Changes of Body Weight and Plasma Ghrelin Levels after Gastric Banding and Gastric Bypass

Objective: Ghrelin is an enteric peptide with strong orexigenic and adipogenic effects. Plasma ghrelin levels are decreased in obese subjects but increase after weight loss; this increase is not observed after Roux‐en‐Y gastric bypass (RYGB). Prospective and comparative data after adjustable silicone gastric banding (ASGB) have not been reported previously. Research Methods and Procedures: Overnight fasting plasma ghrelin concentration was measured in morbidly obese subjects at baseline and 3, 6, 12, and 24 months after ASGB (n = 8) or RYGB (n = 5) and in nonoperated controls (n = 7). Results: After RYGB, body weight (BW) decreased by 29.5 ± 5.5 kg (mean ± SE, p < 0.001), whereas plasma ghrelin failed to increase significantly (+167 ± 119 pg/mL, not significant). In contrast, after ASGB, BW decreased less (by 22.8 ± 5.9 kg; p < 0.001), and plasma ghrelin significantly increased by 377 ± 201 pg/mL (p = 0.025). Neither BW nor plasma ghrelin changed in nonoperated controls. Plasma leptin decreased in both operated groups (similarly p < 0.05) but not in nonoperated controls. Plasma growth hormone and insulin‐like growth factor 1 were not correlated with changes in plasma ghrelin concentrations. Discussion: Plasma ghrelin levels failed to increase during substantial weight loss after RYGB, but did increase in response to lesser weight loss after ASGB. These findings suggest that the plasma ghrelin response after weight loss is impaired after exclusion of major parts of the stomach and the duodenum (RYGB), and the smaller long‐term weight loss after ASGB compared with RYGB may be due, at least in part, to an absent increase in plasma ghrelin after RYGB.     

Body Composition and Energy Metabolism Following Roux‐en‐Y Gastric Bypass Surgery

Roux‐en‐Y gastric bypass (RYGB) surgery has become an accepted treatment for excessive obesity. We conducted a longitudinal study to assess regional body composition, muscle proteolysis, and energy expenditure before RYGB, and 6 and 12 months after RYGB. Whole‐body and regional fat mass (FM) and lean mass (LM) were assessed via dual energy X‐ray absorptiometry (DXA), and myofibrillar protein degradation was estimated by urinary 3‐methylhistidine (3‐MeH) in 29 subjects. Energy expenditure and substrate oxidation were also determined using a whole‐room, indirect calorimeter in 12 of these subjects. LM loss constituted 27.8 ± 10.2% of total weight loss achieved 12 months postoperatively, with the majority of LM loss (18 ± 6% of initial LM) occurring in the first 6 months following RYGB. During this period, the trunk region contributed 66% of whole‐body LM loss. LM loss occurred in the first 6 months after RYGB despite decreased muscle protein breakdown, as indicated by a decrease in 3‐MeH concentrations and muscle fractional breakdown rates. Sleep energy expenditure (SEE) decreased from 2,092 ± 342 kcal/d at baseline to 1,495 ± 190 kcal/day at 6 months after RYGB (P < 0.0001). Changes in both LM and FM had an effect on the reduction in SEE (P < 0.001 and P = 0.005, respectively). These studies suggest that loss of LM after RYGB is significant and strategies to maintain LM after surgery should be explored.     

True fractional calcium absorption is decreased after Roux-en-Y gastric bypass surgery

