Obesity, Type 2 Diabetes, Diabetes remission, Bariatric surgery, NAFLD, NASH
15
Scopus Publications
Scopus Publications
Dodecanedioic acid prevents and reverses metabolic-associated liver disease and obesity and ameliorates liver fibrosis in a rodent model of diet-induced obesity Giulia Angelini, Sara Russo, Fabrizia Carli, Patrizia Infelise, Simona Panunzi, Alessandro Bertuzzi, Maria Emiliana Caristo, Erminia Lembo, Roberta Calce, Stefan R. Bornstein, Amalia Gastaldelli, Geltrude Mingrone FASEB Journal, 2024 Dodecanedioic acid (DC12) is a dicarboxylic acid present in protective polymers of fruit and leaves. We explored the effects of DC12 on metabolic dysfunction‐associated steatohepatitis (MASH) and obesity. DC12 supplementation (100 mg/kg/day) was added to a high‐fat diet (HFD) for 8 weeks in rodents to assess its impact on obesity and MASH prevention. Rats given DC12 experienced significant reductions of weight gain, liver and visceral fat weight, and improved glucose tolerance and insulin sensitivity. Liver histology showed protection against diet‐induced MASH, with reduced steatosis, hepatocyte ballooning, and fibrosis. For weight‐loss and MASH reversion, rats were fed HFD for 14 weeks, followed by 6 weeks with or without DC12. DC12 supplementation (100 mg/kg/day) led to a significant reduction of weight gain and liver weight. DC12 induced white adipose tissue beiging and reduced adiposity with a decrease of visceral fat. It also improved glucose tolerance, insulin sensitivity, and reduced hepatic gluconeogenic gene expression. Liver histology revealed a significant reduction in steatosis, hepatocyte ballooning, and inflammation as well as fibrosis, indicating MASH reversal. DC12 reduced hepatic lipogenesis enzymes as well as de novo lipogenesis measured by deuterated water and increased fatty acid β‐oxidation. Plasma lipid profile showed lower triglycerides and phosphatidylcholines in the DC12 group. Notably, DC12 decreased mINDY expression, the cell membrane Na+‐coupled citrate transporter, reducing citrate uptake and de‐novo lipogenesis, linking its effects to improved lipid metabolism and reduced steatosis. We found that during the hepatic first pass, half of the DC12 ingested with water was taken up by the liver. The concentration of DC12 in the portal vein falls within the range identified in vitro as sufficient to inhibit citrate transport in hepatocytes.
Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis Silvia Sabatini, Partho Sen, Fabrizia Carli, Samantha Pezzica, Chiara Rosso, Erminia Lembo, Ornella Verrastro, Ann Daly, Olivier Govaere, Simon Cockell, Tuulia Hyötyläinen, Geltrude Mingrone, Elisabetta Bugianesi, Quentin M. Anstee, Matej Orešič, Amalia Gastaldelli Cell Reports Medicine, 2024 Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6- 2 H 2 -glucose, U- 2 H 5 -glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2–F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH. • Glucose production is higher in individuals with MASH compared to simple steatosis • Glucose production is higher with liver inflammation and fibrosis, not steatosis • Hepatic and adipose insulin resistance contribute to glucose production in MASH • The putative mechanism involves excess glucogenic/energy substrates to the liver Sabatini et al. demonstrate that glucose production is enhanced in individuals with MASH and is associated with hepatic fibrosis and inflammation. These findings reveal altered hepatic glucose metabolism, driven by hepatic and extrahepatic insulin resistance that contributes to the increased risk of hyperglycemia and T2D in individuals with MASH.
Non-Thyroidal Illness in Chronic Renal Failure: Triiodothyronine Levels and Modulation of Extra-Cellular Superoxide Dismutase (ec-SOD) Antonio Mancini, Andrea Silvestrini, Fabio Marcheggiani, Emmanuele Capobianco, Sonia Silvestri, Erminia Lembo, Patrick Orlando, Flavia Beccia, Nicola Nicolotti, Nicola Panocchia, Luca Tiano Antioxidants, 2024 Oxidative stress (OS) is implicated in several chronic diseases. Extra-cellular superoxide dismutase (ec-SOD) catalyses the dismutation of superoxide anions with a protective role in endothelial cells. In chronic kidney disease (CKD), OS and thyroid dysfunction (low fT3 syndrome) are frequently present, but their relationship has not yet been investigated. This cohort study evaluated ec-SOD activity in CKD patients during haemodialysis, divided into “acute haemodialytic patients” (AH, 1–3 months of treatment) and “chronic haemodialytic patients” (CH, treated for a longer period). We also evaluated plasmatic total antioxidant capacity (TAC) and its relationships with thyroid hormones. Two basal samples (“basal 1”, obtained 3 days after the last dialysis; and “basal 2”, obtained 2 days after the last dialysis) were collected. On the same day of basal 2, a sample was collected 5 and 10 min after the standard heparin dose and at the end of the procedure. The ec-SOD values were significantly higher in CH vs. AH in all determinations. Moreover, the same patients had lower TAC values. When the CH patients were divided into two subgroups according to fT3 levels (normal or low), we found significantly lower ec-SOD values in the group with low fT3 in the basal, 5, and 10 min samples. A significant correlation was also observed between fT3 and ec-SOD in the basal 1 samples. These data, confirming OS and low fT3 syndrome in patients with CKD, suggest that low fT3 concentrations can influence ec-SOD activity and could therefore potentially contribute to endothelial oxidative damage in these patients.
