Lillian F. Lien

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

Comparison of Strategies for Sustaining Weight Loss: The Weight Loss Maintenance Randomized Controlled Trial

CONTEXT Behavioral weight loss interventions achieve short-term success, but re-gain is common. OBJECTIVE To compare 2 weight loss maintenance interventions with a self-directed control group. DESIGN, SETTING, AND PARTICIPANTS Two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). Enrollment at 4 academic centers occurred August 2003-July 2004 and randomization, February-December 2004. Data collection was completed in June 2007. INTERVENTIONS After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology-based intervention, or self-directed control. Main Outcome Changes in weight from randomization. RESULTS Mean entry weight was 96.7 kg. During the initial 6-month program, mean weight loss was 8.5 kg. After randomization, weight regain occurred. Participants in the personal-contact group regained less weight (4.0 kg) than those in the self-directed group (5.5 kg; mean difference at 30 months, -1.5 kg; 95% confidence interval [CI], -2.4 to -0.6 kg; P = .001). At 30 months, weight regain did not differ between the interactive technology-based (5.2 kg) and self-directed groups (5.5 kg; mean difference -0.3 kg; 95% CI, -1.2 to 0.6 kg; P = .51); however, weight regain was lower in the interactive technology-based than in the self-directed group at 18 months (mean difference, -1.1 kg; 95% CI, -1.9 to -0.4 kg; P = .003) and at 24 months (mean difference, -0.9 kg; 95% CI, -1.7 to -0.02 kg; P = .04). At 30 months, the difference between the personal-contact and interactive technology-based group was -1.2 kg (95% CI -2.1 to -0.3; P = .008). Effects did not differ significantly by sex, race, age, and body mass index subgroups. Overall, 71% of study participants remained below entry weight. CONCLUSIONS The majority of individuals who successfully completed an initial behavioral weight loss program maintained a weight below their initial level. Monthly brief personal contact provided modest benefit in sustaining weight loss, whereas an interactive technology-based intervention provided early but transient benefit. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00054925.

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.

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Associations of Internet Website Use With Weight Change in a Long-term Weight Loss Maintenance Program

Background The Weight Loss Maintenance Trial (WLM) compared two long-term weight-maintenance interventions, a personal contact arm and an Internet arm, with a no-treatment control after an initial six-month Phase I weight loss program. The Internet arm focused on use of an interactive website for support of long-term weight maintenance. There is limited information about patterns of website use and specific components of an interactive website that might help promote maintenance of weight loss. Objective This paper presents a secondary analysis of the subset of participants in the Internet arm and focuses on website use patterns and features associated with long-term weight maintenance. Methods Adults at risk for cardiovascular disease (CVD) who lost at least 4 kilograms in an initial 20-week group-based, behavioral weight-loss program were trained to use an interactive website for weight loss maintenance. Of the 348 participants, 37% were male and 38% were African American. Mean weight loss was 8.6 kilograms. Participants were encouraged to log in at least weekly and enter a current weight for the 30-month study period. The website contained features that encouraged setting short-term goals, creating action plans, and reinforcing self-management habits. The website also included motivational modules, daily tips, and tailored messages. Based on log-in and weight-entry frequency, we divided participants into three website use categories: consistent, some, and minimal. Results Participants in the consistent user group (n = 212) were more likely to be older (P = .002), other than African American (P = .02), and more educated (P = .01). While there was no significant difference between website use categories in the amount of Phase I change in body weight (P = .45) or income (P = .78), minimal website users (n = 75) were significantly more likely to have attended fewer Phase I sessions (P = .001) and had a higher initial body mass index (BMI) (P < .001). After adjusting for baseline characteristics including initial BMI, variables most associated with less weight regain included: number of log-ins (P = .001), minutes on the website (P < .001), number of weight entries (P = .002), number of exercise entries (P < .001), and sessions with additional use of website features after weight entry (P = .002). Conclusion Participants defined as consistent website users of an interactive behavioral website designed to promote maintenance of weight loss were more successful at maintaining long-term weight loss. Trial Registration NCT00054925; http://clinicaltrials.gov/ct2/show/NCT00054925 (Archived by WebCite at http://www.webcitation.org/5rC7523ue)

Predictors of long-term weight loss in adults with modest initial weight loss, by sex and race.

