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OBJECTIVE: We used machine learning to develop and validate a multivariable algorithm allowing the accurate and early prediction of postoperative hypocalcemia risk. SUMMARY BACKGROUND: Post-operative hypocalcemia is frequent after total thyroidectomy. An early and accurate individualized prediction of the risk of hypocalcemia could guide the selective prescription of calcium supplementation only to patients most likely to present with hypocalcemia after total thyroidectomy. METHODS: This retrospective study enrolled all patients undergoing total thyroidectomy in a single referral center between November 2019 and march 2022 (derivation cohort) and april 2022 and September 2022 (validation cohort) . The primary study outcome was post-operative hypocalcemia (serum calcium under 80 mg/L). Exposures were multiple clinical and biological variables prospectively collected and analyzed with various machine learning methods, to develop and validate a multi variable prediction algorithm. RESULTS: Among 610 / 118 participants in the derivation / validation cohorts, 100 (16.4%) / 26 (22%) presented post-operative hypocalcemia. The most accurate prediction algorithm was obtained with random forest, and combined intraoperative parathyroid hormone measurements with three clinical variables (age, sex and body mass index), to calculate a postoperative hypocalcemia risk for each patient. After multiple cross validation, the area under the receiver operative characteristic curve was 0.902 (0.829-0.970) in the derivation cohort, and 0.928 (95% CI : 0.86; 0.97) in the validation cohort. Postoperative hypocalcemia risk values of 7% (low threshold) and 20% ( high threshold) had respectively a sensitivity of 92% and a negative likelihood ratio of 0.11, and a specificity of 90% and a positive of 7.6 for the prediction of postoperative hypocalcemia. CONCLUSION: Using machine learning, we developed and validated a simple multivariable model which allowed the accurate prediction of postoperative hypocalcemia. The resulting algorithm could be used at the point of care to guide clinical management after total thyroidectomy.
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OBJECTIVE: To provide a nationwide description of postoperative outcomes and analysis of prognostic factors following adrenalectomy for metastases. SUMMARY BACKGROUND DATA: Adrenal glands are a common site of metastases in many malignancies. Diagnosisof adrenal metastases is on the rise, leading to an increasing number of patient candidates for surgery without consensual management. METHODS: We conducted a population-based study between January 2012 and December 2022 using the French national health data system (SNDS) and the Eurocrine® registry (NCT03410394). The first database exhaustively covers all procedures carried out in France, while the second provides more clinical information on procedures and tumor characteristics, based on the experience of 11 specialized centers. RESULTS: From the SNDS, we extracted 2,515 patients who underwent adrenalectomy for secondary malignancy and 307 from the Eurocrine® database. The most common primary malignancies were lung cancer (n=1,203, 47.8%) and renal cancer (n=555, 22.1%). One-year survival was 84.3% (n=2,120). Thirty-day mortality and morbidity rates were, respectively, 1.3% (n=32) and 29.9% (n=753, including planned ICU stays). Radiotherapy within the year before adrenalectomy was significantly associated with higher 30-day major complication rates (P=0.039). In the Eurocrine® database, the proportion of laparoscopic procedures reached 85.3% without impairing resection completeness (R0: 92.9%). Factors associated with poor overall survival were presence of extra-adrenal metastases (HR=0.64; P=0.031) and incomplete resection (≥R1; HR=0.41; P=0.015). CONCLUSION: The number of patients who can receive local treatment for adrenal metastases is rising, and adrenalectomy is more often minimally invasive and has a low morbidity rate. Subsequent research should evaluate which patients would benefit from adrenal surgery.
