Medications for the treatment of obesity.

After several years with no real therapeutic alternatives, the management of obesity is entering a new era with the development of new surgical and endoscopic bariatric techniques, digital therapeutics and the arrival of new classes of drugs. New medication treatments aim to reduce food intake, targeting the hypothalamic regulation of food intake and satiety. The mechanism of their action remains poorly understood but, combines weight reduction and amelioration of cardiometabolic risk factors with a favorable benefit-risk balance and known side effects, mainly digestive. The future will tell us how these drugs will find their place in the management of this chronic disease that is obesity.

Evolution of the nutritional status of COVID-19 critically-ill patients: A prospective observational study from ICU admission to three months after ICU discharge.

BACKGROUND & AIMS: Malnutrition following intensive care unit (ICU) stay is frequent and could be especially prominent in critically ill Coronavirus Disease 2019 (COVID-19) patients as they present prolonged inflammatory state and long length stay. We aimed to determine the prevalence of malnutrition in critically ill COVID-19 patients both at the acute and recovery phases of infection. METHODS: We conducted a prospective observational study including critically ill COVID-19 patients requiring invasive mechanical ventilation discharged alive from a medical ICU of a university hospital. We collected demographic, anthropometric and ICU stay data (SAPS2, recourse to organ support and daily energy intake). Nutritional status and nutritional support were collected at one month after ICU discharge (M1) by phone interview and at 3 months after ICU discharge (M3) during a specialized and dedicated consultation conducted by a dietitian. Malnutrition diagnosis was based on weight loss and body mass index (BMI) criteria following the Global Leadership Initiative on Malnutrition. Primary outcome was the prevalence of malnutrition at M3 and secondary outcomes were the evolution of nutritional status from ICU admission to M3 and factors associated with malnutrition at M3. RESULTS: From march 13th to may 15th, 2020, 38 patients were discharged alive from the ICU, median [IQR] age 66 [59-72] years, BMI 27.8 [25.5-30.7] kg/m2 and SAPS2 47 [35-55]. Thirty-three (86%) patients were followed up to M3. Prevalence of malnutrition increased during the ICU stay, from 18% at ICU admission to 79% at ICU discharge and then decreased to 71% at M1 and 53% at M3. Severe malnutrition prevailed at ICU discharge with a prevalence of 55% decreasing 32% at M3. At M3, the only factors associated with malnutrition in univariate analysis were the length of invasive mechanical ventilation and length of ICU stay (28 [18-44] vs. 13 [11-24] days, P = 0.011 and 32 [22-48] vs. 17 [11-21] days, P = 0.006, respectively), while no ICU preadmission and admission factors, nor energy and protein intakes distinguished the two groups. Only 35% of undernourished patients at M3 had benefited from a nutritional support. CONCLUSION: Malnutrition is frequent, protracted and probably underrecognized among critically ill Covid-19 patients requiring invasive mechanical ventilation with more than half patients still being undernourished three months after ICU discharge. A particular attention should be paid to the nutritional status of these patients not only during their ICU stay but also following ICU discharge.

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav.

BACKGROUND: Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. MATERIALS AND METHODS: Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC-tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. RESULTS: Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). CONCLUSIONS: Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

Diagnostic of hepatic fibrosis with the XL probe of the Fibroscan versus biopsies in patients candidates to bariatric surgery.

BACKGROUND AND AIMS: The risks of the histological evaluation for metabolic liver disease in severe obese subjects led to the development of the Fibroscan® device. The main objective of our study is to evaluate the diagnostic performance of XL probe for the measurement of hepatic fibrosis compared to histological examination, in obese subjects operated from bariatric surgery. METHODS: We included patients free from chronic liver diseases. Liver measurement and controlled attenuation parameter (CAP) were carried out using the Fibroscan®. Liver biopsies were performed during bariatric surgery and evaluated by two pathologists. Correlation between vibration-controlled transient elastography (VCTE) and fibrosis stage was assessed using the Kendall correlation coefficient. Diagnosis performance was assessed using receiver-operating-characteristic curve analysis together with its 95% confidence interval. Cut-off value maximizing the Youden index was computed together with specificity, sensitivity, positive and negative predictive values. RESULTS: The average age and body mass index were 41 years and 43 kg/m2, respectively (n = 108). Forty-one percent of patients presented fibrosis on the histological results. The Kendall correlation coefficient between fibrosis stage and liver stiffness measurement (LSM) was κ = 0.33, p<10-5. ROC analysis for the detection of fibrosis indicated the following values: 0.70 [0.60-0.79] for F≥1, 0.83 [0.72-0.92] for F≥2, 0.90 [0.83-0.97] for F≥3. Optimal cut-offs maximizing the Youden index were 7.0 kPa for F≥1, 8.1 kPa for F≥2 and 8.7 kPa for F≥3. CONCLUSION: Fibroscan® appears to be reliable for detection of significant and severe fibrosis in severe obese patients such as candidates for bariatric surgery. CLINICAL TRIAL NUMBER: NCT03548597.