Objective: Roux‐en‐Y gastric bypass (RYGB) is considered to be the gold standard alternative treatment for severe obesity. Weight loss after RYGB results primarily from decreased food intake. Inadequate calcium (Ca) intake and metabolic bone disease can occur after gastric bypass. To our knowledge, whether malabsorption of Ca contributes to an altered Ca metabolism in the RYGB patient has not been addressed previously. Research Methods and Procedures: We recruited 25 extremely obese women in order to study true fractional Ca absorption (TFCA) before and 6 months after RYGB surgery, using a dual stable isotope method (⁴²Ca and ⁴³Ca) and test load of Ca (200 mg). Hormones regulating Ca absorption and markers of bone turnover were also measured. Results: In 21 women (BMI 52.7 ± 8.3 kg/m², age 43.9 ± 10.4 years) who successfully completed the study, TFCA decreased from 0.36 ± 0.08 to 0.24 ± 0.09 (p < 0.001) after RYGB. Bone turnover markers increased significantly (p < 0.01). TFCA correlated with estradiol levels (r = 0.512, p < 0.02) and tended to correlate with 1,25 (OH)₂D (r = 0.427, p < 0.06) at final measurement. Stepwise linear regression indicated that estradiol explained 62% of the variance for TFCA at 6 months post‐surgery (p < 0.01). Discussion: TFCA decreases (0.12 ± 0.08) after RYGB surgery but remains within normal range. Although only some patients were estimated to have low Ca absorption after surgery, all of the patients showed a dramatic increase in markers of bone resorption. The alteration in Ca metabolism after RYGB‐induced weight loss appears to be regulated primarily by estradiol levels and might ultimately affect bone mass.     

The Insulin Tolerance Test in Morbidly Obese Patients Undergoing Bariatric Surgery

Objective: To assess the effect of massive weight loss in relation to insulin resistance and its correlation to changes in glycemic homeostasis and lipid profile in severely obese patients. Research Methods and Procedures: A prospective clinical intervention study was carried out with 31 morbidly obese women (body mass index: 54.2 ± 8.8 kg/m²) divided into three groups according to their glucose tolerance test: 14 normal, 8 impaired glucose tolerance, and 9 type 2 diabetes. All subjects underwent an insulin tolerance test with intravenous bolus of 0.1 U insulin/kg body weight before silastic ring vertical gastroplasty Roux‐en‐Y gastric bypass surgery, and again at 2, 4, 6, and 12 months postoperatively. Fasting plasma glucose, hemoglobin A1c, and lipid profile were also evaluated. Results: A reduction of 68 ± 15% in initial excess body weight was evident within 1 year. Along with weight loss, the following statistically significant changes were found: an increase in the insulin‐sensitivity index (Kitt) and a decrease in fasting plasma glucose and hemoglobin A1c, most notably in the type 2 diabetes group. An overall improvement in lipid profile was observed in all three groups. Discussion: Bariatric surgery was an effective therapeutic approach for these obese patients because it reduced both weight and insulin resistance, along with improving metabolic parameters. Significant correlations were found between insulin resistance and metabolic improvements. Weight loss after bariatric surgery induced an improvement in metabolic fitness, related to the reduction in insulin resistance over a range of glucose tolerance statuses from normal to diabetic.     

Improvement of Insulin Resistance and Early Atherosclerosis in Patients after Gastric Banding

Objective: To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS). Research Methods and Procedures: Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose‐tolerance test model analysis. In addition, soluble intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, leptin, high‐sensitivity C‐reactive protein, plasminogen activating factor‐1 (PAI‐1), and tissue plasminogen activator were measured. Results: BMI dropped from 45.22 ± 5.62 to 36.99 ± 4.34 kg/m² after 6 months and 33.72 ± 5.55 kg/m² after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C‐peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E‐selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule‐1 and PAI‐1 were only seen after 6 months. Subclinical inflammation, measured by high‐sensitivity C‐reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule‐1 and tissue plasminogen activator levels. Discussion: Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI‐1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.     

Plasma MR‐proADM Correlates to BMI and Decreases in Relation to Leptin After Gastric Bypass Surgery

Adrenomedullin (ADM) is a vasoactive peptide found to be related to obesity and its comorbidities: type 2 diabetes, hypertension, atherosclerosis, and coronary heart disease. ADM is increased both in plasma and in adipose tissue of obese individuals when compared to lean subjects and is considered as a member of the adipokine family. We determined plasma midregional proadrenomedullin (MR‐proADM) concentrations in a cohort of 357 subjects with BMI ranging from 17.5 to 42.3 kg/m² and no additional medical history. In parallel, 28 severely obese patients scheduled to undergo laparoscopic Roux‐en‐Y gastric bypass (RYGB) surgery were studied at two time points: before and 1 year after surgery. Outcome measurements were: MR‐proADM, cortisol, leptin, C‐reactive protein (CRP) thyroid‐stimulating hormone (TSH), creatinine and metabolic parameters. BMI correlated significantly to plasma MR‐proADM levels (r = 0.714, P < 0.001), also after adjustment for age and gender (r = 0.767, P < 0.001). In obese subjects, there was a positive relationship between MR‐proADM and leptin (r = 0.511, P = 0.006). Following RYGB, plasma MR‐proADM decreased from 0.76 ± 0.03 to 0.62 ± 0.02 pg/ml (P < 0.0001). RYGB‐induced changes in MR‐proADM correlated significantly to changes in leptin (r = 0.533, P = 0.004) and in CRP (r = 0.429, P = 0.023). We conclude that BMI is an independent predictor of circulating MR‐proADM levels. Weight loss after RYGB is associated with a significant decrease in plasma MR‐proADM, which is related to surgery‐induced changes in both circulating leptin and systemic inflammation.     

