Ida M Gether, Emilie Bahne, Henriette H Nerild, Jens F Rehfeld, Bolette Hartmann, Jens J Holst, Tina Vilsbøll, David P Sonne, Filip K Knop
Objective: Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility.
Methods: In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline.
Results: Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043).
Conclusion: Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.
{"title":"Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling.","authors":"Ida M Gether, Emilie Bahne, Henriette H Nerild, Jens F Rehfeld, Bolette Hartmann, Jens J Holst, Tina Vilsbøll, David P Sonne, Filip K Knop","doi":"10.1093/ejendo/lvae033","DOIUrl":"10.1093/ejendo/lvae033","url":null,"abstract":"<p><strong>Objective: </strong>Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility.</p><p><strong>Methods: </strong>In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline.</p><p><strong>Results: </strong>Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043).</p><p><strong>Conclusion: </strong>Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Theresa Wittrien, Alban Ziegler, Anne Rühle, Svenja Stomberg, Ruben Meyer, Dominique Bonneau, Patrice Rodien, Delphine Prunier-Mirebeau, Régis Coutant, Sönke Behrends
Purpose: The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene.
Methods: An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/β1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy.
Results: The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged.
Conclusion: Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.
{"title":"Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction.","authors":"Theresa Wittrien, Alban Ziegler, Anne Rühle, Svenja Stomberg, Ruben Meyer, Dominique Bonneau, Patrice Rodien, Delphine Prunier-Mirebeau, Régis Coutant, Sönke Behrends","doi":"10.1093/ejendo/lvae030","DOIUrl":"https://doi.org/10.1093/ejendo/lvae030","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene.</p><p><strong>Methods: </strong>An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/β1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy.</p><p><strong>Results: </strong>The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged.</p><p><strong>Conclusion: </strong>Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olaf M Dekkers, Kristina Laugesen, Rolf H H Groenwold
Directed acyclic graphs (DAGs), or causal diagrams, are graphical representations of causal structures that can be used in medical research to understand and illustrate potential bias, including bias arising from confounding, selection, and misclassification. Further, they provide guidance for researchers about how to address a potential bias.
{"title":"Directed acyclic graphs in clinical research.","authors":"Olaf M Dekkers, Kristina Laugesen, Rolf H H Groenwold","doi":"10.1093/ejendo/lvae032","DOIUrl":"10.1093/ejendo/lvae032","url":null,"abstract":"<p><p>Directed acyclic graphs (DAGs), or causal diagrams, are graphical representations of causal structures that can be used in medical research to understand and illustrate potential bias, including bias arising from confounding, selection, and misclassification. Further, they provide guidance for researchers about how to address a potential bias.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Margaux Laulhé, Emmanuelle Kuhn, Jérôme Bouligand, Larbi Amazit, Julie Perrot, Elise Lebigot, Peter Kamenickỷ, Marc Lombès, Jérôme Fagart, Say Viengchareun, Laetitia Martinerie
Objective: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome.
Methods: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling.
Results: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop.
Conclusion: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.
{"title":"A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance.","authors":"Margaux Laulhé, Emmanuelle Kuhn, Jérôme Bouligand, Larbi Amazit, Julie Perrot, Elise Lebigot, Peter Kamenickỷ, Marc Lombès, Jérôme Fagart, Say Viengchareun, Laetitia Martinerie","doi":"10.1093/ejendo/lvae031","DOIUrl":"https://doi.org/10.1093/ejendo/lvae031","url":null,"abstract":"<p><strong>Objective: </strong>Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome.</p><p><strong>Methods: </strong>We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling.</p><p><strong>Results: </strong>The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop.</p><p><strong>Conclusion: </strong>This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140861691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Claudia Saglia, Francesca Arruga, Caterina Scolari, Silvia Kalantari, Serena Albanese, Valeria Bracciamà, Angelo Corso Faini, Giulia Brach Del Prever, Maria Luca, Carmelo Romeo, Fiorenza Mioli, Martina Migliorero, Daniele Tessaris, Diana Carli, Antonio Amoroso, Tiziana Vaisitti, Luisa De Sanctis, Silvia Deaglio
Objective: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants.
Design and methods: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs.
Results: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT.
Conclusions: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.