Evolution of hypothalamic lipoma after Roux-en-Y gastric bypass.

Severe obesity is a common consequence of hypothalamic region diseases and their treatment. Only two previous case reports have described hypothalamic lipomas in children with obesity. We described a case of an adult with severe obesity associated with hypothalamic lipoma attached to the third ventricle floor who underwent Roux-en-Y gastric bypass. He lost 38 and 59 kg at 6 and 12 months after surgery, respectively. Weight loss after bariatric surgery was as expected in this patient with severe obesity. At 6 and 12 months, brain magnetic resonance imaging (MRI) showed stability in lipoma's size.

pH monitoring of gastro-oesophageal reflux before and after laparoscopic sleeve gastrectomy.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a common obesity-related co-morbidity that is assessed objectively by 24-h pH monitoring. Some concerns have been raised regarding the risk of de novo GORD or exacerbation of pre-existing GORD after laparoscopic sleeve gastrectomy. Here, 24-h pH monitoring was used to assess the influence of laparoscopic sleeve gastrectomy on postoperative GORD in obese patients with or without preoperative GORD. METHODS: From July 2012 to September 2014, all patients scheduled for laparoscopic sleeve gastrectomy were invited to participate in a prospective follow-up. Patients who underwent preoperative 24-h pH monitoring were asked to repeat the examination 6 months after operation. GORD was defined as an oesophageal pH < 4 for at least 4·2 per cent of the total time recorded. RESULTS: Of 89 patients, 76 had preoperative pH monitoring for GORD evaluation and 50 had postoperative reassessment. Patients without (group 1, 29 patients) or with (group 2, 21 patients) preoperative GORD were similar regarding age, sex ratio and body mass index. In group 1, the median (i.q.r.) total time at pH < 4 was significantly higher after surgery than before: 5·6 (2·5-9·5) versus 1·6 (0·7-2·9) per cent (P < 0·001). Twenty of the 29 patients experienced de novo GORD as determined by 24-h pH monitoring (P < 0·001). In group 2, total time at pH < 4 after surgery was no different from the preoperative value: 5·9 (3·9-10·7) versus 7·7 (5·2-10·3) per cent (P = 0·296). CONCLUSION: Laparoscopic sleeve gastrectomy was associated with de novo GORD in over two-thirds of patients, but did not seem to exacerbate existing GORD.

Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case--control study.

Melanocortin-4 receptor (MC4R) gene mutations are involved in the leptin-melanocortin pathways that control food intake. The effect of these mutations on eating behavior phenotypes is still debated. To determine the association between functional MC4R mutations and eating behaviors, dietary intake and physical activity, we sequenced the MC4R gene in 4653 obese adults. Among them, 19 adults carriers of functional MC4R mutation were matched on age, sex and body mass index with two randomly-paired controls without MC4R mutation (n=57). We found that eating behaviors and physical activity did not differ between groups. In particular, cases were not at increased risk of binge eating disorders. Subjects carriers of MC4R mutation reported a higher proportion of dietary carbohydrates intakes (43.2±7.1 and 39.2±8.1% of total energy intake, respectively, P=0.048) and a lower proportion of dietary lipids (34.3±6.7 and 38.5±6.7% of total energy intake, respectively, P=0.018). In conclusion, mutation carriers differ from controls by a higher consumption of carbohydrates counterbalanced by a lower consumption of lipids expressed as percentage of total energy intake. However, functional MC4R mutations do not have a higher risk of compulsive eating contrary to what was previously suggested.

Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes.

AIM: Glutamic acid decarboxylase (GAD) and/or islet antigen-2 (IA-2) autoantibodies (ab) are present in 90% of patients at the onset of type 1 diabetes (T1D). Few studies have shown that they may persist in the long-term. We analysed the frequency of GADab and IA-2ab and the factors associated with their persistency in patients with long-lasting T1D. METHODS: This cross-sectional study included 430 adult patients with T1D of at least 10-year duration, consecutively seen over one year. GADab and IA-2ab were determined by radio-binding assays. Autoantibodies to thyroperoxydase, gastric parietal cells and transglutaminase were assessed in 418 patients, and HLA DRB1 genotyping in 359. Parameters associated with the persistency of antibodies were studied by multivariate analysis. RESULTS: Median age at diagnosis of T1D was 12 years, and median diabetes duration was 19 years. Extrapancreatic autoimmunity was present in 38% of the patients, and associated autoimmune diseases in 21%. GADab and/or IA-2ab were found in 56% of the patients, and in 32% in those with more than 25-year diabetes duration. GADab were more frequent than IA-2ab. Female sex, an older age at diagnosis, and a shorter duration of diabetes were independently associated with the presence of ab. The same factors and the DR3 allele were associated with GADab, while only diabetes duration and the DR4 allele were associated with IA-2ab. CONCLUSION: In a large proportion of the patients with T1D, the long-term persistency of diabetes-associated antibodies allows aetiological diagnosis, even far from the onset of hyperglycaemia.

Eating behaviour in obese patients with melanocortin-4 receptor mutations: a literature review.

Melanocortin-4 receptor (MC4R) mutations are the most common known cause of monogenic obesity and an important contributor to polygenic obesity. MC4R mutations with partial or total loss of function, as well as the variant rs17782313 mapped near MC4R, are positively associated with obesity. MC4R is involved in the leptin-melanocortin signalling system, located in hypothalamic nuclei, that controls food intake via both anorexigenic or orexigenic signals. Impairment in this receptor might affect eating behaviours. Thus, in the case of MC4R mutation carriers, obesity could be related, at least partly, to inadequate control over eating behaviours. Many published studies address eating behaviours in MC4R mutation carriers. Most studies focus on binge eating disorder, whereas others examine various aspects of intake and motivation. Up to now, no evaluation of this literature has been performed. In this review, we examine the available literature on eating behaviours in carriers of MC4R mutations and variant rs17782313 near MC4R gene. We address binge eating disorder, bulimia nervosa, mealtime hyperphagia, snacking, psychological factors, satiety responsiveness and intake of energy and macro/micronutrient. In a small number of studies, MC4R mutations seem to impair eating behaviours or motivation, but no clear causal effects can be found in the balance of the evidence presented. Improvements in methodologies will be necessary to clarify the behavioural effects of MC4R mutations.

Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: from one crisis to another.

AIM: Epidemiological data suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency may be a risk factor for diabetes. Also, the occurrence of haemolysis in the context of diabetes crises has been reported in patients with G6PD deficiency. A unifying hypothesis could explain these associations. METHODS: We report two patients in whom haemolytic crises occurred soon after acute diabetes decompensation, and revealed G6PD deficiency. We have reviewed the mechanisms that may link the two diseases. RESULTS: One patient was admitted for decompensated ketosis-prone type-2 diabetes (KPT2D), but no acidosis, and was treated with insulin, then metformin and glibenclamide. The second patient had type-1 diabetes and ketoacidosis treated with insulin. Haemolytic crises were recognized 8 and 4 days after admission, respectively, and G6PD deficiency was confirmed in both patients. These patients and the other published cases share, as a unique characteristic, the occurrence of haemolysis after diabetes decompensation, whatever the treatment or associated conditions. Experimental data show that hyperglycaemia can reduce expression of the G6PD gene and activity of the enzyme. Conversely, G6PD deficiency can promote oxidative stress and impairment of insulin secretion by beta cells. CONCLUSION: In patients at risk of G6PD deficiency, the possibility of haemolysis should be explored in case of diabetes crisis. In African patients with KPT2D diabetes, potentially oxidative hypoglycaemic agents should be avoided in the remission phase of the disease. G6PD deficiency and diabetes can aggravate each other, and diabetes could be aetiologically associated with G6PD deficiency.