Reduction of 8-iso-prostaglandin F2α in the first week after Roux-en-Y gastric bypass surgery

Obesity is associated with increased markers of oxidative stress. We examined whether oxidative stress is reduced within the first week after Roux‐en‐Y gastric bypass (RYGB) surgery and could be related to changes in adipose tissue depots. The reactive oxygen species (ROS) marker 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α) and activity of antioxidant glutathione peroxidases (GPX) in plasma were compared before and ～1 week after RYGB. The effects of RYGB on subcutaneous adipose tissue and interstitial fluid 8‐iso‐PGF2α levels and subcutaneous adipose tissue expression of GPX‐3 were also assessed. Levels of 8‐iso‐PGF2α in subcutaneous and visceral adipose tissue were determined. Plasma 8‐iso‐PGF2α levels decreased (122 ± 75 to 56 ± 15 pg/ml, P = 0.001) and GPX activity increased (84 ± 18 to 108 ± 25 nmol/min/ml, P = 0.003) in the first week post‐RYGB. RYGB also resulted in reductions of 8‐iso‐PGF2α in subcutaneous adipose tissue (1,742 ± 931 to 1,132 ± 420 pg/g fat, P = 0.046) and interstitial fluid (348 ± 118 to 221 ± 83 pg/ml, P = 0.046) that were comparable to plasma (26–33%, P = 0.74). Adipose GPX‐3 expression was increased (6.7 ± 4.7‐fold, P = 0.004) in the first postoperative week. The improvements in oxidative stress occurred with minimal weight loss (2.4 ± 3.4%, P = 0.031) and elevations in plasma interleukin‐6 (18.0 ± 46.8 to 28.0 ± 58.9 pg/ml, P = 0.004). Subcutaneous and visceral adipose tissues express comparable 8‐iso‐PGF2α levels (1,204 ± 470 and 1,331 ± 264 pg/g fat, respectively; P = 0.34). These data suggest that RYGB affects adipose tissue leading to the restoration of adipose redox balance within the first postoperative week and that plasma 8‐iso‐PGF2α is primarily derived from subcutaneous adipose tissue.     

Visceral obesity is a negative predictor of remission of diabetes 1 year after bariatric surgery

Our aim was to identify preoperative anthropometric and clinical parameters that predict the remission of diabetes after Roux‐en‐Y gastric bypass (RYGB). Fifty severely obese Korean patients with type 2 diabetes underwent RYGB. Visceral and abdominal subcutaneous fat area (SFA) was assessed using computed tomography before and 6 and 12 months after RYGB. Remission was defined as a glycated hemoglobin (A_1C) level <6.5% and a fasting glucose concentration <126 mg/dl for 1 year or more without the use of medication. The visceral‐to‐SFA ratio decreased from 0.60 ± 0.30 to 0.53 ± 0.29 (P = 0.001) after 6 months and decreased further to 0.42 ± 0.24 (P < 0.001) after 12 months. Thirty‐four of the 50 patients (68%) had remission of diabetes (remission group). Compared with patients in the nonremission group, patients in the remission group had a shorter duration of diabetes and lower preoperative A_1C level, and were less likely to use insulin preoperatively. Preoperative BMI did not differ in two groups. However, the preoperative visceral‐to‐SFA ratio was greater in the nonremission group compared with the remission group (0.79 ± 0.29 vs. 0.53 ± 0.26, P = 0.003). Finally, the preoperative visceral‐to‐SFA ratio was an independent predictor of the remission of diabetes after RYGB in multiple stepwise logistic regression analysis. In conclusion, our data suggest that visceral adiposity negatively influence the likelihood of the patient experiencing the remission of diabetes after RYGB.     

