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The recent discovery that genetically modified α cells can regenerate and convert into ß-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-ß-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into ß-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated ß-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in ß-like cell counts, suggestive of α-to-ß-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated ß-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.
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Diabetes Mellitus/tratamiento farmacológico , Células Secretoras de Glucagón/citología , Células Secretoras de Insulina/citología , Ácido gamma-Aminobutírico/administración & dosificación , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Células Secretoras de Glucagón/efectos de los fármacos , Humanos , Islotes Pancreáticos/citología , Masculino , Ratones , Proteínas del Tejido Nervioso , Ratas , Ratas Wistar , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The deleterious effect of chronic activation of the IL-1ß system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1ß in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1ß, in a glucose-dependent manner. Subsequently, IL-1ß contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1ß signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1ß and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1ß mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1ß and insulin in the regulation of both metabolism and immunity.
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Diabetes Mellitus Tipo 2/inmunología , Inflamación/inmunología , Células Secretoras de Insulina/fisiología , Interleucina-1beta/metabolismo , Macrófagos/fisiología , Animales , Células Cultivadas , Glucosa/metabolismo , Humanos , Inflamasomas/metabolismo , Insulina/metabolismo , Interleucina-1beta/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Periodo Posprandial , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
Multiple transcription factors have been shown to promote pancreatic ß-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced ß-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
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Regulación del Desarrollo de la Expresión Génica , Pez Cebra , Animales , Diferenciación Celular/genética , Ratones , Organogénesis/genética , Páncreas , Pez Cebra/genéticaRESUMEN
Pancreatic-islet inflammation contributes to the failure of ß cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1ß, and palmitate). IL-33 promoted ß cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the ß cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute ß cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.
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Insulina/metabolismo , Interleucina-33/farmacología , Islotes Pancreáticos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Células Mieloides/metabolismo , Tretinoina/metabolismo , Animales , Humanos , Inflamación/inmunología , Secreción de Insulina , Interleucina-33/biosíntesis , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Linfocitos/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Vitamina A/fisiologíaRESUMEN
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 , Islotes Pancreáticos , Humanos , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Interferones/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interferón gamma/metabolismo , Islotes Pancreáticos/metabolismoRESUMEN
AIMS/HYPOTHESIS: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. METHODS: CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1ß, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. RESULTS: CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. CONCLUSIONS/INTERPRETATION: These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. DATA AVAILABILITY: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 .
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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 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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Hiperparatiroidismo Primario , Neoplasia Endocrina Múltiple Tipo 1 , Humanos , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Hiperparatiroidismo Primario/cirugía , Hiperparatiroidismo Primario/complicaciones , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/etiología , Glándulas Paratiroides , Paratiroidectomía , RecurrenciaRESUMEN
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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BACKGROUND: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. APPROACH AND RESULTS: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others. CONCLUSION: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipoproteínas/metabolismo , Apolipoproteínas/metabolismo , Apolipoproteínas/farmacología , Triglicéridos/metabolismo , Hígado/metabolismo , Lipoproteínas VLDL/metabolismoRESUMEN
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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Cirugía Bariátrica , Endoscopía Gastrointestinal , Balón Gástrico , Obesidad , Humanos , Endoscopía Gastrointestinal/métodos , Obesidad/complicaciones , Adulto , Índice de Masa CorporalRESUMEN
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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Cirugía Bariátrica , Endoscopía Gastrointestinal , Obesidad , Humanos , Cirugía Bariátrica/efectos adversos , Endoscopía Gastrointestinal/normas , Endoscopía Gastrointestinal/métodos , Obesidad/complicaciones , Adulto , Balón Gástrico/efectos adversosRESUMEN
OBJECTIVE: To assess the relevance of concomitant laparoscopic metabolic bariatric surgery (MBS) and cholecystectomy. BACKGROUND: Because of the massive weight loss it induces, MBS is associated with an increase in the frequency of gallstones. However, no consensus yet exists on the risk-to-benefit ratio of a concomitant cholecystectomy (CC) during MBS to prevent long-term biliary complications. METHODS: This nationwide retrospective cohort research was conducted in 2 parts using information from a national administrative database (PMSI). The 90-day morbidity of MBS with or without CC was first compared in a matched trial (propensity score). Second, we observed medium-term biliary complication following MBS when no CC had been performed during MBS up to 9 years after MBS (minimum 18 months). RESULTS: Between 2013 and 2020, 289,627 patients had a sleeve gastrectomy (SG: 70%) or a gastric bypass (GBP: 30%). The principal indications of CC were symptomatic cholelithiasis (79.5%) or acute cholecystitis (3.6%). Prophylactic CC occurred only in 15.5% of the cases. In our matched-group analysis, we included 9323 patients in each arm. The complication rate at day 90 after surgery was greater in the CC arm [odds ratio=1.3 (1.2-1.5), P <0.001], independently of the reason of the CC. At 18 months, there was a 0.1% risk of symptomatic gallstone migration and a 0.08% risk of biliary pancreatitis. At 9 years, 20.5±0.52% of patients underwent an interval cholecystectomy. The likelihood of interval cholecystectomy decreased from 5.4% per year to 1.7% per year after the first 18 months the whole cohort, risk at 18 months of symptomatic gallstone migration was 0.1%, of pancreatitis 0.08%, and of angiocholitis 0.1%. CONCLUSION: CC during SG and GBP should be avoided. In the case of asymptomatic gallstones after MBS, prophylactic cholecystectomy should not be recommended.