{"title":"Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia.","authors":"Claudia Saglia, Francesca Arruga, Caterina Scolari, Silvia Kalantari, Serena Albanese, Valeria Bracciamà, Angelo Corso Faini, Giulia Brach Del Prever, Maria Luca, Carmelo Romeo, Fiorenza Mioli, Martina Migliorero, Daniele Tessaris, Diana Carli, Antonio Amoroso, Tiziana Vaisitti, Luisa De Sanctis, Silvia Deaglio","doi":"10.1093/ejendo/lvae035","DOIUrl":"10.1093/ejendo/lvae035","url":null,"abstract":"<p><strong>Objective: </strong>The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants.</p><p><strong>Design and methods: </strong>To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs.</p><p><strong>Results: </strong>Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT.</p><p><strong>Conclusions: </strong>This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lea Tschaidse, Sophie Wimmer, Hanna F Nowotny, Matthias K Auer, Christian Lottspeich, Ilja Dubinski, Katharina A Schiergens, Heinrich Schmidt, Marcus Quinkler, Nicole Reisch
Objective: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents.
Design: Prospective, observational study.
Methods: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed.
Results: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026).
Conclusion: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.
{"title":"Frequency of stress dosing and adrenal crisis in paediatric and adult patients with congenital adrenal hyperplasia: a prospective study.","authors":"Lea Tschaidse, Sophie Wimmer, Hanna F Nowotny, Matthias K Auer, Christian Lottspeich, Ilja Dubinski, Katharina A Schiergens, Heinrich Schmidt, Marcus Quinkler, Nicole Reisch","doi":"10.1093/ejendo/lvae023","DOIUrl":"https://doi.org/10.1093/ejendo/lvae023","url":null,"abstract":"<p><strong>Objective: </strong>Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents.</p><p><strong>Design: </strong>Prospective, observational study.</p><p><strong>Methods: </strong>Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed.</p><p><strong>Results: </strong>In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026).</p><p><strong>Conclusion: </strong>The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andreas H Lange, Miriam G Pedersen, Anne-Marie Ellegaard, Henriette H Nerild, Andreas Brønden, David P Sonne, Filip K Knop
Cholelithiasis and cholecystitis affect individuals of all ages and are often treated by surgical removal of the gallbladder (cholecystectomy), which is considered a safe, low-risk procedure. Nevertheless, recent findings show that bile and its regulated storage and excretion may have important metabolic effects and that cholecystectomy is associated with several metabolic diseases postoperatively. Bile acids have long been known as emulsifiers essential to the assimilation of lipids and absorption of lipid-soluble vitamins, but more recently, they have also been reported to act as metabolic signaling agents. The nuclear receptor, farnesoid X receptor (FXR), and the G protein-coupled membrane receptor, Takeda G protein-coupled receptor 5 (TGR5), are specific to bile acids. Through activation of these receptors, bile acids control numerous metabolic functions. Cholecystectomy affects the storage and excretion of bile acids, which in turn may influence the activation of FXR and TGR5 and their effects on metabolism including processes leading to metabolic conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic syndrome. Here, with the aim of elucidating mechanisms behind cholecystectomy-associated dysmetabolism, we review studies potentially linking cholecystectomy and bile acid-mediated metabolic effects and discuss possible pathophysiological mechanisms behind cholecystectomy-associated dysmetabolism.
胆石症和胆囊炎影响着各个年龄段的人,通常通过手术切除胆囊(胆囊切除术)来治疗,这被认为是一种安全、低风险的手术。然而,最近的研究结果表明,胆汁及其调节储存和排泄可能会对新陈代谢产生重要影响,胆囊切除术术后与多种新陈代谢疾病相关。众所周知,胆汁酸是同化脂质和吸收脂溶性维生素所必需的乳化剂,但最近也有报道称胆汁酸是代谢信号转导物。核受体法尼类固醇 X 受体(FXR)和 G 蛋白偶联膜受体武田 G 蛋白偶联受体 5(TGR5)对胆汁酸具有特异性。通过激活这些受体,胆汁酸可控制多种代谢功能。胆囊切除术会影响胆汁酸的储存和排泄,进而影响 FXR 和 TGR5 的活化及其对新陈代谢的影响,包括导致代谢功能障碍相关性脂肪肝和代谢综合征等代谢疾病的过程。在此,为了阐明胆囊切除术相关代谢紊乱背后的机制,我们回顾了可能将胆囊切除术和胆汁酸介导的代谢效应联系起来的研究,并讨论了胆囊切除术相关代谢紊乱背后可能的病理生理机制。
