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Context Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive. Objective We investigated biomarkers associated with use of lorcaserin (LOR), a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, to identify predictors of clinical efficacy. Methods Thirty individuals with obesity were treated with 7 days of placebo and LOR in a randomized crossover study. Nineteen participants continued on LOR for 6 months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin, and food intake during a meal were also studied. Results LOR induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide β-endorphin after 7 days; β-endorphin/POMC increased by 30% (P < .001). This was accompanied by a substantial decrease in insulin, glucose, and homeostasis model assessment of insulin resistance before WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6 months that were distinct from prior reports after diet alone. Changes in POMC, food intake, or other hormones did not predict WL. However, baseline CSF POMC correlated negatively with WL (P = .07) and a cutoff level of CSF POMC was identified that predicted more than 10% WL. Conclusion Our results provide evidence that LOR affects the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists.

During the past decade, several effective antiobesity medications and devices have been developed. In addition, new information regarding the mechanism of action, benefits, and long-term efficacy of bariatric surgery continues to emerge. More than 90% of patients who qualify for therapy for obesity remain untreated. This article aims to provide an overview of the indications and efficacy of currently available medical and surgical therapies for obesity, along with a look toward promising therapies on the horizon.

Naltrexone/bupropion (NB) is a US Food and Drug Administration-approved antiobesity medication. Clinical trials have shown variable weight loss, with responders and non-responders. NB is believed to act on central dopaminergic pathways to suppress appetite. The Taq1A polymorphism near DRD2 (rs1800497) is associated with the density of striatal dopamine D2 receptors, with individuals carrying the A allele (AA or AG; termed A1+) having 30%-40% fewer dopamine binding sites than those who do not carry the A allele (GG; termed A1-). We performed a pilot study to assess the association of the rs1800497 ANKK1 c.2137G > A (p.Glu713Lys) variant with weight loss with NB treatment in 33 subjects. Mean (SD) weight loss was 5.9% (3.2%) for the A1+ genotype group (n = 15) and 4.2% (4.2%) for the A1- genotype group (n = 18). The mean weight loss for the A1+ genotype group was significantly greater than the predefined clinically significant 4% weight-loss target (one-sample t-test, P = .035), whereas the mean weight loss for the A1- genotype group was not (P = .85). Individuals with the A1+ genotype appear to respond better to NB than A1- individuals.

Bariatric surgery is a treatment option for obese patients with type 2 diabetes mellitus (T2DM). Although sleeve gastrectomy (SG) is growing in favor, some randomized trials show less weight loss and HbA1c improvement compared with Roux-en-Y gastric bypass (RYGB). The study objective was to compare changes in beta-cell function with similar weight loss after SG and RYGB in obese patients with T2DM. Subjects undergoing SG or RYGB were studied with an intravenous glucose tolerance test before surgery and at 5–12% weight loss post-surgery. The primary endpoint was change in the disposition index (DI). Baseline BMI, HbA1c, and diabetes-duration were similar between groups. Mean total weight loss percent was similar (8.4% ± 0.4, p = 0.22) after a period of 21.0 ± 1.7 days. Changes in fasting glucose, acute insulin secretion (AIR), and insulin sensitivity (Si) were similar between groups. Both groups showed increases from baseline to post-surgery in DI (20.2 to 163.3, p = 0.03 for SG; 31.2 to 232.9, p = 0.02 for RYGB) with no significant difference in the change in DI between groups (p = 0.53). Short-term improvements in beta-cell function using an IVGTT were similar between SG and RYGB. It remains unclear if longer-term outcomes are better after RYGB due to greater weight loss and/or other factors.

Background Obesity has emerged as a risk factor for severe coronavirus disease 2019 (COVID-19) infection. To inform treatment considerations the relationship between obesity and COVID-19 complications and the influence of race, ethnicity, and socioeconomic factors deserves continued attention. Objective To determine if obesity is an independent risk factor for severe COVID-19 complications and mortality and examine the relationship between BMI, race, ethnicity, distressed community index and COVID-19 complications and mortality. Methods A retrospective cohort study of 1,019 SARS-CoV-2 positive adult admitted to an academic medical center (n = 928) and its affiliated community hospital (n-91) in New York City from March 1 to April 18, 2020. Results Median age was 64 years (IQR 52–75), 58.7% were men, 23.0% were Black, and 52.8% were Hispanic. The prevalence of overweight and obesity was 75.2%; median BMI was 28.5 kg/m2 (25.1–33.0). Over the study period 23.7% patients died, 27.3% required invasive mechanical ventilation, 22.7% developed septic shock, and 9.1% required renal replacement therapy (RRT). In the multivariable logistic regression model, BMI was associated with complications including intubation (Odds Ratio [OR]1.03, 95% Confidence Interval [CI]1.01–1.05), septic shock (OR 1.04, CI 1.01–1.06), and RRT (OR1.07, CI 1.04–1.10), and mortality (OR 1.04, CI 1.01–1.06). The odds of death were highest among those with BMI ≥ 40 kg/m2 (OR 2.05, CI 1.04–4.04). Mortality did not differ by race, ethnicity, or socioeconomic distress score, though Black and Asian patients were more likely to require RRT. Conclusions and relevance Severe complications of COVID-19 and death are more likely in patients with obesity, independent of age and comorbidities. While race, ethnicity, and socioeconomic status did not impact COVID-19 related mortality, Black and Asian patients were more likely to require RRT. The presence of obesity, and in some instances race, should inform resource allocation and risk stratification in patients hospitalized with COVID-19.