SICOB-endorsed national Delphi consensus on obesity treatment optimization: focus on diagnosis, pre-operative management, and weight regain/insufficient weight loss approach Marco Antonio Zappa, Angelo Iossa, Luca Busetto, Sonja Chiappetta, Francesco Greco, Marcello Lucchese, Fausta Micanti, Geltrude Mingrone, Giuseppe Navarra, Marco Raffaelli, Settimio Fabrizio Altorio, Luigi Angrisani, Claudio Arcudi, Fabrizio Bellini, Paolo Bernante, Rossana Berta, Esmeralda Capristo, Maria Grazia Carbonelli, Giovanni Casella, James Mariolo Casella, Lidia Castagneto Gissey, Maria Rosaria Cerbone, Franco Ciampaglia, Luigi Ciccoritti, Alessandro Contine, Giuseppe Currò, Rosella D’Alessio, Massimiliano De Palma, Daniela Delle Piane, Nino Di Benedetto, Nicola Di Lorenzo, Giovanni Fantola, Rahimi Farnaz, Mirto Foletto, Pietro Forestieri, Lucia Frittitta, Elisa Galfrascoli, Paolo Gentileschi, Cristiano Giardiello, Piero Giustacchini, Maria Paola Giusti, Ilenia Grandone, Caterina Guidone, Amerigo Iaconelli, Erminia Lembo, Silvana Leanza, Erminia Lembo, Giovanni Lezoche, Cesare Lunardi, Gennaro Martines, Bernardo Marzano, Emanuela Paone, Francesco Saverio Papadia, Federico Perrone, Luigi Piazza, Vincenzo Pilone, Pietro Pizzi, Mark Rice, Andrea Rizzi, Ferruccio Santini, Giuliano Sarro, Angelo Schettino, Nicola Tartaglia, Mauro Toppino, Antonella Usai, Maurizio De Luca, and Eating and Weight Disorders, 2023 Purpose Overweight and obesity affects 60% of adults causing more than 1.2 million deaths across world every year. Fight against involved different specialist figures and multiple are the approved weapons. Aim of the present survey endorsed by the Italian Society of Bariatric Surgery (SICOB) is to reach a national consensus on obesity treatment optimization through a Delphi process. Methods Eleven key opinion leaders (KOLs) identified 22 statements with a major need of clarification and debate. The explored pathways were: (1) Management of patient candidate to bariatric/metabolic surgery (BMS); (2) Management of patient not eligible for BMS; (3) Management of patient with short-term (2 years) weight regain (WR) or insufficient weight loss (IWL); (4) Management of the patient with medium-term (5 years) WR; and (5) Association between drugs and BMS as WR prevention. The questionnaire was distributed to 65 national experts via an online platform with anonymized results. Results 54 out of 65 invited panelists (83%) respond. Positive consensus was reached for 18/22 statements (82%); while, negative consensus (s20.4; s21.5) and no consensus (s11.5, s17) were reached for 2 statements, respectively (9%). Conclusion The Delphi results underline the importance of first-line interdisciplinary management, with large pre-treatment examination, and establish a common opinion on how to properly manage post-operative IWL/WR. Level of evidence V Report of expert committees.