{"title":"The bile-gut axis and metabolic consequences of cholecystectomy.","authors":"Andreas H Lange, Miriam G Pedersen, Anne-Marie Ellegaard, Henriette H Nerild, Andreas Brønden, David P Sonne, Filip K Knop","doi":"10.1093/ejendo/lvae034","DOIUrl":"10.1093/ejendo/lvae034","url":null,"abstract":"<p><p>Cholelithiasis and cholecystitis affect individuals of all ages and are often treated by surgical removal of the gallbladder (cholecystectomy), which is considered a safe, low-risk procedure. Nevertheless, recent findings show that bile and its regulated storage and excretion may have important metabolic effects and that cholecystectomy is associated with several metabolic diseases postoperatively. Bile acids have long been known as emulsifiers essential to the assimilation of lipids and absorption of lipid-soluble vitamins, but more recently, they have also been reported to act as metabolic signaling agents. The nuclear receptor, farnesoid X receptor (FXR), and the G protein-coupled membrane receptor, Takeda G protein-coupled receptor 5 (TGR5), are specific to bile acids. Through activation of these receptors, bile acids control numerous metabolic functions. Cholecystectomy affects the storage and excretion of bile acids, which in turn may influence the activation of FXR and TGR5 and their effects on metabolism including processes leading to metabolic conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic syndrome. Here, with the aim of elucidating mechanisms behind cholecystectomy-associated dysmetabolism, we review studies potentially linking cholecystectomy and bile acid-mediated metabolic effects and discuss possible pathophysiological mechanisms behind cholecystectomy-associated dysmetabolism.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inge A L P van Beijsterveldt, Bertrand D van Zelst, Demi J Dorrepaal, Sjoerd A A van den Berg, Anita C S Hokken-Koelega
Importance: Poly- and perfluoroalkyl substances (PFASs) are nondegradable, man-made chemicals. They accumulate in humans with potential harmful effects, especially in susceptible periods of human development, such as the first months of life. We found that, in our cohort, exclusively breastfed (EBF) infants had 3 times higher PFAS plasma levels compared with exclusively formula-fed (EFF) infants at the age of 3 months. Thus, PFASs could potentially reduce the health benefits of breastfeeding.
Objective: We investigated the associations between PFAS levels at the age of 3 months and accelerated gain in fat mass during the first 6 months of life, body composition at 2 years, and whether these associations differ between EBF and EFF infants.
Setting: In 372 healthy term-born infants, we longitudinally assessed anthropometrics, body composition (by air-displacement plethysmography and dual-energy X-ray absorptiometry), and visceral and subcutaneous fat (by abdominal ultrasound) until the age of 2 years.
Measures: The plasma levels of 5 individual PFASs were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry at the age of 3 months.
Main outcomes: We studied associations between PFAS levels and outcomes using multiple regression analyses.
Results: Higher early life plasma perfluorooctanoic acid and total PFAS levels were associated with an accelerated gain in fat mass percentage [FM%; >0.67 SD score (SDS)] during the first 6 months of life. Higher early life PFAS levels were associated with lower fat-free mass (FFM) SDS at the age of 2 years, but not with total FM% SDS at 2 years. Furthermore, we found opposite effects of PFAS levels (negative) and exclusive breastfeeding (positive) at the age of 3 months on FFM SDS at 2 years.
Conclusion: Higher PFAS levels in early life are associated with accelerated gains in FM% during the first 6 months of life and with lower FFM SDS at the age of 2 years, which have been associated with an unfavorable body composition and metabolic profile later in life. Our findings warrant further research with longer follow-up times.
