Nicholas J. Swerdlow

Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss

The enhanced decrease in circulating branched-chain amino acids and their metabolites after gastric bypass occurs by mechanisms other than weight loss. Dissecting the Quick Fix In the Wizard of Oz, when Dorothy encounters a split in the yellow brick road, the Scarecrow assures her that all paths lead to the land of Oz. We’ve witnessed the perils Dorothy met along the path she chose; however, we don’t know what she would have encountered had she followed another route to Oz. Similarly, obese patients with type 2 diabetes can take one of two paths to weight loss—dietary intervention or gastric bypass surgery (GBP). Although the end result—weight loss—is the same, the metabolic shifts that occur en route appear to differ. Now, Laferrère et al. show that in patients with equivalent weight loss, those who underwent GBP displayed a larger decrease in certain circulating amino acids than did subjects who pursued the dietary intervention path. This difference may help to explain why patients who opted for the surgical intervention boasted better improvement in glucose homeostasis—including enhanced insulin sensitivity—than did those who lost weight by controlling their dietary intake. Obese patients with type 2 diabetes strive to lose weight for reasons more momentous than an approaching swimsuit season. Weight loss can improve the body’s ability to metabolize glucose and thus stems the serious complications of diabetes. Patients often can reduce or forgo their diabetes medications. However, in such patients, glycemic control is improved to a greater extent within days after GBP—before weight loss occurs—than after diet-induced shedding of pounds and inches. Precisely why remains a mystery, but research in animal models has revealed that higher-than-normal blood concentrations of branched-chain amino acids (BCAAs) and their metabolites play a role in the loss of insulin sensitivity. Furthermore, recent studies in human patients show a robust positive correlation between insulin resistance and blood levels of BCAAs and their by-products. Finally, obese people have higher circulating concentrations of these amino acids compared to their lean counterparts; the same goes for individuals with versus without diabetes. These observations imply that the rapid reversal of diabetes symptoms in GBP patients may have something to do with BCAA metabolism. Here, the authors measured circulating amounts of a variety of amino acids and acylcarnitines—some of which are produced primarily from BCAA metabolism—to characterize the differential metabolic responses to weight loss induced by GBP versus dietary intervention in obese type 2 diabetes patients. Circulating concentrations of total amino acids, BCAAs, and BCAA metabolites all decreased significantly after GBP but not after dietary intervention, despite equivalent weight loss. These findings were consistent in two patient cohorts, one from the New York Obesity Nutrition Research Center and one from Duke University; in the latter group, the effects were shown to persist for months. These data support the notion that the surgical intervention promoted enhanced BCAA metabolism by mechanisms separate from weight loss and suggest that changes in circulating amino acids pave the road to the correction of glycemic control observed after GBP. Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.

Rise of Oxyntomodulin in Response to Oral Glucose after Gastric Bypass Surgery in Patients with Type 2 Diabetes

CONTEXTnThe mechanisms by which Roux-en-Y gastric bypass surgery (GBP) results in sustained weight loss and remission of type 2 diabetes are not fully understood.nnnOBJECTIVEnWe hypothesized that the anorexic hormone oxyntomodulin (OXM) might contribute to the marked weight reduction and the rapid improvement in glucose metabolism observed in morbidly obese diabetic patients after GBP.nnnMETHODSnTwenty obese women with type 2 diabetes were studied before and 1 month after GBP (n=10) or after a diet-induced equivalent weight loss (n=10). Patients from both groups were matched for age, body weight, body mass index, and diabetes duration and control. OXM concentrations were measured during a 50-g oral glucose challenge before and after weight loss.nnnRESULTSnAt baseline, OXM levels (fasting and stimulated values) were indistinguishable between the GBP and the diet group. However, OXM levels rose remarkably in response to an oral glucose load more than 2-fold (peak, 5.25+/-1.31 to13.8+/-16.2 pmol/liter; P=0.025) after GBP but not after diet. The peak of OXM after glucose was significantly correlated with glucagon-like peptide-1 and peptide YY3-36.nnnCONCLUSIONSnOur data suggest that the observed changes in OXM primarily occur in response to GBP and not as a consequence of weight loss. These changes were observed early after surgery and occurred in parallel with previously reported increases in incretins and peptide YY. We speculate that the combination of gut hormone changes is essential for the improved glucose homeostasis and may partially explain the success of this surgery on diabetes resolution and weight loss.

Gastric bypass surgery, but not caloric restriction, decreases dipeptidyl peptidase 4 activity in obese patients with type 2 diabetes.