Naltrexone/bupropion (NB) is a US Food and Drug Administration-approved antiobesity medication. Clinical trials have shown variable weight loss, with responders and non-responders. NB is believed to act on central dopaminergic pathways to suppress appetite. The Taq1A polymorphism near DRD2 (rs1800497) is associated with the density of striatal dopamine D2 receptors, with individuals carrying the A allele (AA or AG; termed A1+) having 30%−40% fewer dopamine binding sites than those who do not carry the A allele (GG; termed A1−). We performed a pilot study to assess the association of the rs1800497 ANKK1 c.2137G > A (p.Glu713Lys) variant with weight loss with NB treatment in 33 subjects. Mean (SD) weight loss was 5.9% (3.2%) for the A1+ genotype group (n = 15) and 4.2% (4.2%) for the A1− genotype group (n = 18). The mean weight loss for the A1+ genotype group was significantly greater than the predefined clinically significant 4% weight-loss target (one-sample t-test, P = .035), whereas the mean weight loss for the A1− genotype group was not (P = .85). Individuals with the A1+ genotype appear to respond better to NB than A1- individuals.

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.

BackgroundLaparoscopic sleeve gastrectomy (SG) has surpassed Roux-en-Y gastric bypass (RYGB) as the most prevalent bariatric procedure worldwide. While RYGB and SG demonstrate equivalent short-term weight loss, long-term weight loss tends to be greater after RYGB. Differences in the effect of these procedures on gastrointestinal hormones that regulate energy homeostasis are felt to partially underlie differences in outcomes. The objective of this study was to prospectively quantify blood levels of gut hormones of energy and glucose homeostasis at one year follow up to delineate possible reasons for greater efficacy of RYGB over SG in achieving weight loss.MethodsPatients undergoing SG (n = 19) and RYGB (n = 40) were studied before surgery and at 2,12, 26, and 52 weeks postoperatively. Blood samples drawn in the fasted state and after a liquid mixed meal were assayed at baseline, 26, and 52 weeks for peptide YY (PYY), glucagon-like peptide-1 (GLP-1), ghrelin, insulin, glucose, and leptin. Fasting and postprandial appetitive sensations were assessed by visual analog scale.ResultsAt 1 year there was greater weight loss in RYGB compared with SG patients (30% vs 27%; P = 0.03). Area under the curve (AUC) after the mixed meal for PYY was greater in RYGB patients (PConclusionsDifferences in gastrointestinal hormones that regulate energy and glucose homeostasis are a possible mechanism for greater efficacy of RYGB compared to SG.

Objective This study aimed to test the feasibility of a 12-month weight loss intervention using telephone-based counseling plus community-situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors. Methods This multisite cooperative group study enrolled sedentary, female, postmenopausal BC and CRC survivors with BMI ≥ 25 kg/m2 to receive 12-month fitness center memberships and telephone counseling encouraging 150 min/wk of PA and a 500-kcal/ddecrease in energy intake. Feasibility criteria included accrual, adherence, and retention. Target weight loss was ≥ 5%. Results Among 25 BC survivors, median baseline BMI was 37.2 (range: 27.7-54.6), accrual occurred in 10 months, 60% and 28% met diet and exercise goals, 80% provided 12-month measures, and average weight loss was 7.6% (95% CI: -3.9%, 19.2%). Among 23 CRC survivors, median BMI was 31.8 (range: 26.4-48.7), accrual occurred in 24 months, 61% and 17% met diet and exercise goals, 87% provided measures, and average weight loss was 2.5% (95% CI: -8.2%, 13.3%). Conclusions It is feasible to recruit and retain BC survivors in a cooperative group diet and PA weight loss trial. BC survivors achieved clinically meaningful weight loss but did not meet a priori adherence goals. In CRC survivors, recruitment was more difficult, and the intervention was less effective.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) produces greater weight loss compared with a purely restrictive procedure such as laparoscopic adjustable gastric banding (LAGB). OBJECTIVE: The objective of this study was to quantify changes in hormones that regulate energy homeostasis and appetitive sensations before and after LAGB (n=18) and RYGB (n=38) in order to better understand the mechanisms underlying the greater weight loss after RYGB. METHODS: A standardized test meal was administered prior to surgery, at 6 months, and annually thereafter to year 2 after LAGB and year 4 after RYGB. Blood samples were obtained in the fasted state and 30, 60, 90, and 120 minutes post-meal. RESULTS: Progressive increases in fasting PYY were observed after RYGB together with increases in postprandial area under the curve (AUC) levels that were unchanged after LAGB. GLP-1 AUC increased only after RYGB. There was a weight loss-related increase in fasting ghrelin levels after LAGB that was unchanged one year after RYGB despite greater percentage weight loss; ghrelin subsequently increased at years 2-4 post-RYGB. HOMA-IR decreased after both procedures but correlated with weight loss only after LAGB, whereas leptin correlated with weight loss in both groups. Sweet cravings decreased after RYGB. CONCLUSION: A number of weight loss-independent changes in the gut hormonal milieu likely act in concert to promote a decrease in insulin resistance and greater weight loss efficacy after RYGB. A progressive change in hormone levels over time may reflect gut enteroplasticity after RYGB. A decrease in sweet cravings specific to RYGB may further promote superior weight loss outcomes.

The duodenum has recently emerged as a key regulator in glucose metabolism via modulation of a complex network of neural and hormonal signals in response to ingested food. DiaGone™ is an endoscopic device which utilizes precisely controlled laser technology to target the duodenal submucosal neural plexi with the aim of improving glucose control by modulating the gastrointestinal neurohumoral axis. Nine subjects (5 males) with obesity (BMI 34.0 ± 4.6 kg/m2) and type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin were included in this first-in-human trial in order to assess the efficacy and safety of DiaGone™. Subjects were instructed to continue with regular diet 24h after the procedure and metformin dose was not changed during the study period. Biochemical and anthropometric parameters were assessed at baseline and 3 and 6 months after the procedure and continuous glucose monitoring (CGM) and a standard liquid meal test were performed at baseline and 3 months after the procedure. DiaGone™ significantly decreased HbA1C from 78.3 ± 13.3 mmol/mol at baseline to 64.9 ± 6.4 mmol/mol and 64.8 ± 7.1 mmol/mol at 3 and 6 months, respectively (p In conclusion, these pilot results suggest that endoscopic duodenal submucosal laser ablation using the DiaGone™ device is associated with improvements in both baseline and postprandial glycemia as well as HbA1C with no significant changes in insulin levels or body weight while having a favorable safety and tolerability profile. Disclosure M. Mraz: None. I. Marcovitch: Employee; Self; Digma Medical. I. Lankova: None. H. Kratochvilova: None. A. Cinkajzlova: None. M. Benes: None. J. Korner: Board Member; Self; Digma Medical. Stock/Shareholder; Self; Digma Medical. Z. Vlasakova: None. J. Spicak: None. T. Pelikanova: None. M. Haluzik: None. Funding MH CZ - DRO; Institute for Clinical and Experimental Medicine (IN00023001); RVO (VFN64165)

