Publications by authors named "Bertrand Cariou"

189 Publications

Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function.

Atherosclerosis 2021 Apr 20. Epub 2021 Apr 20.

Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France. Electronic address:

Background And Aims: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function.

Methods: We assessed PCSK9 and insulin colocalization in human pancreatic sections by epifluorescent and confocal microscopy. We also investigated the expression and the function of PCSK9 in the human EndoC-βH1 beta cell line, by ELISA and flow cytometry, respectively. PCSK9 was inhibited with Alirocumab or siRNA. LDLR expression and LDL uptake were assessed by flow cytometry.

Results: PCSK9 was expressed and secreted from beta cells isolated from human pancreas as well as from EndoC-βH1 cells. PCSK9 secretion was enhanced by statin treatment. Recombinant PCSK9 decreased LDLR abundance at the surface of these cells, an effect abrogated by Alirocumab. Alirocumab as well as PCSK9 silencing increased LDLR expression at the surface of EndoC-βH1 cells. Neither exogenous PCSK9, nor Alirocumab, nor PCSK9 silencing significantly altered glucose-stimulated insulin secretion (GSIS) from these cells. High-low density lipoproteins (LDL) concentrations decreased GSIS, but the addition of PCSK9 or its inhibition did not modulate this phenomenon.

Conclusions: While PCSK9 regulates LDLR abundance in beta cells, inhibition of exogenous or endogenous PCSK9 does not appear to significantly impact insulin secretion. This is reassuring for the safety of PCSK9 inhibitors in terms of beta cell function.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.044DOI Listing
April 2021

Large-scale screening of lipase acid deficiency in at risk population.

Clin Chim Acta 2021 Apr 20;519:64-69. Epub 2021 Apr 20.

Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France; University Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale UMR 938, Paris, France.

Background: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD).

Methods: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots.

Results: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel.

Conclusion: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.
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http://dx.doi.org/10.1016/j.cca.2021.04.005DOI Listing
April 2021

Impact of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism: A narrative review.

Nutr Metab Cardiovasc Dis 2021 04 5;31(4):981-996. Epub 2021 Jan 5.

Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif, CHU de Nantes, Nantes, France; Université de Nantes, Quai de Tourville, 44000, Nantes, France; L'institut du Thorax, UNIV NANTES, CNRS, INSERM, CHU de Nantes, Nantes, France. Electronic address:

Aims: Primary hyperparathyroidism (PHPT), one of the most frequent endocrine disorders, is not only associated with bone and kidney disorders but also with increased cardiovascular risk. This cardiovascular risk is not part of the indication for surgery owing to discordant evidence of the effects of parathyroidectomy (PTX), especially in mild PHPT which is the most common presentation of PHPT. This literature review focuses on the effects of PTX on the cardiovascular risk in PHPT. The MEDLINE database was searched via the PubMed interface, selecting relevant articles published after 1990 in English.

Data Synthesis: In the most recent series, PTX appeared to have a positive impact on cardiovascular morbidity and mortality. Surgery improves arterial hypertension, markers of glucose homeostasis, vascular and cardiac remodeling and electrocardiographic impairments due to classical PHPT. However, the results of surgery on mild PHPT are conflicting.

Conclusions: PTX seems to improve cardiovascular risk in patients presenting the classical form of PHPT. This improvement is correlated with preoperative serum calcium and/or PTH level, depending on the cardiovascular risk factor. However, many aspects of this improvement are not fully understood. Future studies should assess the effects of PTX on nocturnal hypertension, cardiac morphology and functions. The results for mild PHPT are conflicting owing to the limited size of the cohorts included in studies and the lack of randomized trials. Surgery is not currently recommended for patients presenting mild PHPT based on the cardiovascular risk and more studies are needed to better understand the interest of PTX on cardiovascular outcomes.
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http://dx.doi.org/10.1016/j.numecd.2020.12.029DOI Listing
April 2021

Effect of sotagliflozin as an adjunct to insulin therapy on blood pressure and arterial stiffness in adults with type 1 diabetes: A post hoc pooled analysis of inTandem1 and inTandem2.

