Metabolites and diabetes remission after weight loss.

There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with severe obesity enrolled in the Longitudinal Assessment of Bariatric Surgery (LABS) and the Look AHEAD (Action for Health in Diabetes) studies. Targeted mass spectrometry-based profiling of 135 metabolites was performed in pre-intervention blood samples using a nested design for diabetes remission over five years (n = 93 LABS, n = 80 Look AHEAD; n = 87 remitters), and for extremes of weight loss at five years (n = 151 LABS; n = 75 with high weight loss). Principal components analysis (PCA) was used for dimensionality reduction, with PCA-derived metabolite factors tested for association with both diabetes remission and weight loss. Metabolic markers were tested for incremental improvement to clinical models, including the DiaRem score. Two metabolite factors were associated with diabetes remission: one primarily composed of branched chain amino acids (BCAA) and tyrosine (odds ratio (95% confidence interval) [OR (95% CI)] = 1.4 [1.0-1.9], p = 0.045), and one with betaine and choline (OR [95% CI] = 0.7 [0.5-0.9], p = 0.02).These results were not significant after adjustment for multiple tests. Inclusion of these two factors in clinical models yielded modest improvements in model fit and performance: in a constructed clinical model, the C-statistic improved from 0.87 to 0.90 (p = 0.02), while the net reclassification index showed improvement in prediction compared to the DiaRem score (NRI = 0.26, p = 0.0013). No metabolite factors associated with weight loss at five years. Baseline levels of metabolites in the BCAA and trimethylamine-N-oxide (TMAO)-microbiome-related pathways are independently and incrementally associated with sustained diabetes remission after weight loss interventions in individuals with severe obesity. These metabolites could serve as clinically useful biomarkers to identify individuals who will benefit the most from weight loss interventions.

Intensive Weight Loss Intervention and Cancer Risk in Adults with Type 2 Diabetes: Analysis of the Look AHEAD Randomized Clinical Trial.

OBJECTIVE: This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. METHODS: Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. RESULTS: After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). CONCLUSIONS: An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

Effect of preoperative body mass index on weight loss after obesity surgery.

BACKGROUND: Previous studies suggest that individuals with body mass index (BMI) above versus below 60 kg/m(2) attain lower percentage of excess weight loss (%EWL) after bariatric surgery. The objectives of this study were to (1) test whether conclusions drawn about the effect of preoperative BMI on postoperative weight loss depend on the outcome measure, (2) test for evidence of a threshold effect at BMI = 60 kg/m(2), and (3) test the effect from surgery to 12-month follow-up, relative to 12- to 36-month follow-up. METHODS: Retrospective analyses of participants grouped according to preoperative BMI: 35-39.9 (n = 232); 40-49.9 (n = 1166); 50-59.9 (n = 429);≥60 (n = 166). RESULTS: As anticipated, individuals with higher versus lower preoperative BMI had greater total weight loss but lower %EWL at all postoperative time points (all, P<.0005). However, these individuals also had lower percentage of initial weight loss (%IWL) at all time points beyond 1 month postsurgery (all, P<.0005). From 12- to 36-months, individuals with BMI 35-39.9 had 3.2±14.3 %IWL (P<.0001); 40-49.9 had 1.0±8.9 %IWL (P<.0005); 50-59.9 had-2.4±10.0 %IWL (P<.0005); and≥60 had-3.6±11.5 %IWL (P<.0005). Overall F3,1989 = 20.2, P< .0005. CONCLUSIONS: Conclusions drawn about the effect of preoperative BMI may depend on the outcome measure. A dosage effect of preoperative BMI was apparent, with heavier individuals showing lower percentages of initial and excess weight loss, regardless of BMI above or below 60 kg/m(2). Finally, this effect was particularly apparent after the initial 12-month rapid weight loss phase, when less obese (BMI<50) individuals continued losing weight, while heavier individuals (BMI≥50) regained significant weight.

Pre-bariatric surgery weight loss requirements and the effect of preoperative weight loss on postoperative outcome.

Pre-bariatric surgery requirements vary between surgeons and surgical centers, with standards of practice not yet established. The goal of this systematic review was to summarize and evaluate the available literature on pre-bariatric surgery weight loss requirements and the relation between preoperative weight loss and postoperative outcome. Major databases, including Medline, PubMed and PsychINFO were searched for relevant articles. Case studies, studies>20 years old and studies that utilized self-reported body weight data were excluded. Data on the effect of the following was summarized: (1) preoperative requirements on preoperative weight loss; (2) insurance-mandated preoperative requirements; (3) the contingency of receipt of surgery; (4) preoperative weight loss on postoperative weight loss and (5) preoperative weight loss on perioperative and postoperative complication and comorbidity rates. The majority of studies suggest that: (1) current preoperative requirements held by the majority of third party payer organizations in the United States are ineffective in fostering preoperative weight loss; (2) making receipt of surgery contingent upon achieving preoperative weight loss, and meal-replacement diets, may be particularly effective in fostering preoperative weight loss and (3) preoperative weight loss may lead to improvements in at least some relevant postoperative outcomes. However, a preoperative weight loss mandate may lead to the denial of surgery and subsequent health benefits to individuals who are unable to achieve a prespecified amount of weight. Overall, the limited number and quality of prospective studies in this area prohibits the much-needed establishment of standards of practice for pre-bariatric requirements.