The mechanism by which incretins and their effect on insulin secretion increase markedly following gastric bypass (GBP) surgery is not fully elucidated. We hypothesized that a decrease in the activity of dipeptidyl peptidase‐4 (DPP‐4), the enzyme which inactivates incretins, may explain the rise in incretin levels post‐GBP. Fasting plasma DPP‐4 activity was measured after 10‐kg equivalent weight loss by GBP (n = 16) or by caloric restriction (CR,n = 14) in obese patients with type 2 diabetes. DPP‐4 activity decreased after GBP by 11.6% (p = 0.01), but not after CR. The increased peak glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) response to oral glucose after GBP did not correlate with DPP‐4 activity. The decrease in fasting plasma DPP‐4 activity after GBP occurred by a mechanism independent of weight loss and did not relate to change in incretin concentrations. Whether the change in DPP‐4 activity contributes to improved diabetes control after GBP remains therefore to be determined.

Translational Efficiency of rpoS mRNA from Borrelia burgdorferi: Effects of the Length and Sequence of the mRNA Leader Region

Regulation of the enzootic cycle in Borrelia burgdorferi requires a shift to the RNA polymerase alternative sigma factor, RpoS. We used in vitro and in vivo assays to assess the relative importance of the putative Shine-Dalgarno sequence and its sequestration for the translational efficiency of rpoS. We created mutant leader regions in which we either removed the Shine-Dalgarno sequence, disrupted the secondary structure or both. Binding assays and toeprint assays demonstrated that both the presence and the availability of the Shine-Dalgarno sequence are important to the efficiency and specificity of ribosome binding. Adding a DsrABb mimic in the form of a single-stranded DNA oligonucleotide increased the level and specificity of binding ribosomes to the transcript with an extended leader, presumably by making the Shine-Dalgarno sequence available for binding. In in vivo assays we confirmed that the Shine-Dalgarno sequence must be both present and un-sequestered in order for translation to proceed efficiently. The longer transcript was significantly better translated in B. burgdorferi at 37 °C than at 26 °C, lending support to the hypothesis that DsrABb acts as a temperature-dependent stimulator of translation. These studies demonstrate that translational regulation of gene expression in B. burgdorferi may be an important mechanism for responding to environmental signals important in the enzootic cycle.

Candidate Comprehension of Key Concepts in Kidney Transplantation

BACKGROUNDnAlthough kidney transplant candidates receive education regarding transplantation and donation, little is known about the extent of their comprehension. We aimed to identify factors that affect patient comprehension of important concepts regarding kidney transplantation.nnnMATERIAL AND METHODSnWe performed a cross-sectional survey of consecutive adult kidney transplant candidates seen at our center between July 2013 and October 2013 for initial evaluation (n=100) or for reevaluation (n=117). The main outcome measure was a Knowledge Assessment Questionnaire completed by patients. We assessed factors affecting patient understanding of key kidney transplant concepts as measured by mean knowledge score.nnnRESULTSnMean knowledge scores of those at evaluation (72±21) and those at reevaluation (70±20; p=0.4769) were similar; therefore the entire cohort was analyzed as a single group. Compared to the high-scoring group, low-scorers (<75%; median value) were significantly more likely to be older, Hispanic, with lower education attainment, and have end-stage renal disease due to hypertension or diabetes rather than other etiologies. On multivariate analysis, independent risk factors for low-scores were increasing age (aOR 1.03 (95% CI 1.01-1.06) and educational level (less than high school; aOR 4.23, 95%CI 1.82-9.80; high school or GED aOR2.85, 95% CI 1.43-5.70 compared to some college or technical school). Of 139 candidates that consented to receive ECD and 152 consenting to CDCHR kidneys, 52% and 27%, respectively, answered the high-risk-specific question incorrectly.nnnCONCLUSIONSnEducational level and older age are independent risk factors for poor comprehension. Kidney candidate knowledge of organs with increased risks is suboptimal despite previous consent to receive such organs.

RS06. Risk of Insulin-Dependent Diabetes Mellitus in Patients Undergoing Carotid Endarterectomy