Development and validation of an interpretable machine learning-based calculator for predicting 5-year weight trajectories after bariatric surgery: a multinational retrospective cohort SOPHIA study Patrick Saux, Pierre Bauvin, Violeta Raverdy, Julien Teigny, Hélène Verkindt, Tomy Soumphonphakdy, Maxence Debert, Anne Jacobs, Daan Jacobs, Valerie Monpellier, Phong Ching Lee, Chin Hong Lim, Johanna C Andersson-Assarsson, Lena Carlsson, Per-Arne Svensson, Florence Galtier, Guelareh Dezfoulian, Mihaela Moldovanu, Severine Andrieux, Julien Couster, Marie Lepage, Erminia Lembo, Ornella Verrastro, Maud Robert, Paulina Salminen, Geltrude Mingrone, Ralph Peterli, Ricardo V Cohen, Carlos Zerrweck, David Nocca, Carel W Le Roux, Robert Caiazzo, Philippe Preux, François Pattou Lancet Digital Health, 2023 Background Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery. Methods In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI. Findings 10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m 2 (95% CI 2·6–3·0) and mean RMSE BMI was 4·7 kg/m 2 (4·4–5·0), and the mean difference between predicted and observed BMI was –0·3 kg/m 2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery. Interpretation We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions. Funding SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).
Bariatric–metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial Ornella Verrastro, Simona Panunzi, Lidia Castagneto-Gissey, Andrea De Gaetano, Erminia Lembo, Esmeralda Capristo, Caterina Guidone, Giulia Angelini, Francesco Pennestrì, Luca Sessa, Fabio Maria Vecchio, Laura Riccardi, Maria Assunta Zocco, Ivo Boskoski, James R Casella-Mariolo, Pierluigi Marini, Maurizio Pompili, Giovanni Casella, Enrico Fiori, Francesco Rubino, Stefan R Bornstein, Marco Raffaelli, Geltrude Mingrone Lancet, 2023 BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: ), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.
Rate of post-bariatric hypoglycemia using continuous glucose monitoring: A meta-analysis of literature studies Roberta Lupoli, Erminia Lembo, Carmen Rainone, Luigi Schiavo, Antonio Iannelli, Matteo N.D. Di Minno, Brunella Capaldo Nutrition Metabolism and Cardiovascular Diseases, 2022 Aims. Hypoglycemia is a serious complication of bariatric surgery. The aim of the present meta-analysis was to evaluate the rate and the timing of post-bariatric hypoglycemia (PBH) with different bariatric procedures using reliable data from continuous glucose monitoring (CGM). Data synthesis. Studies were systematically searched in the Web of Science, Scopus and PubMed databases according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The prevalence of PBH was expressed as weighted mean prevalence (WMP) with pertinent 95% confidence intervals (95%CI). A total of 8 studies (16 datasets) enrolling 280 bariatric subjects were identified. The total WMP of PBH was 54.3% (95%CI: 44.5%–63.8%) while the WMP of nocturnal PBH was 16.4% (95%CI: 7.0%–34%). We found a comparable rate of PBH after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) (OR 1.62, 95%CI: 0.71–3.7; P = 0.248); likewise, the percent time spent in hypoglycemia was similar with the two procedures (mean difference 5.3%, 95%CI: −1.4%–12.0%; P = 0.122); however, RYGB was characterized by a higher glycaemic variability than SG. Regression models showed that the time elapsed from surgical intervention was positively associated with a higher rate of both total PBH (Z-value: 3.32, P Conclusions PBH, both post-prandial and nocturnal, is more prevalent than currently believed. The rate of PBH increases at increasing time from surgery and is comparable after RYGB and SG with a higher glucose variability after RYGB.
Uncooked cornstarch for the prevention of hypoglycemic events G. D. Della Pepa, C. Vetrani, R. Lupoli, E. Massimino, E. Lembo, G. Riccardi, B. Capaldo Critical Reviews in Food Science and Nutrition, 2022 Hypoglycemia is a pathological condition characterized by a low plasma glucose concentration associated with typical autonomic and/or neuroglycopenic symptoms, and resolution of these symptoms with carbohydrate consumption. Hypoglycemia is quite common in clinical practice, particularly in insulin-treated patients with diabetes and in other inherited or acquired conditions involving the regulation of glucose metabolism. Beyond symptoms that might strongly affect the quality of life, hypoglycemia can lead to short- and long-term detrimental consequences for health. Hypoglycemia can be prevented by appropriate changes in dietary habits or by relevant modifications of the drug treatment. Several dietary approaches based on the intake of various carbohydrate foods have been tested for hypoglycemia prevention; among them uncooked cornstarch (UCS) has demonstrated a great efficacy. In this narrative review, we have summarized the current evidence on the UCS usefulness in some conditions characterized by high hypoglycemic risk, focusing on some inherited diseases -i.e. glycogen storage diseases and other rare disorders - and acquired conditions such as type 1 diabetes, postprandial hypoglycemia consequent to esophageal-gastric or bariatric surgery, and insulin autoimmune syndrome. We also considered the possible role of UCS during endurance exercise performance. Lastly, we have discussed the dose requirement, the side effects, the limitations of UCS use, and the plausible mechanisms by which UCS could prevent hypoglycemia.