Poor prognosis of pregnancy in women with autoimmune type 1 diabetes mellitus masquerading as gestational diabetes.

AIM: To describe the clinical presentation and the prognosis of autoimmune type 1 diabetes (T1D) that was first revealed during pregnancy masquerading as gestational diabetes mellitus (GDM). METHODS: We reviewed the files of 21 women in whom diabetes was revealed during a pregnancy ("index pregnancy") and progressed to T1D after delivery, and in whom GAD and/or IA-2 autoantibodies were found. RESULTS: The median age and BMI of the women were 31 years and 19.8 kg/m(2). Eleven women had at least one risk factor for GDM. Eight of the 12 multiparous women had had an abnormal outcome of previous pregnancy, including GDM in five. GDM was diagnosed at week 26 (range: 4-38) of gestation by screening in 18, because of macrosomia in two and during hyperglycaemic crises in three. All were treated with insulin, from the time of diabetes diagnosis in 10 and after 4 weeks (range: 2-15) in 11. Term of delivery was 38 (range: 26-41) weeks. Abnormal outcomes occured in 14 pregnancies, including two fetal deaths, four preterm deliveries and eight macrosomic infants. No congenital malformations were reported. After delivery, insulin therapy was stopped in 18 women for 6 months (range: 2-48). The diagnosis of the autoimmune origin of diabetes was established during the index pregnancy in only eight cases. CONCLUSION: T1D may reveal as GDM in women with or without risk factors for GDM and is associated with a poor prognosis, partly because the correct diagnosis and treatment are delayed. Whether screening for autoimmune markers of T1D should be performed more systematically in women with GDM deserves to be studied.

Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies.

OBJECTIVE: We have dissected the rare molecular anomalies that may affect hepatocyte nuclear factor-1a (HNF1A) and hepatocyte nuclear factor-4a (HNF4A) in patients with familial young-onset diabetes for whom HNF1A mutations have been excluded by sequence analysis. METHODS: Eighty-four unrelatedHNF1A-negative patients with diabetes diagnosed before the age of 40 years, a family history of diabetes and the absence of features suggestive of Type 2 diabetes were included. We analysed by sequencing the HNF4A promoter and coding regions, the HNF1A promoter region and specific regions of HNF1A(B) and HNF1A(C) isoforms and searched for large deletions of HNF1A and HNF4A by multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified five novel HNF4A mutations (5 / 84, 6%), including four missense and one in-frame deletion, and one mutation of the HNF1A promoter (1 / 84). Sequence analysis of isoform-specific coding regions of HNF1A did not reveal any mutation. We next identified two whole gene deletions of HNF1A and HNF4A, respectively (2 / 84, 2.4%). CONCLUSIONS: Altogether, the search for rare molecular events in HNF1A and HNF4A led us to elucidate 8 / 84 (9.5%) of our HNF1A-negative cases.This study shows that genetic aetiologies remain to be elucidated in familial young-onset diabetes. It also highlights the difficulty of the differential diagnosis with Type 2 diabetes because of the wide clinical expression of monogenic young-onset diabetes and the absence of specific biomarkers.

Molecular cloning of the precursors of pigment dispersing hormone in crustaceans.

The cDNAs encoding the precursors of a chromactive crustacean hormone, Pigment Dispersing Hormone (PDH) of the shrimp Penaeus vannamei, were studied by PCR and molecular cloning. Three different cDNAs were isolated and sequenced. The PDH precursor consists of a putative 22- or 23-amino acid signal peptide, a 34-amino acid PDH-Precursor Related Peptide (PPRP) of unknown function, and the 18-amino acid mature PDH. The deduced mature PDH amino acid sequences are identical except the change of a Leucine by an Isoleucine in one variant and are very similar to those of other species. The signal peptides appear highly variable. The variability between the PPRP sequences is low between the different species, suggesting that this peptide may have a physiological role.