mean body mass index (BMI) of 30.1 ± 7.1 kg/m2. Overall, mean total operative time (TOT) for all patients (n = 95) was 88.63 ± 32.0 (range: 49–220) minutes. SSRC was not completed in 8 (8.42%) patients: 6 conversions to laparoscopy, 1 conversion to open, and 1 aborted case. The group of patients who were able to complete SSRC (n = 87) had a mean TOT of 83.5 ± 24.5 minutes and mean operative robotic time (RT) of 39.6 ± 15.2 minutes. RT was longer in patients with intra-abdominal adhesions (P = 0.0139) and higher BMI (P = 0.03). A minority of patients required hospital admission (11.6%), readmission (6.3%), or reoperation (1.1%). No bile duct injury or death occurred. Conclusions:SSRC is safe and has a manageable learning curve. Patient factors, such as obesity, did not significantly affect conversion rates or TOTs. SSRC is a promising new technique, which can be offered to a wide array of patients.