Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with elevated ghrelin.
ABSTRACT: We sought to determine: (1) if early weight regain between 1 and 2 years after Roux-en-Y gastric bypass (RYGB) is associated with worsened hepatic and peripheral insulin sensitivity, and (2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB.Hepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at 1 month, 6 months, 1 year, and 2 years postoperatively. Weight regain was defined as ?5% increase in body weight between 1 and 2 years after RYGB.Weight regain occurred in 33% of subjects, with an average increase in body weight of 10?±?5% (8.5?±?3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups.Early weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB.
Project description:Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1?pmol?kg-1 ?min-1 ) in healthy, lean subjects (n?=?9) and non-diabetic, obese subjects (n?=?9) before and 2?weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.
Project description:OBJECTIVE:Changes in insulin sensitivity (IS) and insulin secretion occur with perturbations in energy balance and glycemic load (GL) of the diet that may precede the development of insulin resistance and hyperinsulinemia. Determinants of changes in IS and insulin secretion with weight cycling in non-obese healthy subjects remain unclear. METHODS:In a 6wk controlled 2-stage randomized dietary intervention 32 healthy men (26±4y, BMI: 24±2kg/m2) followed 1wk of overfeeding (OF), 3wks of caloric restriction (CR) containing either 50% or 65% carbohydrate (CHO) and 2wks of refeeding (RF) with the same amount of CHO but either low or high glycaemic index at ±50% energy requirement. Measures of IS (basal: HOMA-index, postprandial: Matsuda-ISI), insulin secretion (early: Stumvoll-index, total: tAUC-insulin/tAUC-glucose) and potential endocrine determinants (ghrelin, leptin, adiponectin, thyroid hormone levels, 24h-urinary catecholamine excretion) were assessed. RESULTS:IS improved and insulin secretion decreased due to CR and normalized upon RF. Weight loss-induced improvements in basal and postprandial IS were associated with decreases in leptin and increases in ghrelin levels, respectively (r = 0.36 and r = 0.62, p<0.05). Weight regain-induced decrease in postprandial IS correlated with increases in adiponectin, fT3, TSH, GL of the diet and a decrease in ghrelin levels (r-values between -0.40 and 0.83, p<0.05) whereas increases in early and total insulin secretion were associated with a decrease in leptin/adiponectin-ratio (r = -0.52 and r = -0.46, p<0.05) and a decrease in fT4 (r = -0.38, p<0.05 for total insulin secretion only). After controlling for GL associations between RF-induced decrease in postprandial IS and increases in fT3 and TSH levels were no longer significant. CONCLUSION:Weight cycling induced changes in IS and insulin secretion were associated with changes in all measured hormones, except for catecholamine excretion. While leptin, adiponectin and ghrelin seem to be the major endocrine determinants of IS, leptin/adiponectin-ratio and fT4 levels may impact changes in insulin secretion with weight cycling. TRIAL REGISTRATION:ClinicalTrials.gov NCT01737034.
Project description:Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB.We studied 40 obese (BMI 48 ± 8 kg/m(2)) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity.Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP.Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.
Project description:Compensatory metabolic changes that accompany weight loss, for example, increased ghrelin, contribute to weight regain and difficulty in long-term weight loss maintenance; however, the separate effects of long-term caloric restriction and exercise on total circulating ghrelin in humans are unknown.A 12-month randomized controlled trial comparing: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week ('exercise'; n = 117); iii) dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle-change control (n = 87).439 overweight or obese postmenopausal women (50-75 y).Fasting total serum ghrelin was measured by radioimmunoassay at baseline and 12 months. Fasting serum leptin, adiponectin and insulin were also measured.Fasting total ghrelin significantly increased in the diet + exercise arm (+7·4%, P = 0·008) but not in either the diet (+6·5%, P = 0·07) or exercise (+1·0%, P = 0·53) arms compared with control. Greater weight loss was associated with increased ghrelin concentrations, regardless of intervention. Neither baseline ghrelin nor body composition modified the intervention effects on changes in total ghrelin. The 12-month change in total ghrelin was inversely associated with changes in leptin, insulin and insulin resistance, and positively associated with change in adiponectin.Greater weight loss, achieved through a reduced calorie diet or exercise, is associated with increased total ghrelin concentrations in overweight or obese postmenopausal women.
