Purpose
This study investigates whether pharmacotherapy with liraglutide is similarly effective in reversing weight regain more than 6 years after Roux-en-Y gastric bypass (RYGB) as revisional ...surgery aimed at restoring restriction.
Methods
Ninety-five consecutive patients (11 male, 84 female; mean BMI 45 ± 6 kg/m
2
) undergoing RYGB 9 ± 4 years ago were treated for 24 months as follows: Patients, who gained less than 10% from weight NADIR, served as controls and were provided lifestyle counseling (DC,
n
= 30). The others were allowed to choose between three different treatment groups: daily s.c. administration of liraglutide (LG,
n
= 34); endosurgery using Apollo’s Overstitch System™ (ES,
n
= 15), or implantation of a Fobi-ring with pouch resizing (FP,
n
= 16).
Results
Controls kept their weight stable during 24 months of study (− 0.1 ± 1.7 kg/m
2
). Weight loss was 4.8 ± 2.9 kg/m
2
for LG and 5.5 ± 2.9 kg/m
2
for FP, both losing more than 85% of regained weight from weight NADIR (
p
< 0.001). In contrast, weight loss in ES was 1.0 ± 0.9 kg/m
2
(i.e., 20% of regained weight). Thirty-seven percent of FP experienced serious complications (
p
< 0.05) in contrast to the other groups. An improved prevalence of hypertension and dyslipidemia was observed in LG and FP (
p
< 0.02) 24 months after intervention.
Conclusions
Weight regain during more than 6 years after RYGB can be safely and effectively reversed with liraglutide. Compared with revisional surgery, pharmacotherapy with liraglutide was low risk and resulted in an important improvement in hypertension and dyslipidemia. Therefore, daily subcutaneous injections of liraglutide are a valid option to treat weight regain after RYGB.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Data on the effects of eating behavior and genetics on outcomes of gastrointestinal surgery for diabesity have been sparse, often flawed, and controversial. We aimed to assess long-term outcomes of ...bariatric operations in patients characterized for eating behavior and rare mutations in the melanocortin-4 receptor (MC4R) gene, which is strongly implicated in energy balance.
Between 1996 and 2005, 1,264 severely obese Swiss patients underwent current laparoscopic adjustable gastric banding, gastroduodenal bypass, or a hybrid operation. Of these, 872 patients were followed for a minimum of 6 years and were screened for MC4R mutations. Using regression models, we studied relationships between eating behavior and MC4R mutations and postoperative weight loss, complications, and reoperations after 6 years.
At baseline, rare functional MC4R mutation carriers exhibited a significantly higher prevalence of binge eating disorder (BED) or loss-of-control eating independent of age, sex, and BMI. Six years after bariatric surgery, the mutation carriers had more major complications than wild-type subjects independent of age, baseline BMI, sex, operation type, and weight loss. Furthermore, high baseline BMI, male sex, BED, and functional MC4R mutations were independent predictors of higher reoperation rates.
Sequencing of MC4R and eating typology, combined with stratification for sex and baseline BMI, might significantly improve patient allocation to banding or bypass operations for diabesity as well as reduce both complication and reoperation rates.
We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in ...both adults and children of European ancestry with an experiment-wise P value of 1.67 × 10−26 in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
About the Authors: David Meyre * E-mail: meyred@mcmaster.ca Affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Philippe Froguel ...Affiliations Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8199, Lille Pasteur Institute, Lille, Nord, France, Department of Genomics of Common Disease, Imperial College London, London, United Kingdom Fritz F. Horber Affiliations Department of Internal Medicine, Landesspital, Vaduz, Liechtenstein, University of Berne, Berne, Switzerland John G. Kral Affiliation: Department of Surgery, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America Citation: Meyre D, Froguel P, Horber FF, Kral JG (2014) Comment On: Valette et al. The authors failed to describe any quality control procedures to ensure the integrity of their genotyping such as: call rate, Hardy-Weinberg equilibrium test, double-genotyping concordance rate and comparison of the MAF with published databases in comparable ethnic groups 5.The very significant departure of the genotypic distribution of the variant rs17782313 described by Valette et al from Hardy-Weinberg equilibrium (P<10−20) suggests an error in technique. ...the stated purpose of the paper was to evaluate surgical weight loss in patients with MC4R mutations and polymorphisms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association ...were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 × 10−7), near MAF (encoding the transcription factor c-MAF, P = 3.8 × 10−13) and near PTER (phosphotriesterase-related gene, P = 2.1 × 10−7).
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction:
Comparative data on long-term outcomes of mechanistically different bariatric operations are scarce.