Diab Vasc Dis Res 2021 Jan-Feb;18(1):1479164121995928

Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA.

Objective: Evaluate the effect of sotagliflozin, a dual inhibitor of sodium glucose cotransporter (SGLT) 1 and 2, on arterial stiffness in patients with type 1 diabetes (T1D) treated with sotagliflozin as adjunct to optimized insulin therapy.

Methods: In this post hoc analysis, indirect markers of arterial stiffness, including pulse pressure, mean arterial pressure (MAP), and double product, were calculated using observed systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at 24 weeks using data from a pooled patient population from the inTandem1 and inTandem2 randomized controlled trials ( = 1575).

Results: Baseline characteristics were similar among groups. Relative to placebo at Week 24, sotagliflozin 200 mg and 400 mg reduced SBP by 2.03 mm Hg (95% CI -3.30 to -0.75;  = 0.0019) and 2.85 mm Hg (-4.12 to -1.57;  < 0.0001), respectively. DBP decreased by 1.1 and 0.9 mm Hg, MAP by 1.4 and 1.6 mm Hg, and double product by 202.5 and 221.1 bpm × mm Hg, respectively ( < 0.05 for all). No increases in heart rate were observed.

Conclusion: In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance.
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http://dx.doi.org/10.1177/1479164121995928DOI Listing
February 2021

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

Diabetologia 2021 04 17;64(4):778-794. Epub 2021 Feb 17.

Service d'Endocrinologie, Diabétologie et Maladies Métaboliques, Groupe Hospitalier Mutualiste Les Portes du Sud, Venissieux, France.

Aims/hypothesis: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19).

Methods: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days.

Results: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors.

Conclusions/interpretation: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period.

Trial Registration: Clinicaltrials.gov identifier: NCT04324736.
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http://dx.doi.org/10.1007/s00125-020-05351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890396PMC
April 2021

Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

Diabetes Obes Metab 2021 05 16;23(5):1162-1172. Epub 2021 Feb 16.

Département d'Endocrinologie, Diabétologie et Maladies Métaboliques, CHU de Rouen, Université de Rouen, Rouen, France.

Aim: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study.

Materials And Methods: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW).

Results: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death.

Conclusions: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.
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http://dx.doi.org/10.1111/dom.14324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013481PMC
May 2021

Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review.

Diabetes Obes Metab 2021 May 10;23(5):1069-1083. Epub 2021 Feb 10.

Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA.

Aims: To conduct a systematic literature review to identify recent epidemiological, biomarker, genetic and clinical evidence that expands our understanding of nonalcoholic fatty liver disease (NAFLD) as a metabolic disorder.

Materials And Methods: We performed a literature search using PubMed to identify trials, observational studies and meta-analyses published in the past 5 years.

Results: A total of 95 publications met prespecified inclusion criteria and reported on the interplay between NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic dysfunction, in terms of disease burden and/or epidemiology (n = 10), pathophysiology, risk factors and associated conditions (n = 29), diagnosis and biomarkers (n = 34), and treatment approaches (n = 22). There is a growing body of evidence on the links between NAFLD/NASH pathogenesis and mechanisms of metabolic dysfunction, through liver lipid accumulation, insulin resistance, inflammation, apoptosis, and fibrogenic remodelling within the liver. The frequent co-occurrence of NAFLD with obesity, metabolic syndrome and type 2 diabetes supports this premise. Therapeutic approaches originally envisaged for type 2 diabetes or obesity (such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, insulin sensitizers and bariatric surgery) have shown promising signs of benefit for patients with NAFLD/NASH.

Conclusions: Given the complex interplay between NAFLD and metabolic dysfunction, there is an urgent need for multidisciplinary collaboration and established protocols for care of patients with NAFLD that are individualized and ideally support reduction of overall metabolic risk as well as treatment for NASH.
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http://dx.doi.org/10.1111/dom.14322DOI Listing
May 2021

Meningiomas and cyproterone acetate: a retrospective, monocentric cohort of 388 patients treated by surgery or radiotherapy for intracranial meningioma.