the purpose of this study is to develop a score to predict the risk of stroke/ death after CAS. Methods:We analyzed the Vascular Quality Initiative dataset from 2009 to the present. Univariate andmultivariate methods were used to identify predictors associated with 30-day stroke/death. Logistic regression was performed and variable selection for the final model was made on backward stepwise selection to achieve model parsimony. This final model was validated by bootstrapping (1000 repetitions) and tested by calibration (Hosmer-Lemeshow) and discrimination (c-statistic). A risk score was made by converting regression coefficients for each predictor to integers from which probability (%) was calculated. Scores were grouped into five simplified categories. Results: We identified 11,479 patients who underwent CAS during the study period with a combined 30-day stroke/death rate of 3.8%. Patients who developed the outcome of 30-day stroke/death were older (median age, 75 years vs 72 years), more likely to be female (41.3% vs 35.8%), symptomatic (58% vs 40.1%), and diabetic (44.8% vs 37.4%), and less likely to be on statins (71.4% vs 81.8%) and antiplatelet agents (aspirin, 78.1% vs 86.8%; P2Y12-inhibitor, 61.8% vs 77.1%; all P < .05). The Table details the demographic variables, comorbidities, preoperative medication, and lesionspecific predictors that were analyzed. Independent predictors included in the final model were age, female gender, diabetes, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, symptomatic status, contralateral occlusion, restenotic lesion, preoperative statin use, and P2Y12-inhibitor use. The model had a c-statistic of 70.9%. The corresponding score for each predictor, risk of 30-day stroke/death and two examples are shown in the Fig. Conclusions: This study introduces an easy to use clinical tool for predicting stroke/death after CAS and will help surgeons and patients in weighing the risks versus the benefits of performing this procedure. In asymptomatic patients with high predicted stroke/death risk, medical management might be the safer option.

IP221. Updated Tibial TransAtlantic Inter-Society Consensus Classification System Fails to Show Improved Differentiation in Outcomes After Endovascular Intervention

specialists and vascular specialists formed the collaborative, developing guidelines and protocols; frontline nonspecialists performing amputations were added to the collaborative in 2015 to decrease the percentage of major amputation performed. Demographics of the patients and fiscal and amputation data were collected, and standard statistical methods were applied. Results: Query revealed 567 total amputations, of which 198 were major and 137 were repeated amputations. Demographics for the entire cohort demonstrated an average age of 56.2 years, 87% nonwhite, 70% indigent, 86% diabetic, and 8% requiring dialysis. Prevalence of smoking and hypertension decreased over time (P < .05) and was the only significant change in patient risk factors. Overall, the ratio of major/total amputations (Fig 1) decreased from 48% to 22%, becoming statistically significant (P < .05) after 2015. A statistically significant difference in total amputations per year was not discovered. Major amputation rates remained highest among uninsured patients (P < .05) compared with public and private insurance. No statistically significant change occurred in patient payer mix. No patient risk or fiscal factors were predictive of repeated amputation. Vascular surgeons performed 14% of amputations in the entire cohort. Population analysis (Fig 2) of the top 10 amputation-prevalent ZIP codes representing 28% of all amputations revealed annual income per person of

PC090. Risk Score for Groin Access Complication in Ultrasound-Guided Percutaneous Aortic Procedures

14,900, 34.2% black, 51.2% Hispanic, 59% employed, 32% uninsured, 37% public insurance, and 32% private insurance. Conclusions: In resource-limited environments, threatened limbs may be managed by specialist and nonspecialist providers who are frontline and greater in number. Inclusion of sparse specialists into only a limb salvage collaborative did not achieve major limb amputation prevention in this study, and only after inclusion of all providers performing amputation did a statistically significant shift from major to minor amputation occur. Further reduction of major and minor amputation may be challenging in this population, given the limitations in system and patient resources, and will likely require alternative paradigms to existing models.

PC064. The Effect of Three-dimensional Image Fusion on Radiation Exposure, Contrast Dose, and Procedural Times During Carotid Artery Stenting

Unadjusted 30-day mortality was 16% in extent 2, 26% in extent 3, 19% in extent 4 disease (P < .03 for overall heterogeneity; Fig and Table); extent 3 was different from extent 2 and extent 4 (P < .009) but extent 2 versus extent 4 were not different from each other (P 1⁄4 .44). Vascular disease risk-burden was significant independent predictor of 30-day mortality, and for each 1-point increase in burden score, the odds of 30-day mortality increased by 1.5 time (P < .0001). After adjustment for other risk factors,

IP059. Early and Late Costs of Endovascular Abdominal Aortic Aneurysm Repair From the Endurant Stent Graft System Post Approval Study (ENGAGE PAS)

TheEffectofThree-dimensional ImageFusionon Radiation Exposure, Contrast Dose, and Procedural Times During Carotid Artery Stenting Nicholas J. Swerdlow, Douglas W. Jones, Alexander B. Pothof, Thomas F. X. O’Donnell, Patric Liang, Chun Li, Mark C. Wyers, Marc L. Schermerhorn. Beth Israel Deaconess Medical Center, Boston, Mass; Boston Medical Center, Boston, Mass; University Medical Center Utrecht, Utrecht, The Netherlands