Objective We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. Methods To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. Results We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. Conclusions We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis., Graphical abstract Image 1Schematic of the proposed gut to pancreas blood glucose concentration regulatory circuit. Abbreviations used: TH, tyrosine hydroxylase; AADC, Aromatic l-amino acid decarboxylase; L-DOPA, L-3,4-dihydroxyphenylalanine; D2R, Dopamine receptor type 2, DA, Dopamine; LAAT, L-Type Amino Acid Transporter 1; DAT, dopamine active transporter; VMAT2, Vesicular monoamine transporter type 2; GSIS, glucose-stimulated insulin secretion. Grey boxes show tissue bypassed by GS, Sleeve Gastrectomy, and RYGB, Roux-en-Y Gastric Bypass surgeries., Highlights • Nutritional tyrosine is metabolized to L DOPA and DA in the foregut. • Postprandial L-DOPA and DA plasma concentrations rise in response to tyrosine. • Oral stable isotope labeled tyrosine is found postprandially in the pancreas as DA. • L-DOPA and DA are inhibitors of beta cell glucose-stimulated insulin secretion. • Postprandial L-DOPA and DA excursions are muted in certain bariatric surgery patients.

Context Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents. Objective We sought to determine whether there is a relationship between plasma AgRP and hypothalamic AgRP in rats and to evaluate the relationship between cortisol and plasma AgRP in humans. Methods We retrospectively evaluated plasma AgRP levels prior to transsphenoidal surgery in 31 patients with Cushing disease (CD) vs 31 sex- and body mass index–matched controls from a separate study. We then prospectively measured plasma AgRP, before and 6 to 12 months after surgery, in a subgroup of 13 patients with CD. Plasma and hypothalamic AgRP were measured in adrenalectomized rats with and without corticosterone replacement. Results Plasma AgRP was stimulated by corticosterone in rats and correlated with hypothalamic AgRP expression. Plasma AgRP levels were higher in patients with CD than in controls (139 ± 12.3 vs 54.2 ± 3.1 pg/mL; P < 0.0001). Among patients with CD, mean 24-hour urine free cortisol (UFC) levels were 257 ± 39 μg/24 hours. Strong positive correlations were observed between plasma AgRP and UFC (r = 0.76; P < 0.0001). In 11 of 13 patients demonstrating surgical cure, AgRP decreased from 126 ± 20.6 to 62.5 ± 8.0 pg/mL (P < 0.05) postoperatively, in parallel with a decline in UFC. Conclusions Plasma AgRP levels are elevated in CD, are tightly correlated with cortisol concentrations, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. AgRP’s role as a potential biomarker and as a mediator of the adverse metabolic consequences of CD deserves further study.

Context Roux-en-Y gastric bypass (RYGB) is associated with postprandial hyperinsulinemia. Objective This study assessed whether increased blood insulin levels may be due to an increase in maximal β-cell function. Design, Setting, and Participants We performed a cross-sectional study at Columbia University Medical Center, New York, New York. Subjects without a history of diabetes were studied after surgery (n = 12) and were compared with nonsurgical controls (n = 10) who were mean matched for body mass index, insulin sensitivity, and hemoglobin A1c and with nonobese controls (n = 8). Methods Subjects underwent a mixed-meal tolerance test and on a separate day an intravenous glucose tolerance test followed by a hyperglycemic clamp (450 mg/dL; 25 mM blood glucose) and arginine stimulation. The main outcome measure was maximal insulin secretion quantified after arginine stimulation (AinsRmax). Results The RYGB group exhibited greater peak postprandial glucose levels and fourfold greater peak insulin levels than control groups; however, there were no significant differences in insulinogenic index or AinsRmax. Another finding was significantly greater postprandial glucagon levels in the RYGB group compared with controls. Conclusions Our results suggest that after RYGB, the increase in postprandial levels of insulin are not due to changes in maximal β-cell function but appear to be an appropriate response to altered nutrient flow and absorption.

Background Serum concentrations of fatty acid binding protein 4, an adipose tissue fatty acid chaperone, have been correlated with insulin resistance and cardiovascular risk factors. The objective of this study were to assess relationships among Roux-en-Y gastric bypass, intensive lifestyle modification and medical management protocol, fatty acid binding protein 4, and metabolic parameters in obese patients with severe type 2 diabetes mellitus; and to evaluate the relative contribution of abdominal subcutaneous adipose and visceral adipose to the secretion of fatty acid binding protein 4. Methods Participants were randomly assigned to intensive lifestyle modification and medical management protocol (n = 29) or to intensive lifestyle modification and medical management protocol augmented with Roux-en-Y gastric bypass (n = 34). Relationships among fatty acid binding protein 4 and demographic characteristics, metabolic parameters, and 12-month changes in these values were examined. Visceral and subcutaneous adipose tissue explants from obese nondiabetic patients (n = 5) were obtained and treated with forskolin to evaluate relative secretion of fatty acid binding protein 4 in the different adipose tissue depots. Results The intensive lifestyle modification and medical management protocol and Roux-en-Y gastric bypass cohorts had similar fasting serum fatty acid binding protein 4 concentrations at baseline. At 1 year, mean serum fatty acid binding protein 4 decreased by 42% in Roux-en-Y gastric bypass participants (P = .002) but did not change significantly in the intensive lifestyle modification and medical management protocol cohort. Percentage of weight change was not a significant predictor of 12-month fatty acid binding protein 4 within treatment arm or in multivariate models adjusted for treatment arm. In adipose tissue explants, fatty acid binding protein 4 was secreted similarly between visceral and subcutaneous adipose tissue. Conclusion After Roux-en-Y gastric bypass, fatty acid binding protein 4 is reduced 12 months after surgery but not after intensive lifestyle modification and medical management protocol in patients with type 2 diabetes mellitus. Fatty acid binding protein 4 was secreted similarly between subcutaneous and visceral adipose tissue explants.