{"title":"Early life poly- and perfluoroalkyl substance levels and adiposity in the first 2 years of life.","authors":"Inge A L P van Beijsterveldt, Bertrand D van Zelst, Demi J Dorrepaal, Sjoerd A A van den Berg, Anita C S Hokken-Koelega","doi":"10.1093/ejendo/lvae039","DOIUrl":"10.1093/ejendo/lvae039","url":null,"abstract":"<p><strong>Importance: </strong>Poly- and perfluoroalkyl substances (PFASs) are nondegradable, man-made chemicals. They accumulate in humans with potential harmful effects, especially in susceptible periods of human development, such as the first months of life. We found that, in our cohort, exclusively breastfed (EBF) infants had 3 times higher PFAS plasma levels compared with exclusively formula-fed (EFF) infants at the age of 3 months. Thus, PFASs could potentially reduce the health benefits of breastfeeding.</p><p><strong>Objective: </strong>We investigated the associations between PFAS levels at the age of 3 months and accelerated gain in fat mass during the first 6 months of life, body composition at 2 years, and whether these associations differ between EBF and EFF infants.</p><p><strong>Setting: </strong>In 372 healthy term-born infants, we longitudinally assessed anthropometrics, body composition (by air-displacement plethysmography and dual-energy X-ray absorptiometry), and visceral and subcutaneous fat (by abdominal ultrasound) until the age of 2 years.</p><p><strong>Measures: </strong>The plasma levels of 5 individual PFASs were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry at the age of 3 months.</p><p><strong>Main outcomes: </strong>We studied associations between PFAS levels and outcomes using multiple regression analyses.</p><p><strong>Results: </strong>Higher early life plasma perfluorooctanoic acid and total PFAS levels were associated with an accelerated gain in fat mass percentage [FM%; >0.67 SD score (SDS)] during the first 6 months of life. Higher early life PFAS levels were associated with lower fat-free mass (FFM) SDS at the age of 2 years, but not with total FM% SDS at 2 years. Furthermore, we found opposite effects of PFAS levels (negative) and exclusive breastfeeding (positive) at the age of 3 months on FFM SDS at 2 years.</p><p><strong>Conclusion: </strong>Higher PFAS levels in early life are associated with accelerated gains in FM% during the first 6 months of life and with lower FFM SDS at the age of 2 years, which have been associated with an unfavorable body composition and metabolic profile later in life. Our findings warrant further research with longer follow-up times.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linus Haberbosch, James MacFarlane, Olympia Koulouri, Daniel Gillett, Andrew S Powlson, Sue Oddy, David J Halsall, Kevin A Huynh, Jonathan Jones, Heok K Cheow, Joachim Spranger, Knut Mai, Christian J Strasburger, Richard J Mannion, Mark Gurnell
Background: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly.
Methods: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%).
Results: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery.
Conclusion: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.
{"title":"Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.","authors":"Linus Haberbosch, James MacFarlane, Olympia Koulouri, Daniel Gillett, Andrew S Powlson, Sue Oddy, David J Halsall, Kevin A Huynh, Jonathan Jones, Heok K Cheow, Joachim Spranger, Knut Mai, Christian J Strasburger, Richard J Mannion, Mark Gurnell","doi":"10.1093/ejendo/lvae028","DOIUrl":"10.1093/ejendo/lvae028","url":null,"abstract":"<p><strong>Background: </strong>L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly.</p><p><strong>Methods: </strong>A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%).</p><p><strong>Results: </strong>A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery.</p><p><strong>Conclusion: </strong>In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Riedmeier, Sonir R R Antonini, Silvia Brandalise, Tatiana El Jaick B Costa, Camila M Daiggi, Bonald C de Figueiredo, Ronald R de Krijger, Karla Emília De Sá Rodrigues, Cheri Deal, Jaydira Del Rivero, Gernot Engstler, Martin Fassnacht, Gabriela C Fernandes Luiz Canali, Carlos A Fernandes Molina, Elmas Nazli Gonc, Melis Gültekin, Harm R Haak, Tulay Guran, Emile J Hendriks Allaird, Jan Idkowiak, Michaela Kuhlen, David Malkin, Jagdish Prasad Meena, Christina Pamporaki, Emilia Pinto, Soraya Puglisi, Raul C Ribeiro, Lester D R Thompson, Bilgehan Yalcin, Max Van Noesel, Verena Wiegering
Objective: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.
Methods: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements.
Results: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required.
Conclusions: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
{"title":"International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.","authors":"Maria Riedmeier, Sonir R R Antonini, Silvia Brandalise, Tatiana El Jaick B Costa, Camila M Daiggi, Bonald C de Figueiredo, Ronald R de Krijger, Karla Emília De Sá Rodrigues, Cheri Deal, Jaydira Del Rivero, Gernot Engstler, Martin Fassnacht, Gabriela C Fernandes Luiz Canali, Carlos A Fernandes Molina, Elmas Nazli Gonc, Melis Gültekin, Harm R Haak, Tulay Guran, Emile J Hendriks Allaird, Jan Idkowiak, Michaela Kuhlen, David Malkin, Jagdish Prasad Meena, Christina Pamporaki, Emilia Pinto, Soraya Puglisi, Raul C Ribeiro, Lester D R Thompson, Bilgehan Yalcin, Max Van Noesel, Verena Wiegering","doi":"10.1093/ejendo/lvae038","DOIUrl":"10.1093/ejendo/lvae038","url":null,"abstract":"<p><strong>Objective: </strong>Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.</p><p><strong>Methods: </strong>A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements.</p><p><strong>Results: </strong>We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required.</p><p><strong>Conclusions: </strong>The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}