Project description:Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 diabetes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabetics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to diabetes. Only leptin and IL-6 had a significant association with the measured metabolites. Leptin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes.
Project description:<h4>Objective</h4>It has been previously reported that early after Roux-en-Y-gastric bypass, dopamine (DA) type 2 and 3 receptor (D2/3R) binding potential (BP<sub>ND</sub> ) was decreased from preoperative levels. The current study aimed to determine whether calorie restriction without weight loss modifies D2/3R BP<sub>ND</sub> and whether such changes are explained by neuroendocrine regulation.<h4>Methods</h4>Fifteen females with obesity (BMI?=?39?±?6 kg/m<sup>2</sup> ) were studied before and after ?10 days of a very-low-calorie-diet (VLCD). Outcome measures included fasting insulin, leptin, acyl ghrelin, and glucose, and insulin sensitivity and disposition index were estimated using the oral-minimal model (OMM) method. Participants underwent positron emission tomography scanning with the displaceable radioligand [<sup>18</sup> F]fallypride to estimate available regional D2/3R levels. Regions of interest included the caudate, putamen, ventral striatum, hypothalamus, and substantia nigra (SN).<h4>Results</h4>With the VLCD, weight decreased slightly (-3 kg). Insulin, glucose, and leptin decreased significantly, but there was no change in acyl ghrelin or measures from OMM. SN D2/3R BP<sub>ND</sub> decreased significantly, with trends toward decreased levels in the remaining regions. The decrease in leptin concentration strongly predicted the change in D2/3R BP<sub>ND</sub> in all regions (all P???0.004).<h4>Conclusions</h4>In obesity, reductions in regional D2/3R availability after VLCD are suggestive of increased endogenous DA competing with the radioligand. Changes in regional D2/3R availability were associated with decreases in leptin concentrations that occurred before clinically significant weight loss.
Project description:BACKGROUND AND STUDY AIMS: Endoscopic implantation of a duodenal-jejunal bypass liner (DJBL) is a novel bariatric technique to induce weight loss and remission of type 2 diabetes mellitus. Placement of the DJBL mimics the bypass component of the Roux-en-Y gastric bypass (RYGB) procedure. In this observational study, we evaluated improvement of glycemic control and weight loss in the course of the treatment (0 - 24 weeks after DJBL implantation) and analyzed accompanying gut hormone responses. PATIENTS AND METHODS: 12 obese individuals with type 2 diabetes were selected for DJBL implantation. Body weight, fat mass, and fasting plasma levels of glucose, insulin, C-peptide, and glycated hemoglobin (HbA1c), were analyzed at 0, 1, 4 and 24 weeks post-implant. Fasting ghrelin, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP-1) were determined at 0, 1 and 4 weeks post-implant. RESULTS: Besides significant weight loss, fat mass, fasting insulin, and homeostasis model assessment-estimated insulin resistance (HOMA-IR) index were also significantly decreased after DJBL implantation and a 42 % reduction was found in diabetes medication (P < 0.05). The fasting GLP-1 response in the first 4 weeks post-implant was significantly correlated with the fasting insulin and HOMA-IR response. Fasting ghrelin was found to be significantly elevated, in contrast to the decrease in ghrelin that is found after RYGB surgery. CONCLUSIONS: DJBL implantation provoked significant weight loss, a decrease in fat mass, and an early remission of type 2 diabetes, comparable to results seen after RYGB surgery. Gut hormone analyses revealed a potential role of fasting GLP-1 in early remission of type 2 diabetes. Interestingly, the DJBL-induced elevation of ghrelin contradicts the suggested role of reduced ghrelin levels after RYGB in improvement of glycemic control.