This study aims to quantify changes in fibroblast growth factor 19 (FGF19) and bile acids (BAs) in patients with uncontrolled type 2 diabetes randomized to Roux-en-Y gastric bypass (RYGB) vs intensive medical management (IMM) and matched for similar reduction in HbA1c after 1 year of treatment.Blood samples were drawn from patients who underwent a test meal challenge before and 1 year after IMM (n = 15) or RYGB (n = 15).Mean HbA1c decreased from 9.7 to 6.4% after RYGB and from 9.1 to 6.1% in the IMM group. At 12 months, the number of diabetes medications used per subject in the RYGB group (2.5 ± 0.5) was less than in the IMM group (4.6 ± 0.3). After RYGB, FGF19 increased in the fasted (93 ± 15 to 152 ± 19 pg/ml; P = 0.008) and postprandial states (area under the curve (AUC), 10.8 ± 1.9 to 23.4 ± 4.1 pg × h/ml × 10(3); P = 0.006) but remained unchanged following IMM. BAs increased after RYGB (AUC ×10(3), 6.63 ± 1.3 to 15.16 ± 2.56 μM × h; P = 0.003) and decreased after IMM (AUC ×10(3), 8.22 ± 1.24 to 5.70 ± 0.70; P = 0.01). No changes were observed in the ratio of 12α-hydroxylated/non-12α-hyroxylated BAs. Following RYGB, FGF19 AUC correlated with BAs (r = 0.54, P = 0.04) and trended negatively with HbA1c (r = -0.44; P = 0.09); these associations were not observed after IMM.BA and FGF19 levels increased after RYGB but not after IMM in subjects who achieved similar improvement in glycemic control. Further studies are necessary to determine whether these hormonal changes facilitate improved glucose homeostasis.

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.

Large-scale randomized clinical trials are needed to assess the role of Roux-en-Y gastric bypass (RYGB) in treating patients with type 2 diabetes mellitus (T2DM). Recruitment challenges must be understood.One hundred twenty participants were needed for a prospective randomized controlled trial investigating treatments for hyperglycemia and cardiovascular disease risk factors in patients with T2DM. The trial had two arms-intensive medical management plus a rigorous lifestyle intervention (LS/IMM) versus LS/IMM with RYGB. Medical inclusion criteria included glycosylated hemoglobin (HbA1c) ≥ 8.0 % while under the care of a physician and body mass index (BMI) 30.0-39.9 kg/m(2). Another inclusion criterion was expressed willingness to accept randomization and participate fully. Varied recruitment strategies were employed at four academic hospitals in the USA and Taiwan, including referrals, mass media, direct mail to patients drawn from a practice-based database, and direct mail to commercial mailing lists.Between February 2008 and December 2011, 2,648 candidates were phone-screened and 240 were screened on site; 120 participants were eventually randomized. Impediments included stringent medical inclusion criteria and a lack of equipoise (i.e., strong beliefs or preferences) among patients and their personal community-based physicians. To meet timeline requirements, the upper limit for BMI was increased from 34.9 to 39.9 kg/m(2) and an additional site was added.We successfully recruited 120 participants with poorly controlled T2DM and mild to moderate obesity. Participants had to be willing to accept randomization to either surgical or nonsurgical treatments. Recruitment took 4 years.

Objective: Obese individuals have high levels of circulating leptin and are resistant to the weight-reducing effect of leptin administration at physiological doses. Although Roux-en-Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post-RYGB patients would promote further weight reduction. Design and Methods: This was a randomized, double-blind, placebo-controlled cross-over study of 27 women who were at least 18 months post-RYGB and lost on average 30.8% of their presurgical body weight. Subjects received either leptin or placebo via subcutaneous injection twice daily for 16 weeks, then crossed over to receive the alternate treatment for 16 weeks. Results: Weight change after 16 weeks of placebo was not significantly different from that after 16 weeks of leptin. No changes were observed in percent fat mass, resting energy expenditure, thyroid hormones, or cortisol levels. Conclusion: Contrary to our hypothesis, we did not observe a significant effect of leptin treatment on body weight in women with relative hypoleptinemia after RYGB.

Background The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM). Materials and Methods Between April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30–35 kg/m2). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c

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.The objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery.University Hospital.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).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.Preoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, β-endorphin (β-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF β-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and β-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and β-EP declined in CSF, whereas acutely, only β-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Bariatric surgery leads to significant improvements in insulin sensitivity and secretion, in large part due to caloric restriction and weight loss. However, altered nutrient transport and glucose absorption due to surgery also lead to changes in gut hormone secretion that influence insulin action and β-cell function. The contribution of changes in bile acid reabsorption, amino acid metabolism, and carbohydrate metabolism following bariatric surgery remains to be seen. Studies of how β-cell activity and insulin sensitivity are altered by bariatric surgery have highlighted the enteroendocrine function of the gastrointestinal tract.