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INTRODUCTION: Non-functioning pancreatic neuroendocrine tumor (NF-PanNET) ≤ 2 cm can be observed or resected. Surgery remains recommended for NF-PanNET > 2 cm but its extent, enucleation (EN) versus formal resection, remains controversial. METHODS: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short and long-term outcomes were compared according to tumor size on imaging ≤ 2 cm vs > 2 cm. RESULTS: 131patients underwent EN for NF-PanNET, including 103 (79.0%) ≤ 2 cm and 28 (21.0%) > 2 cm (extremes, 4-55 mm). Patients' characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs 17.9%, p= 1.00) with one death in NF-PanNET ≤ 2cm. Grade B/C pancreatic fistula were comparable (16.5% vs 10.7%, p= 0.850). In NF-PanNET > 2cm there were more pT2/3 stage tumors (85.7% vs 21.4%, p<0.001), similar rates of grade G2/3 tumors (25% vs 16.5%, p= 0.408) with a median Ki67 of 2 (IQR: 1-3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET > 2 cm (4 vs 3, p= 0.01). All were pN0. R0 resection rate (78.6% vs 82.5%, respectively; p= 0.670) was equivalent. Five-year overall (100% vs 99%, p= 0.602) and 10-year disease-free (96% vs 92%, respectively; p= 0.532) survivals were comparable. CONCLUSIONS: EN for selected NF-PanNET > 2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤ 2 cm.
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We postulated that T2D predisposes to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (methylationEPIC arrays) of the exocrine pancreas of 141 donors, assessing the impact of T2D. Epigenome-wide association study (EWAS) for T2D identified a hypermethylation in an enhancer of the Pancreatic-Lipase-Related-Protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (in 191K participants of the UKbiobank) associated with elevated glycemia and LDL-cholesterol. Mendelian Randomisation using 2.5M SNP OmniArrays in 111 donors evidenced that T2D was causal of PNLIPRP1 hypermethylation, which was causal for LDL-cholesterol. Further AR42J rat exocrine cell studies demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known pre-pancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and on exocrine pancreas function with potential implications for pancreatic diseases.
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Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.
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Tecido Adiposo , Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Fator 15 de Diferenciação de Crescimento , Hepatócitos , Macrófagos , Obesidade , Fator 15 de Diferenciação de Crescimento/metabolismo , Fator 15 de Diferenciação de Crescimento/genética , Animais , Obesidade/metabolismo , Obesidade/patologia , Hepatócitos/metabolismo , Masculino , Macrófagos/metabolismo , Camundongos , Humanos , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Fígado/patologia , Modelos Animais de Doenças , Transdução de SinaisRESUMO
This joint ASGE-ESGE guideline provides an evidence-based summary and recommendations regarding the role of endoscopic bariatric and metabolic therapies (EBMTs) in the management of obesity. The document was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. It evaluates the efficacy and safety of EBMT devices and procedures that currently have CE mark or FDA-clearance/approval, or that had been approved within five years of document development. The guideline suggests the use of EBMTs plus lifestyle modification in patients with a BMI of ≥30âkg/m2, or with a BMI of 27.0-29.9âkg/m2 with at least 1 obesity-related comorbidity. Furthermore, it suggests the utilization of intragastric balloons and devices for endoscopic gastric remodeling (EGR) in conjunction with lifestyle modification for this patient population.
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Cirurgia Bariátrica , Endoscopia Gastrointestinal , Obesidade , Humanos , Cirurgia Bariátrica/efeitos adversos , Endoscopia Gastrointestinal/normas , Endoscopia Gastrointestinal/métodos , Obesidade/complicações , Adulto , Balão Gástrico/efeitos adversosRESUMO
INTRODUCTION: The International Federation for Surgery for Obesity and Metabolic Disorders (IFSO) Global Registry aims to provide descriptive data about the caseload and penetrance of surgery for metabolic disease and obesity in member countries. The data presented in this report represent the key findings of the eighth report of the IFSO Global Registry. METHODS: All existing Metabolic and Bariatric Surgery (MBS) registries known to IFSO were invited to contribute to the eighth report. Aggregated data was provided by each MBS registry to the team at the Australia and New Zealand Bariatric Surgery Registry (ANZBSR) and was securely stored on a Redcap™ database housed at Monash University, Melbourne, Australia. Data was checked for completeness and analyzed by the IFSO Global Registry Committee. Prior to the finalization of the report, all graphs were circulated to contributors and to the global registry committee of IFSO to ensure data accuracy. RESULTS: Data was received from 24 national and 2 regional registries, providing information on 502,150 procedures. The most performed primary MBS procedure was sleeve gastrectomy, whereas the most performed revisional MBS procedure was Roux-en-Y gastric bypass. Asian countries reported people with lower BMI undergoing MBS along with higher rates of diabetes. Mortality was a rare event. CONCLUSION: Registries enable meaningful comparisons between countries on the demographics, characteristics, operation types and approaches, and trends in MBS procedures. Reported outcomes can be seen as flags of potential issues or relationships that could be studied in more detail in specific research studies.