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Cálculos Biliares , Derivación Gástrica , Obesidad Mórbida , Pancreatitis , Humanos , Derivación Gástrica/efectos adversos , Cálculos Biliares/epidemiología , Cálculos Biliares/cirugía , Cálculos Biliares/complicaciones , Estudios Retrospectivos , Obesidad Mórbida/cirugía , Obesidad Mórbida/complicaciones , Colecistectomía/efectos adversos , Gastrectomía/efectos adversos , Pancreatitis/cirugíaRESUMEN
OBJECTIVE: To investigate the way robotic assistance affected rate of complications in bariatric surgery at expert robotic and laparoscopic surgery facilities. BACKGROUND: While the benefits of robotic assistance were established at the beginning of surgical training, there is limited data on the robot's influence on experienced bariatric laparoscopic surgeons. METHODS: We conducted a retrospective study using the BRO clinical database (2008-2022) collecting data of patients operated on in expert centers. We compared the serious complication rate (defined as a Clavien score≥3) in patients undergoing metabolic bariatric surgery with or without robotic assistance. We used a directed acyclic graph to identify the variables adjustment set used in a multivariable linear regression, and a propensity score matching to calculate the average treatment effect (ATE) of robotic assistance. RESULTS: The study included 35,043 patients [24,428 sleeve gastrectomy (SG); 10,452 Roux-en-Y gastric bypass (RYGB); 163 single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S)], with 938 operated on with robotic assistance (801 SG; 134 RYGB; 3 SADI-S), among 142 centers. Overall, we found no benefit of robotic assistance regarding the risk of complications (average treatment effect=-0.05, P =0.794), with no difference in the RYGB+SADI group ( P =0.322) but a negative trend in the SG group (more complications, P =0.060). Length of hospital stay was decreased in the robot group (3.7±11.1 vs 4.0±9.0 days, P <0.001). CONCLUSIONS: Robotic assistance reduced the length of stay but did not statistically significantly reduce postoperative complications (Clavien score≥3) following either GBP or SG. A tendency toward an elevated risk of complications following SG requires more supporting studies.
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Cirugía Bariátrica , Derivación Gástrica , Laparoscopía , Obesidad Mórbida , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Estudios Retrospectivos , Puntaje de Propensión , Cirugía Bariátrica/efectos adversos , Derivación Gástrica/efectos adversos , Gastrectomía , Obesidad Mórbida/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: Describe the diagnostic workup and postoperative results for patients treated by adrenalectomy for primary aldosteronism in France from 2010 to 2020. BACKGROUND: Primary aldosteronism (PA) is the underlying cause of hypertension in 6% to 18% of patients. French and international guidelines recommend CT-scan and adrenal vein sampling as part of diagnostic workup to distinguish unilateral PA amenable to surgical treatment from bilateral PA that will require lifelong antialdosterone treatment.Adrenalectomy for unilateral primary aldosteronism has been associated with complete resolution of hypertension (no antihypertensive drugs and normal ambulatory blood pressure) in about one-third of patients and complete biological success in 94% of patients.These results are mainly based on retrospective studies with short follow-up and aggregated patients from various international high-volume centers. METHODS: Here we report results from the French-Speaking Association of Endocrine Surgery (AFCE) using the Eurocrine® Database. RESULTS: Over 11 years, 385 patients from 10 medical centers were eligible for analysis, accounting for >40% of adrenalectomies performed in France for primary aldosteronism over the period.Preoperative workup was consistent with guidelines for 40% of patients. Complete clinical success (CCS) at the last follow-up was achieved in 32% of patients, and complete biological success was not sufficiently assessed.For patients with 2 follow-up visits, clinical results were not persistent at 1 year for one-fifth of patients.Factors associated with CCS on multivariate analysis were body mass index, duration of hypertension, and number of antihypertensive drugs. CONCLUSIONS: These results call for an improvement in thorough preoperative workup and long-term follow-up of patients (clinical and biological) to early manage hypertension and/or PA relapse.
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Hiperaldosteronismo , Hipertensión , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirugía , Estudios Retrospectivos , Monitoreo Ambulatorio de la Presión Arterial/efectos adversos , Adrenalectomía/efectos adversos , Hipertensión/etiología , FranciaRESUMEN
In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.
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Diabetes Mellitus Tipo 1 , Trasplante de Islotes Pancreáticos , Trasplante de Páncreas , Humanos , Diabetes Mellitus Tipo 1/cirugía , Estudios Retrospectivos , Estudios de Cohortes , Insulina/uso terapéutico , Trasplante de Páncreas/métodos , Páncreas , Supervivencia de InjertoRESUMEN
BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
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1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Alanina Transaminasa/sangre , Apolipoproteínas E/genética , Variación Genética , Enfermedad del Hígado Graso no Alcohólico/genética , Biomarcadores/sangre , Europa (Continente) , Exoma , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Fenotipo , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , TranscriptomaRESUMEN
BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published "omics"-defined NASH signatures. APPROACH AND RESULTS: Here, we have explored transcriptomic profiles of livers starting from a 910-obese-patient cohort, which was further stratified based on stringent histological characterization, to define "NoNASH" and "NASH" patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF-calculated gene signatures identified NASH patients in independent cohorts with high accuracy. CONCLUSIONS: This large-scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.
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Enfermedad del Hígado Graso no Alcohólico/metabolismo , Femenino , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/complicaciones , Obesidad/metabolismo , Factores de Riesgo , Factores Sexuales , TranscriptomaRESUMEN
BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Estudios de Cohortes , Humanos , Esperanza de Vida , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Mutación , Neoplasias Pancreáticas/cirugía , ProbabilidadRESUMEN
Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk, Jnk3, Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3, CCND1 and CCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.