The aim of this study was to examine the effect of small bowel resection with and without sleeve gastrectomy on glucose homeostasis in an obese rodent model of type 2 diabetes.Zucker diabetic fatty rats were randomized into three surgical groups: Sham, small bowel resection, and small bowel resection with sleeve gastrectomy (BRSG). Weight and fasting glucose levels were measured at randomization and monitored after surgery. Oral glucose tolerance testing was performed at baseline and 45 days after surgery to assess glucose homeostasis and peptide changes.At baseline, all animals exhibited impaired glucose tolerance and showed no difference in weight or fasting (area under the curve) AUC(glucose). At sacrifice, Sham animals weighed more than BRSG animals (p = 0.047). At day 45, the Sham group experienced a significant increase in AUC(glucose) compared to baseline (p = 0.02), whereas there was no difference in AUC(glucose) in either surgical group at any time point: BR (p = 0.58) and BRSG (p = 0.56). Single-factor ANOVA showed a significant difference in AUC(glucose) of p = 0.004 between groups postoperatively: Sham (50,745 ± 11,170) versus BR (23,865 ± 432.6) (p = 0.01); Sham versus BRSG (28,710 ± 3188.8) (p = 0.02). There was no difference in plasma insulin, GLP-1, or adiponectin levels before surgery, although 45 days following surgery adiponectin levels where higher in the BRSG group (p = 0.004).Partial small bowel resection improved glucose tolerance independent of weight. The combination of small bowel resection and sleeve gastrectomy leads to an increase in adiponectin levels, which may contribute to improved glucose homeostasis.

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Worldwide, there is an epidemic of obesity and its associated diseases. The past decade of research has brought about a paradigm shift in our understanding of both the mechanisms underlying energy homeostasis and the multiple factors contributing to the pathophysiology of obesity. Metabolic surgery is currently far more effective than diet and exercise or pharmacotherapy in achieving durable weight loss. Moreover, the remarkable results of surgery in achieving a rapid remission of type 2 diabetes mellitus has sparked tremendous excitement and research into the mechanisms through which metabolic surgery has its dramatic effect. As opposed to the traditional understanding of “restriction” and “malabsorption,” current evidence suggests that metabolic surgery alters the expression of multiple hormones that affect both short-term and long-term signals of energy balance. We review the hormonal changes following the most common types of metabolic operations currently being performed. The profile of hormonal changes provides a guide to tailor the choice of operation for each individual patient toward achieving the desired metabolic result. In the future, individualized metabolic surgery alone or modulated by targeted pharmacological therapy may achieve the most reliable and effective results with the highest safety and lowest side effect profile. Mt Sinai J Med 77:446–465, © 2010 Mount Sinai School of Medicine

Background The aim of this study was to evaluate the effect of sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB) on glucose homeostasis and to evaluate the utility of positron emission tomography (PET) scanning for assessing β-cell mass. Methods Goto-Kakizaki rats were divided into 4 groups: control, sham, SG, or DJB. Oral glucose tolerance, insulin, and glucagon-like peptide-1 (GLP-1) were measured before and after surgery. Before and 90 days after treatment, [11C] DTBZ micro PET scanning was performed. Results The control and sham animals gained more weight compared with SG and DJB animals (P ≤ .05). Compared with control animals, the glucose area under the curve was lower in DJB animals 30 and 45 days after operations (P ≤ .05). At killing, GLP-1 levels were greater in the DJB group compared with sham and SG (P ≤ .05), whereas insulin levels were greater in both DJB and SG compared with sham (P ≤ .05). With PET scanning, the 90-day posttreatment mean vesicular monoamine transporter type 2 binding index was greatest in the DJB animals (2.45) compared with SG (1.17), both of which were greater than baseline control animals (0.81). Conclusion In type 2 diabetic rodents, DJB leads to improved glucose homeostasis and an increase in VMAT2 density as measured by PET scanning.

Importance The Roux-en-Y gastric bypass is effective in achieving established diabetes treatment targets, but durability is unknown. Objective To compare durability of Roux-en-Y gastric bypass added to intensive lifestyle and medical management in achieving diabetes control targets. Design, Setting, and Participants Observational follow-up of a randomized clinical trial at 4 sites in the United States and Taiwan, involving 120 participants who had a hemoglobin A1c(HbA1c) level of 8.0% or higher and a body mass index between 30.0 and 39.9 (enrolled between April 2008 and December 2011) were followed up for 5 years, ending in November 2016. Interventions Lifestyle-intensive medical management intervention based on the Diabetes Prevention Program and LookAHEAD trials for 2 years, with and without (60 participants each) Roux-en-Y gastric bypass surgery followed by observation to year 5. Main Outcomes and Measures The American Diabetes Association composite triple end point of hemoglobin A1cless than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg at 5 years. Results Of 120 participants who were initially randomized (mean age, 49 years [SD, 8 years], 72 women [60%]), 98 (82%) completed 5 years of follow-up. Baseline characteristics were similar between groups: mean (SD) body mass index 34.4 (3.2) for the lifestyle–medical management group and 34.9 (3.0) for the gastric bypass group and had hemoglobin A1clevels of 9.6% (1.2) and 9.6% (1.0), respectively. At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (difference, 19%; 95% CI, 4%-34%;P = .01). In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle–medical management group achieved an HbA1clevel of less than 7.0% (difference, 41%; 95% CI, 19%-63%;P = .002). Gastric bypass had more serious adverse events than did the lifestyle–medical management intervention, 66 events vs 38 events, most frequently gastrointestinal events and surgical complications such as strictures, small bowel obstructions, and leaks. Gastric bypass had more parathyroid hormone elevation but no difference in B12deficiency. Conclusions and Relevance In extended follow-up of obese adults with type 2 diabetes randomized to adding gastric bypass compared with lifestyle and intensive medical management alone, there remained a significantly better composite triple end point in the surgical group at 5 years. However, because the effect size diminished over 5 years, further follow-up is needed to understand the durability of the improvement. Trial Registration clinicaltrials.gov Identifier:NCT00641251