Sphingolipid Content of Human Adipose Tissue: Relationship to Adiponectin and Insulin Resistance

Ceramides (Cer) are implicated in obesity‐associated skeletal muscle and perhaps adipocyte insulin resistance. We examined whether the sphingolipid content of human subcutaneous adipose tissue and plasma varies by obesity and sex as well as the relationship between ceramide content and metabolic indices. Abdominal subcutaneous adipose biopsies were performed on 12 lean adults (males = 6), 12 obese adults (males = 6) for measurement of sphingolipid content and activity of the main ceramide metabolism enzymes. Blood was sampled for glucose, insulin (to calculate homeostasis model assessment‐estimated insulin resistance (HOMA_IR)) adiponectin, and interleukin‐6 (IL‐6) concentrations. Compared to lean controls, total ceramide content (pg/adipocyte) was increased by 31% (P < 0.05) and 34% (P < 0.05) in obese females and males, respectively. In adipocytes from obese adults sphingosine, sphinganine, sphingosine‐1‐phosphate, C14‐Cer, C16‐Cer, and C24‐Cer were all increased. C18:1‐Cer was increased in obese males and C24:1‐Cer in obese females. For women only, there was a negative correlation between C16‐Cer ceramide and plasma adiponectin (r = ?0.77, P = 0.003) and a positive correlation between total ceramide content and HOMA_IR (r = 0.74, P = 0.006). For men only there were significant (at least P < 0.05), positive correlations between adipocyte Cer‐containing saturated fatty acid and plasma IL‐6 concentration. We conclude that the sexual dimorphism in adipose tissue behavior in humans extends to adipose tissue sphingolipid content its association with adiponectin, IL‐6 and insulin resistance.     

Basal and Stimulated Plasma Leptin in Diabetic Subjects

LIU, JIANMEI, HASAN ASKARI, AND SAMUEL DAGOGO-JACK. Basal and stimulated plasma leptin in diabetic subjects. Obes Res. Objective: To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls. Research Methods and Procedures: Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as “negative” if ≤0.1 ng/mL or “positive” if ≥0.3 ng/mL, in fasting plasma. Results: Basal plasma leptin levels were 19. 7±2. 2 ng/mL in nondiabetic subjects, 13. 4±1. 5 ng/ml in C-peptide negative (n = 28) and 26. 1±23. 7 ng/mL in C-peptide positive (n = 26, p = 0. 001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145±17% of baseline values at 8 hours (p = O. O3), 224±18% at 16 hours (p = 0. 01), and 134218% at 40 hours (p = 0. 05). The corresponding changes were 108±13%, 126±23%, and 98±16% in C-peptide negative (n = 6), and 121±10%, 144±16% (p = 0. 03), and 147±23% (p = 0. 11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0. 02) in controls, but not in the diabetic patients, following dexamethasone. Discussion: Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.     

Bone and Gastric Bypass Surgery: Effects of Dietary Calcium and Vitamin D

Objective:To examine bone mass and metabolism in women who had previously undergone Roux‐en‐Y gastric bypass (RYGB) and determine the effect of supplementation with calcium (Ca) and vitamin D. Research Methods and Procedures: Bone mineral density and bone mineral content (BMC) were examined in 44 RYGB women (≥3 years post‐surgery; 31% weight loss; BMI, 34 kg/m²) and compared with age‐ and weight‐matched control (CNT) women (n = 65). In a separate analysis, RYGB women who presented with low bone mass (n = 13) were supplemented to a total 1.2 g Ca/d and 8 μg vitamin D/d over 6 months and compared with an unsupplemented CNT group (n = 13). Bone mass and turnover and serum parathyroid hormone (PTH) and 25‐hydroxyvitamin D were measured. Results:Bone mass did not differ between premenopausal RYGB and CNT women (42 ± 5 years), whereas postmenopausal RYGB women (55 ± 7 years) had higher bone mineral density and BMC at the lumbar spine and lower BMC at the femoral neck. Before and after dietary supplementation, bone mass was similar, and serum PTH and markers of bone resorption were higher (p < 0.001) in RYGB compared with CNT women and did not change significantly after supplementation. Discussion: Postmenopausal RYGB women show evidence of secondary hyperparathyroidism, elevated bone resorption, and patterns of bone loss (reduced femoral neck and higher lumbar spine) similar to other subjects with hyperparathyroidism. Although a modest increase in Ca or vitamin D does not suppress PTH or bone resorption, it is possible that greater dietary supplementation may be beneficial.     

