Blandine Laferrère

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes

CONTEXT Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels. OBJECTIVE Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. DESIGN AND METHODS Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss. SETTING This outpatient study was conducted at the General Clinical Research Center. MAIN OUTCOME MEASURES Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load. RESULTS At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 +/- 6 to 112 +/- 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 +/- 27.5 to 44.8 +/- 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP. CONCLUSIONS These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.

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.

Stress and obesity: the role of the hypothalamic-pituitary-adrenal axis in metabolic disease.

Purpose of reviewChronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic–pituitary–adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. Recent findingsDysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. SummaryThe present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases.

Depression Score Predicts Weight Loss following Roux-en-Y Gastric Bypass

Background: The prevalence of obesity is increasing in the United States. Bariatric surgery is the only intervention that can reliably induce and maintain significant weight loss in obese patients. The association between pre-surgical severity of depression and success at weight loss following Roux-en-Y gastric bypass (RYGBP) has not yet been fully elucidated. Methods: 145 charts of patients who underwent RYGBP for morbid obesity were reviewed. 47 patients who filled out the Beck Depression Inventory (BDI) before surgery and completed 1 year of follow-up were studied. The relationship between pre-surgical severity of depression and success at weight loss was examined through multivariate regression analysis using percent excess weight loss (%EWL) as a dependent variable and BDI score as one of the predictors. Results: Weight loss at 1 year was significantly related to the BDI score before surgery (P =0.014). BDI score was also found to be a significant predictor of the amount of weight lost (kg) 1 year after surgery (P =0.027). Age (P =0.03) and initial body mass index (BMI) (P =0.011) were the only other variables with significant independent relations to %EWL. Conclusions: Our data show a positive correlation between pre-surgical severity of depression as measured by BDI score and the 1-year success at weight loss after RYGBP as measured by %EWL. More depressed individuals tend to lose greater amounts of weight compared with less depressed individuals. Future prospective studies should examine possible mechanisms and effects of depression and other psychiatric disturbances on long-term weight loss after RYGBP.

Do Incretins Play a Role in the Remission of Type 2 Diabetes after Gastric Bypass Surgery: What are the Evidence?

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

Calorie Intake and Meal Patterns up to 4 Years after Roux-en-Y Gastric Bypass Surgery

Background: Roux-en-Y gastric bypass (RYGBP) is the most popular surgical treatment for morbid obesity in the U.S.A., producing significant and durable weight loss with improvement in co-morbidities. Although a greater number of patients are undergoing surgical treatment for obesity, little data are available regarding their food intake after surgery. This study was undertaken to evaluate the caloric amount, nutrient composition and meal patterns of patients 18 months to 4 years after RYGBP. Ethnic differences in food intake were also investigated. Methods: Questionnaires were mailed to 360 patients who had undergone RYGBP at least 18 months prior to the onset of the study. Results: Data were available from 69 patients, 52% Caucasian, 25% African-American, 23% Hispanic. 30 months after surgery, the average daily calorie intake was 1733 ± 630 kcal (n=68, range 624-3486 kcal), with 44% of calories from carbohydrates, 22% from protein and 33% from fat. Sugar-sweetened beverages represented 7% of total caloric intake. Patients consumed 3 meals and 3 snacks per day on average. Food intake from dinner and an evening snack represented 40% of the daily caloric intake. Snacks accounted for 37% of the daily intake. Percent excess weight loss (%EWL) was 58 ± 17% and was not different among ethnic groups. However, Hispanics reported consuming fewer snacks and fewer calories. %EWL correlated with the total daily caloric intake (r= .446, P <0.001). Follow-up attendance was 54% at 1 year after surgery but fell to 10% at 3 years. Only 77% of patients were taking vitamin supplements. Conclusion: RYGBP resulted in significant weight loss. Caloric intake was quite variable. Long-term follow-up remained low, putting patients at risk for metabolic and vitamin deficiencies. The relationship between caloric intake and long-term weight changes remains to be studied.

Short sleep duration, glucose dysregulation and hormonal regulation of appetite in men and women.