Objective The objective of this study was to quantify hormones that regulate energy and glucose homeostasis in order to establish possible mechanisms for the greater efficacy of Roux-en-Y gastric bypass (RYGB) compared with laparascopic adjustable gastric banding (LAGB) in achieving weight loss and improved insulin sensitivity. Design Longitudinal study of patients undergoing LAGB (n=15) and RYGB (n=28) who were studied prior to surgery and at 2, 12, 26 and 52 wks afterwards. Measurements Fasting blood samples were drawn at each visit. Postprandial blood samples were also obtained prior to surgery and at 26 and 52 wks. Samples were assayed for peptide YY (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, leptin, thyrotropic hormone (TSH), free T4 and free T3. Results At one year there was greater weight loss in RYGB compared with LAGB patients (30% vs 15%), but final body mass index was similar (34 vs 33 kg/m2). At wk 52, area under the curve (AUC) for PYY in RYGB subjects was greater than LAGB (P

Background The aim of this study was to measure the circulating levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon in patients who had undergone adjustable gastric banding (BND) or Roux-en-Y gastric bypass (RYGB) to understand the differences in glucose and insulin regulation after these procedures. Methods This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state and throughout a 3-hour period after a liquid meal. Results The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 μU/mL) than in the RYGB (6.2 μU/mL; P r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups. Conclusion Exaggerated postprandial GLP-1 and blunted glucose-dependent insulinotropic peptide secretion after RYGB might contribute to the greater weight loss and improved glucose homeostasis compared with BND.

OBJECTIVE We compared 3-year achievement of an American Diabetes Association composite treatment goal (HbA1c RESEARCH DESIGN AND METHODS A total of 120 adult participants, with BMI 30.0–39.9 kg/m2 and HbA1c ≥8.0%, were randomized 1:1 to two treatment arms at three clinical sites in the U.S. and one in Taiwan. All patients received the lifestyle-medical management intervention for 24 months; half were randomized to also receive gastric bypass. RESULTS At 36 months, the triple end point goal was met in 9% of lifestyle-medical management patients and 28% of gastric bypass patients (P = 0.01): 10% and 19% lower than at 12 months. Mean (SD) HbA1c values at 3 years were 8.6% (3.5) and 6.7% (2.0) (P < 0.001). No lifestyle-medical management patient had remission of diabetes at 36 months, whereas 17% of gastric bypass patients had full remission and 19% had partial remission. Lifestyle-medical management patients used more medications than gastric bypass patients: mean (SD) 3.8 (3.3) vs. 1.8 (2.4). Percent weight loss was mean (SD) 6.3% (16.1) in lifestyle-medical management vs. 21.0% (14.5) in gastric bypass (P < 0.001). Over 3 years, 24 serious or clinically significant adverse events were observed in lifestyle-medical management vs. 51 with gastric bypass. CONCLUSIONS Gastric bypass is more effective than lifestyle-medical management intervention in achieving diabetes treatment goals, mainly by improved glycemic control. However, the effect of surgery diminishes with time and is associated with more adverse events.

To help understand the mechanisms by which weight loss is maintained after Roux-en-Y gastric bypass (RYGBP), we measured circulating concentrations of total and bioactive octanoylated ghrelin, peptide YY (PYY), glucose, and insulin in the fasted state and in response to a liquid test meal in three groups of adult women: lean (n = 8); weight-stable 35 +/- 5 months after RYGBP (n = 12; mean body mass index, 33 kg/m(2)); and matched to the surgical group for body mass index and age (n = 12). Fasting plasma total ghrelin levels were nearly identical between RYGBP (425 +/- 54 pg/ml) and the matched controls (424 +/- 28 pg/ml) and highest in lean controls (564 +/- 103 pg/ml). The response to the test meal was comparable between lean and RYGBP groups, with 27% and 20% maximal suppression, respectively, whereas the magnitude of suppression was significantly diminished in the matched controls (17%) compared with the lean group. Fasting levels of octanoylated ghrelin were highest in the lean controls, 220 +/- 36 pg/ml vs. 143 +/- 27 in the RYGBP group (P = 0.05) and 127 +/- 12 pg/ml in the matched controls (P < 0.05). The magnitude of maximal postmeal suppression of octanoylated ghrelin was more marked than with total ghrelin, but similar among groups, ranging from 44-47%. In response to the test meal, there was an early exaggerated rise in PYY in the RYGBP group, such that the peak PYY concentration was 163 +/- 24 pg/ml compared with 58 +/- 17 (P < 0.01) and 77 +/- 23 (P < 0.05) in the matched and lean controls, respectively; area under the curve at 90 min was significantly greater compared with both control groups. Leptin and fasting insulin concentrations and homeostasis model of assessment insulin resistance indices were nearly identical between lean and RYGBP subjects and significantly higher in the body mass index-matched controls. In summary, the absence of a compensatory increase in ghrelin concentrations that usually occurs with diet-induced weight loss, and the exaggerated postprandial PYY response after RYGBP, may contribute to weight loss and to the ability of an individual to maintain weight loss after this surgical procedure.

Obesity is a chronic disease characterized by an accumulation of excess adipose tissue and associated with an increased risk of multiple morbidities and mortality. Weight loss prevents or tempers the severity of many obesity-related morbidities. Unfortunately, once adipose tissue accumulates, a system of overlapping neuroendocrine responses prevents it from diminishing. When food intake is limited, counterregulatory mechanisms cause an increase in appetite and a decrease in energy expenditure as protective measures against starvation, and make volitional weight loss by a hypocaloric diet difficult to achieve (1). Pharmacological intervention is, therefore, often necessary to aid in inducing weight loss and maintenance. This review summarizes the current pharmacotherapy for obesity and highlights how our understanding of the complex network of energy regulation may lead to more targeted and effective treatments. Current pharmacotherapy for weight loss Pharmacotherapy should be considered in overweight and obese patients with a body mass index greater than 27 kg/m 2 , particularly in the presence of comorbidites such as type 2 diabetes or hypertension or an increased waist circumference when conservative measures such as behavior therapy, diet, and exercise have not resulted in the desired weight loss (2). A realistic treatment goal is usually loss of 5–10% of initial body weight over a 6- to 12-month period, followed by longterm maintenance of reduced weight. Most cardiovascular risk factors are improved even at this level of modest weight reduction because of the predominant loss of visceral fat leading to disproportionate improvement in the risk of developing complications. The NIH guidelines recommend that if a chosen medication does not lead to a 2-kg weight loss in the first month of treatment, the dose should be adjusted or the medication discontinued. Only two drugs, sibutramine (Meridia, Abbott Laboratories, Abbott Park, IL) and orlistat (Xenical, Hoffman-LaRoche, Nutley, NJ), are approved by the Food and Drug Administration for long-term use. Sibutramine inhibits norepinephrine and serotonin reuptake. Although ineffective as an antidepressant, for which purpose it was originally developed, sibutramine was found to reduce body weight and appetite and increase satiety. More than 10 prospective, randomized, controlled trials of sibutramine have supported its efficacy (3). An analysis of three trials of at least 1-yr duration shows that patients on sibutramine lost 4.3 kg or 4.6% more weight than those taking