Project description:BACKGROUND:Apolipoprotein A-IV (ApoA-IV) has been shown to be involved in obesity and diabetes pathogenesis in animal studies, but its role in humans is uncertain. OBJECTIVES:The objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery. SETTING:University Hospital. METHODS:The patients (n = 49) included lean controls (n = 8) and patients before and after a mean of 7 months after laparoscopic adjustable gastric banding (LAGB, n = 12), laparoscopic Roux-en-Y gastric bypass (RYGB, n = 22), or laparoscopic sleeve gastrectomy (SG, n = 11). ApoA-IV and other hormone assays were performed in the fasting and the postprandial state. Pearson's correlation analyses controlled for baseline BMI and percent excess weight loss (EWL) were used to determine relationships between ApoA-IV levels and insulin resistance (HOMA-IR). RESULTS:With all bariatric procedures combined, the change in ApoA-IV [533 versus 518 microg/L, P = .813] or ApoA-IV area under the curve (AUC - 1072 versus 1042, P = .939) was not significant. None of the surgeries individually affected levels of fasting or ApoA-IV AUC. Bariatric surgery resulted in a decrease in HOMA-IR (5.3 versus 2.0, P<.001). In the RYGB group, higher baseline ApoA-IV levels correlated with decrease in HOMA-IR [r = -.6, P = .008]. This relationship was independent of EWL and was not observed in the LAGB or SG group. There was no association of ApoA-IV levels with EWL, insulin secretion, Peptide-YY, or leptin levels. CONCLUSION:Preoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB.
Project description:Despite of its significant therapeutic effects on obesity and metabolic diseases, Roux-en-Y gastric bypass (RYGB) has limited clinical application because of considerable impacts on the gastrointestinal structure and postoperative complications. This study aims to develop a simplified surgical approach with less damage and complication but efficient metabolic benefit.The effects of Esophagus-Duodenum gastric bypass (EDGB) on body weight, food intake, glucose and lipid metabolism were compared to RYGB in mice.EDGB is simple, has higher survival rate and less complication. Relative to RYGB, EDGB demonstrated modest body weight control, identical improvement of glucose and lipid metabolism in obese mice. Blood glucose increased significantly 15 and 30min after oral glucose administration, then markedly decreased in both EDGB and RYGB groups relative to the sham surgery, indicating a quicker absorption of oral glucose and improvement in glucose uptake by insulin targeted tissues. Insulin sensitivity was identically improved. EDGB significantly decreased plasma and hepatic triglyceride levels, while increased browning in visceral and subcutaneous white adipose tissue to the extent identical to RYGB. Levels of ghrelin and nesfatin-1 increased significantly after EDGB and RYGB.EDGB is a valuable model to study the metabolic benefit of bariatric surgery in mice.
Project description:OBJECTIVE:The aim of this study was to investigate whether baseline (pre-weight loss) metabolic variables can predict weight regain. METHODS:About 117 women with overweight completed a weight loss program to achieve BMI?<?25 kg/m2 and were followed for 2 years. Resting metabolic rate, respiratory quotient, insulin sensitivity, and serum leptin concentration were measured pre-weight loss, while on energy balance, and as predictors of weight regain at 1 and 2 years. Rate and amount of weight loss also were examined as predictors, as these outcomes may reflect metabolic phenotype. RESULTS:Average weight loss was 12 (SD 2.5) kg, and regain was 48% (SD 35%) and 80% (SD 52%) at 1 and 2 years, respectively. In regression modeling, metabolic variables (both pre-weight loss and changes with weight loss) did not predict weight regain. However, initial weight loss and time to achieve BMI?<?25 were significant predictors of weight regain at 1 and 2 years, even after adjusting for confounders. CONCLUSIONS:Baseline (pre-weight loss) resting metabolic rate, respiratory quotient, insulin sensitivity, and leptin did not predict weight regain. However, a larger and faster weight loss was associated with a lower weight regain. Understanding the mechanisms behind interindividual variation in magnitude and rate of weight loss is needed to ensure better weight loss maintenance.