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Cirurgia Bariátrica , Derivação Gástrica , Doenças Metabólicas , Obesidade Mórbida , Humanos , Obesidade Mórbida/cirurgia , Cirurgia Bariátrica/métodos , Obesidade/cirurgia , Derivação Gástrica/métodos , Doenças Metabólicas/cirurgia , Sistema de Registros , Gastrectomia/métodos , DemografiaRESUMO
This joint ASGE-ESGE guideline provides an evidence-based summary and recommendations regarding the role of endoscopic bariatric and metabolic therapies (EBMTs) in the management of obesity. The document was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. It evaluates the efficacy and safety of EBMT devices and procedures that currently have CE mark or FDA-clearance/approval, or that had been approved within five years of document development. The guideline suggests the use of EBMTs plus lifestyle modification in patients with a BMI of ≥ 30 kg/m2, or with a BMI of 27.0-29.9 kg/m2 with at least 1 obesity-related comorbidity. Furthermore, it suggests the utilization of intragastric balloons and devices for endoscopic gastric remodeling (EGR) in conjunction with lifestyle modification for this patient population.
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Cirurgia Bariátrica , Endoscopia Gastrointestinal , Balão Gástrico , Obesidade , Humanos , Endoscopia Gastrointestinal/métodos , Obesidade/complicações , Adulto , Índice de Massa CorporalRESUMO
BACKGROUND: The multicentre randomised trial YOMEGA (NCT02139813) comparing the one anastomosis gastric bypass (OAGB) with the Roux-en-Y gastric bypass (RYGB) confirmed the non-inferiority of OAGB on weight loss outcomes at 24 months. We aimed to report weight loss, metabolic, and safety outcomes at 5 years. METHODS: YOMEGA is a prospective, open-label, non-inferiority, randomised trial conducted at nine centres in France. Inclusion criteria were BMI of 40 kg/m2 or more, or 35 kg/m2 or more with comorbidities. Key exclusion criteria were severe gastro-oesophageal reflux disease or Barrett's oesophagus and previous bariatric surgery. Patients were randomly assigned (1 :1) to OAGB (one gastrojejunal anastomosis with a 200 cm biliopancreatic limb) or RYGB (with a 150 cm alimentary limb and a 50 cm biliary limb), stratified by centre, with blocks of variable size. The primary endpoint of this extension study was percentage excess BMI loss and was analysed in the per-protocol population, including patients with data who were operated on with the technique randomly assigned to them and excluding patients with major deviations from the protocol during the follow-up (change of surgical technique, death, or withdrawal of consent). Non-inferiority was concluded for the primary endpoint if the upper bound of the CI was less than the non-inferiority limit (7 percentage points). YOMEGA is registered with ClinicalTrials.gov, NCT02139813, and the 5-year follow-up of YOMEGA is registered with ClinicalTrials.gov, NCT05549271. FINDINGS: Between May 13, 2014, and March 2, 2016, 253 patients were randomly assigned to OAGB (n=129) or RYGB (n=124), and from these patients 114 in the OAGB group and 118 in the RYGB group were included in the per-protocol analysis. In the per-protocol population, at baseline, mean age was 43·0 years (SD 10·8), mean BMI was 44·0 kg/m2 (5·6), 54 (23%) patients were male and 178 (77%) were female; 55 (27%) of 207 patients had type 2 diabetes. After 5 years, mean percentage excess BMI loss was -75·6% (SD 28·1) in the OAGB group versus -71·4% (SD 29·8) in the RYGB group, confirming non-inferiority (mean difference -4·1% [90% CI -12·0 to 3·7], p=0·0099). Remission of type 2 diabetes was similar in both groups. Nutritional status did not differ; the most common adverse event was clinical gastro-oesophageal reflux disease, occurring in 27 (41%) of 66 patients in the OAGB group versus 14 (18%) of 76 patients in the RYGB group (p=0·0030). Among serious adverse events, ten (8%) of 127 patients converted from OAGB to RYGB. 171 (68%) of 253 patients were followed up. INTERPRETATION: OAGB was not inferior to RYGB regarding percentage excess BMI loss at 5 years with similar metabolic outcomes. The high rate of clinical gastro-oesophageal reflux disease after OAGB raises questions about its long-term consequences, which need to be further investigated. FUNDING: Medtronic.