Expert panel report on a study of Splenda in male rats.

A recent study in rats investigated the retail sweetener product, Granulated SPLENDA No Calorie Sweetener (Splenda) (Abou-Donia et al., 2008. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health A, 71, 1415-1429), which is composed of (by dry weight) maltodextrin ( approximately 99%) and sucralose ( approximately 1%). The investigators reported that Splenda increased body weight, decreased beneficial intestinal bacteria, and increased the expression of certain cytochrome P450 (CYP450) enzymes and the transporter protein, P-glycoprotein (P-gp), the latter of which was considered evidence that Splenda or sucralose might interfere with the absorption of nutrients and drugs. The investigators indicated that the reported changes were attributable to the sucralose present in the product tested. An Expert Panel conducted a rigorous evaluation of this study. In arriving at its conclusions, the Expert Panel considered the design and conduct of the study, its outcomes and the outcomes reported in other data available publicly. The Expert Panel found that the study was deficient in several critical areas and that its results cannot be interpreted as evidence that either Splenda, or sucralose, produced adverse effects in male rats, including effects on gastrointestinal microflora, body weight, CYP450 and P-gp activity, and nutrient and drug absorption. The study conclusions are not consistent with published literature and not supported by the data presented.

Self-help weight loss versus a structured commercial program after 26 weeks: a randomized controlled study.

PURPOSE: There have been few randomized controlled trials of commercial weight-loss programs. This ongoing study compares the effects of a self-help program and a commercial program on weight loss and other measures of obesity in overweight and obese men and women. SUBJECTS AND METHODS: We report the results of the first 26 weeks of a multicenter, randomized, 2-year study of 423 subjects who had a body mass index of 27 to 40 kg/m(2). Subjects were randomly assigned to either a self-help program, consisting of two 20-minute sessions with a nutritionist and provision of printed materials and other self-help resources, or to attendance at meetings of a commercial program (Weight Watchers). Outcome measures were changes in body weight, body mass index, waist circumference, and body fat. Changes in serum homocysteine levels were measured in a subsample of participants during the first 12 weeks. RESULTS: After 26 weeks, subjects in the commercial program, as compared with those in the self-help program, had greater decreases in body weight [mean (+/- SD) -4.8+/-5.6 vs -1.4+/-4.7 kg] and body mass index (-1.7+/-1.9 vs -0.5+/-1.6 kg/m(2), both P<0.001) in intention-to-treat analyses. Among subjects measured at week 26, mean waist circumference (-4.3+/-10.5 vs -0.7+/-12.7 cm) and fat mass (-3.8 +/-7.0 vs -1.5+/-7.6 kg, both P<0.05) also decreased more among subjects in the commercial program. Mean serum homocysteine levels improved in the commercial program compared with self-help (-0.5+/-1.3 vs 0.9+/-1.8 microM, P<0.05). CONCLUSIONS: A structured commercial weight-loss program is more likely to be effective for managing moderately overweight patients than brief counseling and self-help.

Large changes in food intake in diabetic rats fed high-fat and low-fat diets.

Groups of male Sprague-Dawley rats were predominantly fed either a high-fat or a high-carbohydrate (CHO) diet. For designated 2-day periods, their diets were switched. After baseline measurements of food and water intake, the rats were made diabetic by injections of either 40 or 46-50 mg/kg streptozotocin. Food and water intake gradually increased over a 15-day period for rats on the CHO diet. Whenever the diets were switched, many of the rats showed large changes in food and fluid intake. Body weight showed a gradual decline, but the rats retained half of the dissectable abdominal body fat at sacrifice. Measurements of plasma glucose, insulin and glucagon proved that the rats were diabetic. The changes in average food intake were reasonably consistent with the "utilizable fuel" theory for the control of food intake assuming that the CHO component of each diet was non-utilizable. The distribution of the fat/CHO utilizable fuel ratio in both experiments was flat and non-normal showing that some rats ate as much of the high fat diet as the high CHO diet. Other rats tended to avoid the high fat to an extent that was greater than predicted by the theory, suggesting that the fat diet may have caused malaise. Thus, the individual rat data did not provide strong support for the "utilizable fuel" theory.