Purpose of review Obesity is a chronic disease characterized by an accumulation of excess adipose tissue and associated with an increased risk of multiple morbidities and mortality. Recent findings have provided a myriad of complex interrelationships between the central and peripheral control of energy homeostasis. This review aims to select and interpret the most influential and powerful recent literature. Recent findings A complex system of overlapping neuroendocrine control mechanisms maintains energy homeostasis and makes weight loss maintenance very difficult. Meal size, feeding initiation, and energy store status have all been shown to be controlled, at least in part, by various hormones and neural signals. The hypothalamus serves as the center for this crosstalk and biochemical modulation of energy homeostasis. Weight loss is associated with a change in concentrations of circulating levels of hormones that trigger the hypothalamic production of neuropeptides that induce hunger and decrease energy expenditure, and the suppression of molecules that inhibit food intake and increase energy expenditure. Summary A greater understanding of these complex networks of energy regulation systems will invariably lead to effective treatments for obesity and associated comorbidities such as type 2 diabetes.

Summary Background Conventional treatments for patients with type 2 diabetes are often inadequate. We aimed to assess outcomes of diabetes control and treatment risks 2 years after adding Roux-en-Y gastric bypass to intensive lifestyle and medical management. Methods We report 2-year outcomes of a 5-year randomised trial (the Diabetes Surgery Study) at four teaching hospitals (three in the USA and one in Taiwan). At baseline, eligible participants had to have HbA 1c of at least 8·0% (64 mmol/mol), BMI between 30·0 and 39·9 kg/m 2 , and type 2 diabetes for at least 6 months, and be aged 30–67 years. We randomly assigned participants to receive either intensive lifestyle and medical management alone (lifestyle and medical management), or lifestyle and medical management plus standard Roux-en-Y gastric bypass surgery (gastric bypass). Staff from the clinical centres had access to data from individual patients, but were masked to other patients' data and aggregated data until the 2-year follow-up. Drugs for hyperglycaemia, hypertension, and dyslipidaemia were prescribed by protocol. The primary endpoint was achievement of the composite treatment goal of HbA 1c less than 7·0% (53 mmol/mol), LDL cholesterol less than 2·59 mmol/L, and systolic blood pressure less than 130 mm Hg at 12 months; here we report the composite outcome and other pre-planned secondary outcomes at 24 months. Analyses were done on an intention-to-treat basis, with multiple imputations for missing data. This study is registered with ClinicalTrials.gov, number NCT00641251, and is still ongoing. Findings Between April 21, 2008, and Nov 21, 2011, we randomly assigned 120 eligible patients to either lifestyle and medical management alone (n=60) or with the addition of gastric bypass (n=60). One patient in the lifestyle and medical management group died (from pancreatic cancer), thus 119 were included in the primary analysis. Significantly more participants in the gastric bypass group achieved the composite triple endpoint at 24 months than in the lifestyle and medical management group (26 [43%] vs eight [14%]; odds ratio 5·1 [95% CI 2·0–12·6], p=0·0004), mainly through improved glycaemic control (HbA 1c vs 14 [24%]; treatment difference −1·9% (−2·5 to −1·4); p=0·0001). 46 clinically important adverse events occurred in the gastric bypass group and 25 in the lifestyle and medical management group (mainly infections in both groups [four in the lifestyle and medical management group, eight in the gastric bypass group]). With a negative binomial model adjusted for site, the event rate for the gastric bypass group was non-significantly higher than the lifestyle and medical management group by a factor of 1·67 (95% CI 0·98–2·87, p=0·06). Across both years of the study, the gastric bypass group had seven serious falls with five fractures, compared with three serious falls and one fracture in the lifestyle and medical management group. All fractures happened in women. Many more nutritional deficiencies occurred in the gastric bypass group (mainly deficiencies in iron, albumin, calcium, and vitamin D), despite protocol use of nutritional supplements. Interpretation The addition of gastric bypass to lifestyle and medical management in patients with type 2 diabetes improved diabetes control, but adverse events and nutritional deficiencies were more frequent. Larger and longer studies are needed to investigate whether the benefits and risk of gastric bypass for type 2 diabetes can be balanced. Funding Covidien, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Nutrition Obesity Research Centers, and the National Center for Advancing Translational Sciences.