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Diabetes Mellitus Tipo 2 , Derivação Gástrica , Refluxo Gastroesofágico , Obesidade Mórbida , Adulto , Feminino , Humanos , Masculino , Diabetes Mellitus Tipo 2/cirurgia , Diabetes Mellitus Tipo 2/etiologia , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Refluxo Gastroesofágico/etiologia , Obesidade Mórbida/cirurgia , Estudos Prospectivos , Redução de PesoRESUMO
BACKGROUND: Prophylactic central neck dissection (pCND) remains controversial during the initial surgery for preoperative and intraoperative node-negative (cN0) papillary thyroid carcinoma (PTC). METHODS: Patients undergoing thyroidectomy with or without pCND (Nx) for PTC in nine French surgical departments, registered in the EUROCRINE® national data in France between January 2015 and June 2021, were included in a cohort study. Demographic and clinicopathological characteristics, complications, and recurrence rates were compared using multivariate regression analysis. RESULTS: A total of 1905 patients with cN0 PTC were enrolled, including 1534 who had undergone pCND and 371 who hadn't (Nx). Of these, 1546 (81.2%) were female, and the median age was 49 years (range: 15-89 years). Patients who had undergone pCND were more likely to have multifocal tumors (n = 524 [34.2%] vs. n = 68 [18.3%], p < .001) and larger tumors (15.3 vs. 10.2 mm, p = .01) than patients with Nx. Of the patients with pCND, 553 (36%) had positive central LN (N1a), with a median of 1 N1 (IQR 0-5). pCND was associated with a higher temporary hypocalcemia rate (n = 25 [8%] vs. n = 15 [4%], p < .001). The rates of permanent hypocalcemia and temporary and permanent recurrent laryngeal nerve (RLN) palsy were not significantly different between the two groups (p > .2). After adjusting for covariates (age, sex, multifocality, and pathological T stage) in a multivariable Cox PH model, the performance of lymph node dissection (pCND vs. no-pCND) was not associated with PTC recurrence (p = .2). CONCLUSION: pCND in PTC does not reduce recurrence and is associated with a two-fold increase in the incidence of transient hypoparathyroidism. These data should be considered while issuing further guidelines regarding the treatment of patients with cN0 PTC.
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Carcinoma Papilar , Hipocalcemia , Neoplasias da Glândula Tireoide , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Esvaziamento Cervical/efeitos adversos , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Estudos de Coortes , Hipocalcemia/epidemiologia , Hipocalcemia/etiologia , Hipocalcemia/prevenção & controle , Carcinoma Papilar/cirurgiaRESUMO
AIMS/HYPOTHESIS: The proinflammatory cytokines IFN-α, IFN-γ, IL-1ß and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. METHODS: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. RESULTS: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1ß and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. CONCLUSIONS/INTERPRETATION: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.
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Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Humanos , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Interferons/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama/metabolismo , Ilhotas Pancreáticas/metabolismoRESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci, we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.