Effective weight management interventions could reduce race—sex disparities in cardiovascular disease (CVD), yet little is known about factors associated with successful weight loss maintenance in race—sex subgroups. In the Weight Loss Maintenance trial (WLM), overweight/obese (BMI 25–45 kg/m2) adults who lost ≥4 kg in a 6‐month behavioral weight loss intervention (phase I) were randomized into one of three 30‐month maintenance interventions (phase II). To investigate predictors in subgroups, randomized groups were combined for this analysis. Of 1,685 phase I participants, 1,032 (61%) entered phase II, including 12% black men (BM), 26% black women (BW), 25% white men (WM), and 37% white women (WW). Weight change over the 36‐month study ranged from −2.3% (95% confidence interval = −3.1 to −1.5%) in BW to −4.5% (95% confidence interval = −5.7 to −4.0%) in WM, the result of differential weight loss during phase I. Within race, men lost significantly more weight than women, but within sex group, weight loss did not differ significantly between races. Although participants regained weight during phase II, regain did not differ by race—sex group, and mean weight at the end of the study was significantly lower than phase I entry weight for each subgroup. In regression models, phase I weight loss predicted overall 36‐month weight loss in all race—sex groups. Healthy dietary pattern at entry, improvement in dietary pattern, or both were predictive in three of four race—sex groups. Few other variables other than initial weight loss and dietary pattern were predictive. Future research should identify additional modifiable influences on long‐term maintenance after a modest weight loss.

Dietary Intakes Associated with Successful Weight Loss and Maintenance during the Weight Loss Maintenance Trial

BACKGROUND Dietary components effective in weight maintenance efforts have not been adequately identified. OBJECTIVE To determine the effects of changes in dietary consumption on weight loss and maintenance during the Weight Loss Maintenance clinical trial. DESIGN Weight Loss Maintenance was a randomized controlled trial. Successful weight loss participants who completed Phase I of the trial and lost 4 kg were randomized to one of three maintenance intervention arms in Phase II and followed for an additional 30 months. PARTICIPANTS/SETTING The multicenter trial was conducted from 2003 through 2007. This substudy included 828 successful weight loss participants. METHODS The Block Food Frequency Questionnaire (FFQ) was used to assess nutrient intake levels and food group servings. Carbohydrates, proteins, fats, dietary fiber, fruit/vegetable, and dairy servings were utilized as predictor variables. The FFQ was collected on all participants at study entry (beginning of Phase I). Those randomized to Phase II completed the FFQ at three additional time points: randomization (beginning of Phase II), 12 months, and 30 months. INTERVENTION The main intervention focused on long-term maintenance of weight loss using the Dietary Approaches to Hypertension diet. This substudy examined if changes to specific dietary variables were associated with weight loss and maintenance. STATISTICAL ANALYSES PERFORMED Linear regression models that adjusted for change in total energy examined the relationship between changes in dietary intake and weight for each time period. Site, age, race, sex, and a race-sex interaction were included as covariates. RESULTS Participants who substituted protein for fat lost, on average, 0.33 kg per 6 months during Phase I (P<0.0001) and 0.07 kg per 6 months during Phase II (P<0.0001) per 1% increase in protein. Increased intake of fruits and vegetables was associated with weight loss in Phases I and II: 0.29 kg per 6 months (P<0.0001) and 0.04 kg per 6 months (P=0.0062), respectively, per 1-serving increase. Substitution of carbohydrates for fat and protein for carbohydrates were associated with weight loss during both phases. Increasing dairy intake was associated with significant weight loss during Phase II (-0.17 kg per 6 months per 1-serving increase, P=0.0002), but not during Phase I. Dietary fiber revealed no significant findings. CONCLUSIONS Increasing fruits, vegetables, and low-fat dairy may help achieve weight loss and maintenance.

In vitro modeling of spinal anesthesia. A digital video image processing technique and its application to catheter characterization.