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Agouti-related protein (AGRP) is synthesized in the same neurones in the arcuate nucleus as neuropeptide Y (NPY), another potent orexigenic peptide. AGRP antagonizes the action of alpha-melanocyte stimulating hormone, a derivative of pro-opiomelanocortin (POMC) at the hypothalamic MC4 receptor to increase food intake. Although leptin has been shown to regulate Agrp/Npy and Pomc-expressing neurones, there are differences with respect to Agrp regulation in leptin receptor-deficient mice and rats. Unlike the obese leptin receptor-deficient db/db mouse, which exhibits upregulation of Agrp mRNA expression in the medial basal hypothalamus (MBH) compared to lean controls, the obese leptin receptor-deficient (faf; Koletsky) rat does not exhibit upregulation of Agrp expression. To determine whether this represents a general difference between leptin receptor-deficient mice and rats, neuropeptide gene expression was analysed in the MBH of lean and obese rats segregating for a different leptin receptor mutation, Leprfa (Zucker). Fasting in lean rats (+/fa) for 72 h significantly increased Agrp and Npy mRNA expression, and decreased Pomc mRNA expression as detected by a sensitive solution hybridization/S1 nuclease protection assay. Npy mRNA levels were significantly increased in fed obese fa/fa compared to lean rats, and further increased in the obese animals after fasting. In contrast, Agrp mRNA levels did not differ between fed lean and fed obese rats, and fasting did not significantly change Agrp levels in obese rats. To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin. Fasting significantly increased Agrp and Npy, and decreased Pomc mRNA levels. Leptin infusion almost completely reversed these changes such that there was no significant difference between the levels in the fasted rats and those that were fed ad libitum. Thus, in fasted lean rats, Agrp and Npy are upregulated in parallel when leptin levels fall and are downregulated by leptin infusion. By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA.

Obesity and osteoarthritis are two commonly encountered clinical problems that can lead to significant physical and emotional disability. This report examines the association between obesity and osteoarthritis, and discusses potential mechanisms by which obesity influences osteoarthritis. Special attention is devoted to reviewing the molecular and genetic mechanisms that underlie the development of clinical obesity. Improved understanding of obesity will hopefully lead to improved treatment and subsequent amelioration of this important risk factor for osteoarthritis.

Agouti-related protein provides an orexigenic signal, probably through interaction with central melanocortin receptors. Expression of Agrp is markedly increased in the hypothalamus of mice deficient in leptin (Lep ob /Lep ob ) or its receptor (Lepr db /Lepr db ), suggesting that leptin mediates signals suppressing Agouti-related protein production. The regulation of Agrp expression in the rat hypothalamus has not been reported. We, therefore, analyzed the expression of Agrp in the medial basal hypothalamus of lean (1/1, 1/fa f ) and obese leptin receptor-deficient (fa f /fa f ) LA/N rats. Using a sensitive solution hybridization/S1 nuclease protection assay, we found no significant difference in Agrp messenger RNA (mRNA) levels (pg/mg total RNA 6 SEM) in obese rats (n 5 5), compared with lean controls (n 5 5): 0.46 6 0.06 vs. 0.47 6 0.06 (P 5 0.9). Similarly, no difference in Agrp expression was found using in situ hybridization or semiquantitative RT-PCR. In contrast to Agrp, Pomc mRNA levels were significantly suppressed in the obese, compared with the lean, rats (P 5 0.001). Thus, the ratio of Pomc to Agrp mRNA is decreased in the obese rats and may be an important modulator of food intake. To assess the physiological regulation of Agrp in rats, we examined the effect of food deprivation in lean Sprague Dawley (SD) rats. There was a 273% increase in medial basal hypothalamus Agrp mRNA in SD rats fasted for 48 h (n 5 8), compared with rats fed ad libitum (n 5 8): 0.82 6 0.23 vs. 0.30 6 0.08 (P 5 0.0001). Lean LA/N rats (n 5 7) fasted for 48 h also showed a 231% increase in Agrp expression, compared with fed lean controls (n 5 8): 0.74 6 0.11 vs. 0.32 6 0.03 (P 5 0.002), whereas Pomc expression was decreased by 32% in fasted animals from the same experiment (0.34 6 0.05 vs. 0.50 6 0.07; P 5 0.03). There were no significant differences in Agrp or Pomc mRNA levels between fasted and fed obese LA/N-fa f rats. These results suggest that, in the rat, the Agrp response to fasting may involve leptin-mediated phenomena, but factors in addition to leptin must also be involved in the regulation of Agrp gene expression. (Endocrinology 141: 2465‐2471, 2000)

The mechanisms by which leptin influences energy homeostasis are not entirely understood. Several observations indicate that proopiomelanocortin (POMC) is involved in the regulation of food intake and may be a mediator of leptin action. To further study this interaction, a sensitive solution hybridization assay was used to compare the levels of POMC mRNA in the medial basal hypothalamus (MBH) of lean (+/+, +/faf) and obese leptin receptor-deficient (faf/faf) rats. POMC peptide products were also measured by RIA in the same animals. Cytoplasmic POMC RNA levels were significantly reduced by 53% in obese rats as compared with lean controls: 0.30 ± 0.04 vs. 0.64 ± 0.07 pg/µg total RNA (p < 0.02). Significant reductions in mean concentrations of hypothalamic POMC-derived peptides from the same dissections were detected in the obese rats vs. lean controls: α-MSH 1.77 ± 0.07 vs. 2.34 ± 0.10; β-EP 4.06 ± 0.24 vs. 5.86 ± 0.36; γ3-MSH 5.32 ± 0.20 vs. 6.52 ± 0.12 ng/mg protein (p < 0.001). To determine whether leptin stimulates POMC gene transcription, the acute effect of an intracerebroventricular (i.c.v.) injection of leptin (5 µg) on POMC primary transcript was quantified in the MBH of lean rats after a 16-hour fast. There was a significant 167% increase in mean POMC hnRNA levels 3 h after i.c.v. leptin injection (1.15 ± 0.22 pg/MBH; p < 0.02), but not after 1 h (0.76 ± 0.08 pg/MBH), compared to saline controls (0.69 ± 0.08 pg/MBH). 4 h after the injection of leptin, POMC hnRNA was still increased, but to a lesser extent (140%), as compared with control animals (p = 0.006). These studies demonstrate for the first time in the leptin receptor-deficient rat that there is an associated decrease in POMC gene expression and peptide levels in the MBH. Furthermore, the acute increase in the levels of POMC primary transcript in non-obese rats after a single i.c.v. injection of leptin supports a role for leptin in the regulation of POMC gene transcription. Taken together, these studies provide further evidence that POMC is an important mediator of the effects of leptin on food intake and energy expenditure.