Weight loss therapy improves pancreatic endocrine function in obese older adults

Objective: Obesity and aging increase the risk of type 2 diabetes (T2D). We evaluated whether weight loss therapy improves pancreatic endocrine function and insulin sensitivity in obese older adults. Methods and Procedures: Twenty‐four obese (BMI: 38 ± 2 kg/m²) older (age: 70 ± 2 years) adults completed a 6‐month randomized, controlled trial. Participants were randomized to diet and exercise (treatment group) or no therapy (control group). β‐Cell function (assessed using the C‐peptide minimal model), α‐cell function (assessed by the glucagon response to an oral glucose load), insulin sensitivity (assessed using the glucose minimal model), and insulin clearance rate were evaluated using a 5‐h modified oral glucose tolerance test. Results: Body weight decreased in the treatment group, but did not change in the control group (?9 ± 1% vs. 0 ± 1%; P < 0.001). Insulin sensitivity doubled in the treatment group and did not change in the control group (116 ± 49% vs. ?11 ± 13%; P < 0.05). Even though indices of β‐cell responsivity to glucose did not change (P > 0.05), the disposition index (DI), which adjusts β‐cell insulin response to changes in insulin sensitivity, improved in the treatment group compared with the control group (100 ± 47% vs. ?22 ± 9%; P < 0.05). The glucagon response decreased in the treatment but not in the control group (?5 ± 2% vs. 4 ± 4%; P < 0.05). Insulin secretion rate did not change (P > 0.05), but insulin clearance rate increased (51 ± 25%; P < 0.05), resulting in lower plasma insulin concentrations. Discussion: Weight loss therapy concomitantly improves β‐cell function, lowers plasma glucagon concentrations, and improves insulin action in obese older adults. These metabolic effects are likely to reduce the risk of developing T2D in this population.     

Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance

Objective: To study the effect of weight loss in response to a lifestyle modification program on the circulating levels of adipose tissue derived cytokines (adipokines) in obese individuals with insulin resistance. Research Methods and Procedures: Twenty‐four insulin‐resistant obese subjects with varying degrees of glucose tolerance completed a 6‐month program consisting of combined hypocaloric diet and moderate physical activity. Adipokines [leptin, adiponectin, resistin, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6)] and highly sensitive C‐reactive protein were measured before and after the intervention. Insulin sensitivity index was evaluated by the frequently sampled intravenous glucose tolerance test. Results: Participants had a 6.9 ± 0.1 kg average weight loss, with a significant improvement in sensitivity index and reduction in plasma leptin (27.8 ± 3 vs. 23.6 ± 3 ng/mL, p = 0.01) and IL‐6 (2.75 ± 1.51 vs. 2.3 ± 0.91 pg/mL, p = 0.012). TNF‐α levels tended to decrease (2.3 ± 0.2 vs. 1.9 ± 0.1 pg/mL, p = 0.059). Adiponectin increased significantly only among diabetic subjects. The reductions in leptin were correlated with the decreases in BMI (r = 0.464, p < 0.05) and with changes in highly sensitive C‐reactive protein (r = 0.466, p < 0.05). Discussion: Weight reduction in obese individuals with insulin resistance was associated with a significant decrease in leptin and IL‐6 and a tendency toward a decrease in circulating TNF‐α, whereas adiponectin was increased only in diabetic subjects. Further studies are needed to elucidate the relationship between changes of adipokines and the health benefits of weight loss.     

Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Independent Evolution of Heart Autonomic Function and Insulin Sensitivity During Weight Loss

In order to investigate the improvement of insulin resistance and cardiac autonomic function along massive weight loss, 12 obese women were evaluated before, and 3 and 12 months after Roux‐en‐Y gastric bypass. The 12‐month values were compared to those of BMI‐matched controls. Insulin sensitivity was assessed by euglycemic clamp and the cardiac autonomic function by the analysis of the Heart Rate Variability (HRV). After surgery, glucose uptake progressively increased from 4.3 ± 0.5 mg/kg lean body mass (LBM)/min preoperative (pre‐op) to 4.9 ± 0.5 and 7.0 ± 0.5, 3‐ and 12‐month postoperative (post‐op) (P = 0.04 and P = 0.006 vs. pre‐op), whereas the cardiac autonomic function showed a biphasic pattern. HRV values increased 3 months post‐op, and decreased at 12 months, thus indicating an early sympathetic withdrawal followed by a later reactivation (e.g., the standard deviation of the normal‐to‐normal intervals was 116 ± 7 ms in pre‐op, 161 ± 10 at 3 months, P = 0.008 vs. pre‐op, and 146 ± 15 at 12 months, P = 0.03 vs. pre‐op and P = 0.02 vs. 3 m). Insulin sensitivity was significantly related to body weight (P = 0.02), whereas the cardiac indexes were significantly linked to the profile of energy intake (e.g., HRV triangular index vs. energy intake P = 0.003). No significant relationship linked insulin sensitivity to the cardiac autonomic indexes. Insulin sensitivity and cardiac parameters of the 12‐month post‐op patients were similar to their matched controls. During massive weight loss, the cardiac autonomic deregulation and insulin resistance improved concomitantly but independently from each other. Our results suggest that the extent of the improvement is associated with the final body weight.     

Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity following Roux-en-Y gastric bypass surgery

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB (P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery (P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB (P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time (P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.     

Dynamics of Change in Total and Regional Body Composition After Gastric Bypass in Obese Patients

Little is known on patterns of change over time in body composition, especially lean body mass (LBM), during massive weight loss after Roux‐en‐Y gastric bypass (RYGB) in obese patients. We performed sequential measurements of total and regional body composition in patients after RYGB, and we compared a subsample of patients after surgery to a nonsurgical control group of similar age and body fatness. We used dual‐energy X‐ray absorptiometry (DXA) before and at 3, 6, and 12 months after RYGB in 42 obese women (before surgery: age 39.5 ± 11.6 years; BMI 44.6 ± 6.1 kg/m²; mean ± s.d.) and in 48 control obese women referred for nonsurgical weight management, before weight loss. During 1‐year follow‐up after RYGB, there was a continuous decrease in body weight (?36.0 ± 12.5 kg at 1 year), total fat mass (FM) (?26.0 ± 9.1 kg), as well as in trunk and appendicular FM. In contrast, the decrease in total LBM (?9.8 ± 4.8 kg at 1 year), as well as in trunk and appendicular LBM, plateaued after 3–6 months. Rates of loss in weight, FM, and LBM were highest during the first 3‐month period after RYGB (6.4 ± 1.8, 4.1 ± 1.7, and 2.3 ± 1.2 kg/month, respectively), then decreased continuously for FM but plateaued for LBM. There was no evidence of a decrease in total, trunk, or appendicular LBM in weight‐reduced subjects compared to the control group. In conclusion, follow‐up of these obese women revealed a differential pattern of change in FM and LBM after RYGB. Despite an important loss in LBM, especially during the 3–6 months of initial period, LBM appears to be spared thereafter.     

Effect of the Interleukin‐6 (−174) G/C Promoter Polymorphism on Adiponectin and Insulin Sensitivity

We investigated the relation among the interleukin (IL)‐6 (?174) G/C promoter polymorphism, adipose tissue gene expression of IL6, circulating adiponectin, and systemic insulin sensitivity. Eighty‐five Swedish male subjects who had participated in our previous prediabetic phenotype characterization study were genotyped for the IL6 (?174) G/C polymorphism. Subcutaneous adipose tissue gene expression of IL6 and adiponectin was measured in 44 subjects. The IL6 (?174) G allele carriers had higher fasting plasma insulin levels (C/C, 7.8 ± 1.1; G/C, 9.0 ± 0.6; G/G, 10.5 ± 1.0 mU/L) and higher homeostasis model assessment for insulin resistance (C/C, 1.6 ± 0.2; G/C, 1.9 ± 0.1; G/G, 2.2 ± 0.2) compared with subjects with the C/C genotype. The circulating adiponectin levels were lower in the G allele carriers (C/C, 7.93 ± 0.45; G/C, 7.05 ± 0.44; G/G, 7.02 ± 0.46 μg/mL), whereas the IL‐6 levels did not differ among the three genotypes. Adipose tissue IL6 gene expression was significantly higher in the G allele carriers compared with the subjects homozygous for the C allele (C/C, 0.29 ± 0.15; G/C, 0.84 ± 0.29; G/G, 0.62 ± 0.35). Our results suggest that IL6 (?174) G/C polymorphism is associated with insulin resistance and increased adipose tissue IL6 gene expression, which can impair adiponectin production.     

Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery

Background

Roux-en-Y gastric bypass (RYGB) surgery is associated with weight loss, improved insulin sensitivity and glucose homeostasis, and a reduction in co-morbidities such as diabetes and coronary heart disease. To generate further insight into the numerous metabolic adaptations associated with RYGB surgery, we profiled serum metabolites before and after gastric bypass surgery and integrated metabolite changes with clinical data.

Methodology and Principal Findings

Serum metabolites were detected by gas and liquid chromatography-coupled mass spectrometry before, and 3 and 6 months after RYGB in morbidly obese female subjects (n = 14; BMI = 46.2±1.7). Subjects showed decreases in weight-related parameters and improvements in insulin sensitivity post surgery. The abundance of 48% (83 of 172) of the measured metabolites changed significantly within the first 3 months post RYGB (p<0.05), including sphingosines, unsaturated fatty acids, and branched chain amino acids. Dividing subjects into obese (n = 9) and obese/diabetic (n = 5) groups identified 8 metabolites that differed consistently at all time points and whose serum levels changed following RYGB: asparagine, lysophosphatidylcholine (C18:2), nervonic (C24:1) acid, p-Cresol sulfate, lactate, lycopene, glucose, and mannose. Changes in the aforementioned metabolites were integrated with clinical data for body mass index (BMI) and estimates for insulin resistance (HOMA-IR). Of these, nervonic acid was significantly and negatively correlated with HOMA-IR (p = 0.001, R = −0.55).

Conclusions

Global metabolite profiling in morbidly obese subjects after RYGB has provided new information regarding the considerable metabolic alterations associated with this surgical procedure. Integrating clinical measurements with metabolomics data is capable of identifying markers that reflect the metabolic adaptations following RYGB.     

Visceral Obesity and Insulin Resistance Are Associated with Plasma Aldosterone Levels in Women

GOODFRIEND, THEODORE L., DAVID E. KELLEY, BRET H. GOODPASTER, AND STEPHEN J. WINTERS. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res. Objective: Both obesity and insulin resistance increase the risk of hypertension and other cardiovascular diseases, but the mechanisms linking these abnormalities are unknown. The current study was undertaken to examine the effects of obesity, fat distribution, and insulin resistance on plasma levels of aldosterone and other adrenal steroids that might contribute to sequelae of obesity. Research Methods and Procedures: Twenty-eight normo-tensive premenopausal women and 27 normotensive men with a wide range of body fat underwent measurements of visceral adipose tissue by CT scan, total fat mass by dual energy X-ray absorptiometry, blood pressure, insulin sensitivity, and plasma levels of three adrenal steroid hormones. Results: Plasma aldosterone in women correlated directly with visceral adipose tissue (r = 0. 66, p<0. 001) and inversely with insulin sensitivity (r = ?0. 67, p<0. 001), and these associations were independent of plasma renin activity. There were no corresponding correlations in men. Plasma aldosterone was significantly correlated with plasma cortisol and dehydroepiandrosterone sulfate in women. Seventeen women and 15 men completed a weight-reduction regimen, losing an average of 15. 1±1. 2 kg. After weight loss, plasma aldosterone was significantly lower and insulin sensitivity higher; however, the correlations of aldosterone with visceral adipose tissue and insulin sensitivity in women persisted (p = 0. 09 and 0. 07, respectively). Although none of the women were hypertensive, blood pressure correlated with plasma aldosterone both before and after weight loss. Discussion: We conclude that visceral adiposity and insulin resistance are associated with increased plasma aldosterone and other adrenal steroids that may contribute to cardiovascular diseases in obese women.