BackgroundMaldistribution of intrathecal local anesthetic has recently been implicated as a contributor to neurotoxic injury. In vitro modeling can be used to understand the distribution of anesthetic agents within the subarachnoid space. We describe an in vitro modeling technique that uses digital video image processing and its application to catheter injection of local anesthetic. MethodsA clear plastic model of the subarachnoid space, including a simulated spinal cord and cauda equina, was filled with lactated Ringers solution. Phthalocyanine blue dye of known concentration was injected into the model through small-bore (28-G) and large-bore (18-G) catheters. Injections were performed at a variety of controlled rates and sacral catheter positions, and the propagation of dye throughout the model was recorded on videotape, digitized by computer, and converted to a two-dimensional image of dye concentration. A subset of data was compared with results obtained from spectrophotometric analysis. ResultsThere was a strong correlation (r = 0.98) between data obtained with analysis by digital video image processing and those obtained spectrophotometrically. Catheter size, catheter angle, and injection rate significantly influenced the distribution and peak concentration of simulated anesthetic. No major differences in distribution or peak concentration were observed with the two types of 28-G catheters. ConclusionsThe digital video image processing technique can be used to quantify anesthetic distribution rapidly within a model of the subarachnoid space without disturbing the distribution. The current results demonstrate a strong dependence of anesthetic distribution on catheter angle, catheter size, and injection rate. Comparisons between 28-G catheters suggest that the difference in reported incidence of cauda equlna syndrome associated with different 28-G catheters cannot be explained on the basis of differences in anesthetic distribution

Blood Pressure-Lowering Mechanisms of the DASH Dietary Pattern

Potential blood pressure- (BP-) lowering mechanisms of the DASH dietary pattern were measured in 20 unmedicated hypertensive adults in a controlled feeding study. At screening, participants averaged 44.3 ± 7.8 years, BMI 33.9 ± 6.6 Kg/m2, and BP 144.2 ± 9.38/88.5 ± 6.03 mmHg. All consumed a control diet for one week, then were randomized to control or DASH for another two weeks (week one and two). With DASH, but not controls, SBP fell by 10.65 ± 12.89 (P = 0.023) and 9.60 ± 11.23 (P = 0.039) mmHg and DBP by 5.95 ± 8.01 (P = 0.069) and 8.60 ± 9.13 mmHg (P = 0.011) at the end of week one and two, respectively. Univariate regressions showed that changes in urinary sodium/potassium ratio (β = 1.99) and plasma renin activity (β = −15.78) and percent change in plasma nitrite after hyperemia were associated with SBP changes at week one (all P < 0.05). Plasma nitrite following hyperemia showed a treatment effect (P = 0.014) and increased at week two (P = 0.001). Pulse wave velocity decreased over time with DASH (trend P = 0.019), and reached significance at week two (P = 0.026). This response may be mediated by an improvement in upregulation of nitric oxide bioavailability. Early natriuresis and reductions in oxidative stress cannot be ruled out. Future studies are needed to verify these findings, assess the possibility of earlier effects, and examine other potential mediators.

Optimizing hospital use of intravenous insulin therapy: improved management of hyperglycemia and error reduction with a new nomogram.

OBJECTIVE To assess the efficacy and safety of intravenous (IV) insulin administration with use of our institutions old protocol (pre-nomogram phase) as compared with our new insulin nomogram (post-nomogram phase), which titrates insulin dose based on the rate of change of plasma glucose values and uses multipliers to determine the new insulin infusion rate. METHODS Hospitalized adults receiving an IV insulin infusion in our tertiary care medical center were enrolled in this study after informed consent was obtained. The study was an observational analysis conducted before and after implementation of the new insulin infusion nomogram. Measurements included episodes of hypoglycemia and incidence of the following errors in the insulin infusion process: (1) episodes of documented failure to increase insulin infusion rate despite persistent hyperglycemia and (2) number of times the IV infusion was stopped without subcutaneous administration of insulin. RESULTS Overall, 66 patients were analyzed (38 in the pre-nomogram phase and 28 in the post-nomogram phase). The new nomogram reduced by nearly 3-fold (from 0.89 +/- 0.68 to 0.36 +/- 0.49 occurrence per patient per 24 hours; P<0.001) the mean incidence of failure to give insulin subcutaneously before discontinuation of IV insulin infusion. Moreover, the nomogram nearly eliminated the error of caregiver nonresponsiveness to persistent hyperglycemia: mean incidence 0.39 +/- 0.65 occurrence per patient per 24 hours before implementation of the new nomogram versus 0.02 +/- 0.09 afterward (P<0.002). There was no statistically significant difference in episodes of hypoglycemia between the 2 study groups. CONCLUSION Safe IV administration of insulin through error prevention is essential. Implementation of a new IV insulin infusion nomogram, which adjusts insulin infusion using multipliers, reduces errors and improves glycemic control without increasing hypoglycemic episodes.