STUDY OBJECTIVE To determine the hormonal effects of reducing sleep duration under controlled feeding conditions. DESIGN Randomized, crossover study. SETTING Inpatient. PARTICIPANTS Twenty-seven normal weight, 30- to 45-yr-old men and women habitually sleeping 7-9 hr/night. INTERVENTION PARTICIPANTS WERE STUDIED UNDER TWO SLEEP CONDITIONS: short (4 hr in bed) or habitual (9 hr in bed) sleep. A controlled diet was provided for each 4-day study period. MEASUREMENTS AND RESULTS Fasting blood samples were obtained daily and frequent blood samples were obtained throughout day 4. The main outcomes measures included glucose, insulin, leptin, ghrelin, adiponectin, total glucagon-like peptide 1 (GLP-1) and peptide YY(3-36) (PYY(3-36)) concentrations. Body weights were reduced by 2.2 ± 0.4 lb and 1.7 ± 0.4 lb during the habitual and short sleep phases, respectively (both P < 0.0001). There was no effect of sleep duration on glucose, insulin, and leptin profiles (all P > 0.05). Ghrelin and GLP-1 responses differed by sex. Short sleep increased fasting (P = 0.054) and morning (08:00-12:00) (P = 0.042) total ghrelin in men but not women. The reverse was observed for GLP-1: afternoon levels (12:30-19:00) were lower (P = 0.016) after short sleep compared with habitual sleep in women but not men. CONCLUSIONS These data suggest that, in the context of negative energy balance, short sleep does not lead to a state of increased insulin resistance, but may predispose to overeating via separate mechanisms in men and women. CLINICAL TRIAL INFORMATION Trial registration on http://www.clinicaltrials.gov. #NCT00935402.

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

CONTEXT The 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. OBJECTIVE We 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. METHODS Twenty 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. RESULTS At 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. CONCLUSIONS Our 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.

Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery

Background:  The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short‐ and long‐term changes in hormonal determinants of blood glucose.

Effect of Weight Loss by Diet or Gastric Bypass Surgery on Peptide YY3–36 Levels

Objective:To examine the effect of an equivalent weight loss, by gastric bypass surgery (GBP) or by diet, on peptide YY3–36 (PYY3–36), ghrelin, and leptin levels and to determine the effect of diabetes status on PYY3–36 levels. Summary Background Data:The increased PYY3–36 levels after GBP may be involved in the magnitude and the sustainability of weight loss after surgery. Methods:Of the 30 morbidly obese women who participated in the study, 21 had type 2 diabetes mellitus, and were studied before and after equivalent weight loss of 10 kg by either GBP (n = 11) or by diet (n = 10). Results:PYY3–36 levels were higher in obese diabetic as compared with nondiabetic individuals (64.1 ± 34.4 pg/mL vs. 39.9 ± 21.1 pg/mL; P < 0.05). PYY3–36 levels increased markedly in response to oral glucose after GBP (peak: 72.3 ± 20.5 pg/mL–132.7 ± 49.7 pg/mL; P < 0.001; AUC0–180: 51.5 ± 23.3 pg/mL.min−1–91.1 ± 32.2 pg/mL.min−1 P < 0.001), but not after diet (peak: 85.5 ± 51.9 pg/mL–84.8 ± 41.13 pg/mL; P = NS; AUC0–180: 68.3 ± 38.5 pg/mL.min−1–61.1 ± 42.2 pg/mL.min−1 P = NS). Fasting ghrelin levels increased after diet (425 ± 91 pg/mL–519 ± 105 pg/mL; P < 0.05), but did not change after GBP (506 ± 121 pg/mL–482 ± 196 pg/mL; P = NS). Conclusions:Diabetes status seems to be a determinant of PYY3–36 levels. GBP, but not diet-induced weight loss, resulted in markedly increased glucose-stimulated PYY3–36 levels. The increase in stimulated PYY3–36 levels after GBP is likely a result of the surgery rather than a secondary outcome of weight loss. Changes in PYY3–36 levels and ghrelin could contribute to the success of GBP in sustaining weight loss.