J Neurooncol 2021 Mar 3;152(1):115-123. Epub 2021 Jan 3.

Neurotraumatology, Neurosurgery Department, Hotel-Dieu, CHU Nantes, Nantes, France.

Purpose: Meningiomas are the most common intracranial tumors, accounting for 20-30% of central nervous system tumors. Recently, the European Medicines Agency issued an alert on cyproterone acetate (CPA) based on the results of a study that found an increased risk of meningioma 7 to 20 times higher when a patient is on CPA. The primary objective of this study was to determine the prevalence of CPA exposure in patients who had one or more intracranial meningiomas treated surgically or with radiation therapy. The secondary objectives were to establish a description of the patients who had intracranial meningioma in Nantes and to establish whether there was a difference in the intrinsic and tumoral characteristics of patients exposed to CPA compared with patients who had no hormonal exposure and patients who had been exposed to other hormones.

Methods: Monocentric, retrospective study including all patients treated by surgery or radiotherapy for intracranial meningioma from 2014 to 2017 excluding those with a history of exposure to ionizing radiation or neurofibromatosis type 2.

Results: 388 patients were included, 277 were treated by surgery and 111 by radiotherapy. 3.9% of the patients had a history or current use of CPA, 16.2% were taking other hormonal treatment. Compared with the group without hormonal exposure, the CPA-exposed group had significantly an earlier onset of meningiomas at 48.9 vs. 61.9 years (p = 0.0005) and had more multiple meningiomas, 26.7% vs. 6.1% (p = 0.0115).

Conclusions: In our study, patients with a history or current use of CPA had significantly more meningiomas and were significantly younger at the onset.
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http://dx.doi.org/10.1007/s11060-020-03683-6DOI Listing
March 2021

Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.

Diabetes Metab 2020 Dec 10;47(5):101216. Epub 2020 Dec 10.

Department of Endocrinology, Diabetes Mellitus and Nutrition, Amiens University Hospital, 80054 Amiens, France; PériTox = UMR_I 01, University of Picardie Jules Verne, Amiens, France.

Aims: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19.

Methods: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach.

Results: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P =  0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P <  0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively.

Conclusion: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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http://dx.doi.org/10.1016/j.diabet.2020.101216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832745PMC
December 2020

Phenotypic Characteristics and Development of a Hospitalization Prediction Risk Score for Outpatients with Diabetes and COVID-19: The DIABCOVID Study.

J Clin Med 2020 Nov 20;9(11). Epub 2020 Nov 20.

Department of Endocrinology, Metabolic Diseases and Nutrition, Pôle ENDO, APHM, 13005 Marseille, France.

Diabetes mellitus (DM) has been identified as a risk factor for severe COVID-19. DM is highly prevalent in the general population. Defining strategies to reduce the health care system burden and the late arrival of some patients thus seems crucial. The study aim was to compare phenotypic characteristics between in and outpatients with diabetes and infected by COVID-19, and to build an easy-to-use hospitalization prediction risk score. This was a retrospective observational study. Patients with DM and laboratory- or CT-confirmed COVID-19, who did ( = 185) and did not ( = 159) require hospitalization between 10 March and 10 April 2020, were compared. Data on diabetes duration, treatments, glycemic control, complications, anthropometrics and peripheral oxygen saturation (SpO) were collected from medical records. Stepwise multivariate logistic regressions and ROC analyses were performed to build the DIAB score, a score using no more than five easy-to-collect clinical parameters predicting the risk of hospitalization. The DIAB score was then validated in two external cohorts ( = 132 and = 2036). Hospitalized patients were older (68.0 ± 12.6 vs. 55.2 ± 12.6 years, < 0.001), with more class III obesity (BMI ≥ 40 kg/m, 9.7 vs. 3.5%, = 0.03), hypertension (81.6 vs. 44.3%, < 0.0001), insulin therapy (37% vs. 23.7%, = 0.009), and lower SpO (91.6 vs. 97.3%, < 0.0001) than outpatients. Type 2 DM (T2D) was found in 94% of all patients, with 10 times more type 1 DM in the outpatient group (11.3 vs. 1.1%, < 0.0001). A DIAB score > 27 points predicted hospitalization (sensitivity 77.7%, specificity 89.2%, AUC = 0.895), and death within 28 days. Its performance was validated in the two external cohorts. Outpatients with diabetes were found to be younger, with fewer diabetic complications and less severe obesity than inpatients. DIAB score is an easy-to-use score integrating five variables to help clinicians better manage patients with DM and avert the saturation of emergency care units.
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http://dx.doi.org/10.3390/jcm9113726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699790PMC
November 2020

Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia.