Methods:
In this prospective, observational study, consecutive patients with severe ...obesity were studied using a predefined reoperation algorithm to determine long-term health outcomes after bariatric surgery (BS): adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD). All patients were assessed for mortality, postoperative weight loss, rate of reoperation, comorbidities, and quality of life (QoL) 8 years after surgery.
Results:
Between 1996 and 2008, 2364 Swiss patients, with a mean body mass index of 43 ± 7 kg/m
2
(mean ± SD) underwent AGB (n = 1404), RYGB (n = 790), or BPD (n = 170). Two thousand two hundred twenty-eight (94%) were followed for 8 years after BS. Eight-year mortality of the whole study group was 34.3 per 10
4
person-years. Percent excessive weight loss at 8 years was 56.7 ± 1.4% (95% confidence interval) in AGB, 62.5 ± 2.4% in RYGB and 64.8+-3.0% in BPD. The rate of major reoperation was highest in AGB and significantly lower in RYGB and BPD (63.4 vs 54.3 vs 47.2 per 10
3
person-years,
P
< 0.001). Remission of comorbidities was observed across all 3 groups, with key improvement (
P
< 0.01) in esophagitis in the RYGB group, and type 2 diabetes (T2D) (>60%) in procedures involving duodenal exclusion. Total improvement in QoL was similar between the 3 types of operations but was strongly correlated with weight loss preservation (
P
< 0.001).
Conclusions:
BS, at the expense of a high reoperation rate but low procedural mortality, considerably improves the QoL and results in sustained remission of comorbidities, especially T2D using a predefined reoperation algorithm developed to prevent weight regain and operation-specific complications.
Introduction:. Comparative data on long-term outcomes of mechanistically different bariatric operations are scarce. Methods:. In this prospective, observational study, consecutive patients with ...severe obesity were studied using a predefined reoperation algorithm to determine long-term health outcomes after bariatric surgery (BS): adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD). All patients were assessed for mortality, postoperative weight loss, rate of reoperation, comorbidities, and quality of life (QoL) 8 years after surgery. Results:. Between 1996 and 2008, 2364 Swiss patients, with a mean body mass index of 43 ± 7 kg/m2 (mean ± SD) underwent AGB (n = 1404), RYGB (n = 790), or BPD (n = 170). Two thousand two hundred twenty-eight (94%) were followed for 8 years after BS. Eight-year mortality of the whole study group was 34.3 per 104 person-years. Percent excessive weight loss at 8 years was 56.7 ± 1.4% (95% confidence interval) in AGB, 62.5 ± 2.4% in RYGB and 64.8+-3.0% in BPD. The rate of major reoperation was highest in AGB and significantly lower in RYGB and BPD (63.4 vs 54.3 vs 47.2 per 103 person-years, P < 0.001). Remission of comorbidities was observed across all 3 groups, with key improvement (P < 0.01) in esophagitis in the RYGB group, and type 2 diabetes (T2D) (>60%) in procedures involving duodenal exclusion. Total improvement in QoL was similar between the 3 types of operations but was strongly correlated with weight loss preservation (P < 0.001). Conclusions:. BS, at the expense of a high reoperation rate but low procedural mortality, considerably improves the QoL and results in sustained remission of comorbidities, especially T2D using a predefined reoperation algorithm developed to prevent weight regain and operation-specific complications.
Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees
Fanny Stutzmann 1 ,
Karen Tan 2 ,
Vincent Vatin 1 ,
Christian Dina 1 ,
...Béatrice Jouret 3 ,
Jean Tichet 4 ,
Beverley Balkau 5 ,
Natascha Potoczna 6 ,
Fritz Horber 6 ,
Stephen O'Rahilly 2 ,
I. Sadaf Farooqi 2 ,
Philippe Froguel 1 7 and
David Meyre 1
1 Centre National de la Recherche Scientifique-8090, Institute of Biology, Pasteur Institute, Lille, France
2 University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge,
U.K
3 Institut National de la Santé et de la Recherche Médicale U563, Children's Hospital, Toulouse, France
4 Institut inter Régional pour la Santé, La Riche, France
5 Institut National de la Santé et de la Recherche Médicale U780-IFR69, Villejuif, Université Paris-Sud, Orsay, France
6 Klinik Lindberg, Winterthur, and University of Berne, Berne, Switzerland
7 Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K
Corresponding author: Philippe Froguel, p.froguel{at}imperial.ac.uk
Abstract
OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding
the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.
RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional
impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers
and 94 noncarriers from three generations.
RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of
obese versus 0.15% of nonobesed subjects ( P = 6.9 × 10 −10 ). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers.
Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60%
in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent
penetrance (37% at 20 years versus 60% at >40 years).
CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect
on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate
manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically
predisposed to it.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 June 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 5, 2008.
Received February 3, 2008.
DIABETES
Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in ...obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.
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