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BACKGROUND & AIMS: The value of non-invasive tests for monitoring the resolution of significant liver fibrosis after treatment is poorly investigated. We compared the performances of six non-invasive tests to predict the resolution of significant fibrosis after bariatric surgery. METHODS: Participants were individuals with obesity submitted to needle liver biopsy at the time of bariatric surgery, and 12 and/or 60 months after surgery. We calculated the fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), Hepatic fibrosis score (HFS), Fibrotic NASH index (FNI), and Liver risk score (LRS) at each time point, and compared their performances for predicting significant fibrosis (F ≥ 2) and its resolution following surgery. RESULTS: At baseline, 2436 patients had liver biopsy, including 261 (10.7 %) with significant fibrosis. Overall, 672 patients had pre- and post-operative biopsies (564 at M12 and 328 at M60). The fibrosis stage decreased at M12 and M60 (p < 0.001 vs M0). Resolution of significant fibrosis occurred in 58/121 (47.9 %) at M12 and 32/50 (64 %) at M60. The mean value of all tests decreased after surgery, except for FIB-4. Performances for predicting fibrosis resolution was higher at M60 than at M12 for all tests, and maximal at M60 for FNI and LRS: area under the curve 0.843 (95%CI 0.71-0.95) and 0.92 (95%CI 0.84-1.00); positive likelihood ratio 3.75 (95 % CI 1.33-10.59) and 4.58 (95 % CI 1.65-12.70), respectively. CONCLUSIONS: Results showed the value and limits of non-invasive tests for monitoring the evolution of liver fibrosis after an intervention. Following bariatric surgery, the best performances to predict the resolution of significant fibrosis were observed at M60 with tests combining liver and metabolic traits, namely FNI and LRS.
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Cirurgia Bariátrica , Hepatopatia Gordurosa não Alcoólica , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/cirurgia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , FibroseRESUMO
OBJECTIVE: To assess recurrence according to the type of surgery for primary hyperparathyroidism (pHPT) in multiple endocrine neoplasia type 1 ( MEN1 ) patients and to identify the risk factors for recurrence after the initial surgery. BACKGROUND: In MEN1 patients, pHPT is multiglandular, and the optimal extent of initial parathyroid resection influences the risk of recurrence. METHODS: MEN1 patients who underwent initial surgery for pHPT between 1990 and 2019 were included. Persistence and recurrence rates after less than subtotal parathyroidectomy (LTSP) and subtotal parathyroidectomy (STP) were analyzed. Patients with total parathyroidectomy with reimplantation were excluded. RESULTS: Five hundred seventeen patients underwent their first surgery for pHPT: 178 had LTSP (34.4%) and 339 STP (65.6%). The recurrence rate was significantly higher after LTSP (68.5%) than STP (45%) ( P < 0.001). The median time to recurrence after pHPT surgery was significantly shorter after LTSP than after STP: 4.25 (1.2-7.1) versus 7.2 (3.9-10.1) years ( P < 0.001). A mutation in exon 10 was an independent risk factor of recurrence after STP (odds ratio = 2.19; 95% CI: 1.31; 3.69; P = 0.003). The 5 and 10-year recurrent pHPT probabilities were significantly higher in patients after LTSP with a mutation in exon 10 (37% and 79% vs 30% and 61%; P = 0.016). CONCLUSIONS: Persistence, recurrence of pHPT, and reoperation rate are significantly lower after STP than LTSP in MEN1 patients. Genotype seems to be associated with the recurrence of pHPT. A mutation in exon 10 is an independent risk factor for recurrence after STP, and LTSP may not be recommended when exon 10 is mutated.
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Hiperparatireoidismo Primário , Neoplasia Endócrina Múltipla Tipo 1 , Humanos , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/complicações , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Glândulas Paratireoides , Paratireoidectomia , RecidivaRESUMO
OBJECTIVE: Randomized controlled trials (RCTs) have demonstrated the superiority of metabolic surgery (MS) over medical therapy (MT) in patients with obesity and type 2 diabetes, leading, to a joint statement in 2016 proposing MS to patients with class I obesity and uncontrolled glycemia. Yet, these RCTs included few patients with class I obesity (body mass index 30-35 kg/m2) and even fewer patients with overweight. Our aim was to provide an updated systematic review (SR) with meta-analysis (MA) of RCTs reporting diabetes remission (DR) after MS in these patients. RESEARCH DESIGN AND METHODS: We included in the SR with MA only RCTs with at least 24-month follow-up found in Medline, Cochrane Library, Embase, and LiSSA between January 2008 and September 2022 comparing DR post-MT versus post-MS. We calculated relative risk (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel random-effects approach to examine differences in DR between patients allocated to MS versus MT. RESULTS: DR was significantly higher in MS versus MT after 36 months' follow-up in patients with obesity (RR = 6.65 [95 %CI 2.24;19.79]; I² = 27 %; 5 trials, 404 patients), but also specifically in patients with class I obesity (RR = 5.27 [1.31;21.23]; I² = 0 %; 4 trials, 80 patients). Furthermore, and in line with previous results, all additional MAs performed in patients with obesity in this work favor MS (specifically Roux-en-Y gastric bypass) over MT at 24, 36 (only) and 60 months of follow-up. CONCLUSIONS: Although the data available in patients with class I obesity and type 2 diabetes remains limited, MA shows higher rates of DR after MS compared with MT after 36 months' follow-up in these patients. Consequently, the French National Authority for Health French (HAS) recommends MS for these patients.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Derivação Gástrica , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/cirurgia , Derivação Gástrica/métodos , Diabetes Mellitus Tipo 2/cirurgia , SobrepesoRESUMO
Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.
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Insulin secretion from pancreatic ß cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on ß cells. The granin protein VGF has dual roles in ß cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and ß-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of ß-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into ß cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on ß-cell maintenance. These findings demonstrate a novel autocrine mechanism of ß-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.
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Sistema A de Transporte de Aminoácidos , Células Secretoras de Insulina , Proteínas do Tecido Nervoso , Animais , Humanos , Camundongos , Glucose/metabolismo , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sistemas Neurossecretores/metabolismo , Peptídeos/metabolismo , Sistema A de Transporte de Aminoácidos/metabolismoRESUMO
In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Humanos , Camundongos , Masculino , Ratos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Células Secretoras de Insulina/metabolismo , Amiloide/metabolismo , Ilhotas Pancreáticas/metabolismoRESUMO
BACKGROUND: Although bariatric surgery (BS) is recommended for patients with type 2 diabetes (T2D) and moderate to severe obesity, only approximately 2% of patients undergo surgery. OBJECTIVE: To compare the knowledge and perception of BS with that of other treatments for diabetes among patients with diabetes. SETTING: French social media platforms. METHODS: A self-administered questionnaire was distributed from May 13 to June 3, 2020, via different French social media, including patients with T2D (main target), and patients with type 1 diabetes (control population). Different profiles of reluctance to BS were identified using a factorial analysis. RESULTS: Of the 4481 responders (50.4% women, 33.9% aged over 65), 60% had T2D. Of the 1736 patients who had heard of BS (38.7%), 1493 declared they never addressed it with their physician. Among T2D patients, BS is the treatment that elicits the most negative response, with more than 10% showing reluctance. Four reluctance profiles were identified: (1) cluster 1 (43.4%), fear of consequences on their eating habits and irreversibility of the procedure; (2) cluster 2 (34.9%), fear of poorer diabetes control; (3) cluster 3 (9.3%), fear of surgical risk; and (4) cluster 4 (12.4%), fear of side effects. In all clusters, the opinion of their physician would be the most important factor to change their mind. CONCLUSION: Bariatric surgery for T2D is rarely addressed in routine medical visits. Fear of operative risks and irreversibility of the procedure largely explains the reluctance to BS. Information and education campaigns on the benefit of metabolic surgery for patients with T2D remain necessary.