Arterioscler Thromb Vasc Biol 2021 01 19;41(1):e63-e71. Epub 2020 Nov 19.

Hospices Civils de Lyon, UF Dyslipidémies Service de Biochimie et de Biologie Moléculaire Grand Est, Bron, France (X.V., D.C., O.M., E.D., M.D.F.).

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the (apolipoprotein B) and genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia.

Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.
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http://dx.doi.org/10.1161/ATVBAHA.120.315491DOI Listing
January 2021

PCSK9 post-transcriptional regulation: Role of a 3'UTR microRNA-binding site variant in linkage disequilibrium with c.1420G.

Atherosclerosis 2020 12 10;314:63-70. Epub 2020 Oct 10.

Service de Biochimie et Biologie Moléculaire Grand Est, Laboratoire de Biologie Médicale Multi-sites, Hospices Civils de Lyon, F-69677, Bron Cedex, France; Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, F-69100, Villeurbanne, France. Electronic address:

Background And Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression.

Methods: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs.

Results: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR.

Conclusions: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.10.010DOI Listing
December 2020

Genetic Inhibition of PCSK9 and Liver Function.

JAMA Cardiol 2021 Mar;6(3):353-354

L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

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http://dx.doi.org/10.1001/jamacardio.2020.5341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643040PMC
March 2021

Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study.

Diabetes Metab 2021 03 19;47(2):101202. Epub 2020 Oct 19.

L'Institut du Thorax, Université de Nantes, CHU Nantes, CNRS, Inserm, Nantes, France.

Aim: Patients with type 2 diabetes mellitus (T2DM) represent a high-risk population for both cardiovascular diseases and severe coronavirus disease 2019 (COVID-19). Recent studies have reported interactions between statin treatment and COVID-19-related outcomes. The study reported here specifically assessed the association between routine statin use and COVID-19-related outcomes in inpatients with T2DM.

Methods: The Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study was a nationwide observational study aiming to describe the phenotypic characteristics and prognosis of T2DM patients with COVID-19 admitted to 68 French hospitals between 10 March and 10 April 2020. The composite primary outcome comprised tracheal intubation and/or death within 7 and 28 days of admission. The association between statin use and outcomes was estimated by logistic regression analysis after applying inverse probability of treatment weighting (IPTW) using a propensity score-weighting approach.

Results: Of the 2449 patients with T2DM (881 women, 1568 men; aged 70.9 ± 12.5 years) suitable for analysis, 1192 (49%) were using statin treatment before admission. In unadjusted analyses, patients using statins had rates of the primary outcome similar to those of non-users within both 7 (29.8% vs 27.0%, respectively; P = 0.1338) and 28 days (36.2% vs 33.8%, respectively; P = 0.2191) of admission. However, mortality rates were significantly higher in statin users within 7 (12.8% vs 9.8%, respectively; P = 0.02) and 28 days (23.9% vs 18.2%, respectively; P < 0.001). After applying IPTW, significant associations were observed with statin use and the primary outcome within 7 days (OR [95% CI]: 1.38 [1.04-1.83]) and with death within both 7 (OR [95% CI]: 1.74 [1.13-2.65]) and 28 days (OR [95% CI]: 1.46 [1.08-1.95]).

Conclusion: Routine statin treatment is significantly associated with increased mortality in T2DM patients hospitalized for COVID-19.
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http://dx.doi.org/10.1016/j.diabet.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572108PMC
March 2021

Relationship between obesity and severe COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

Diabetes Obes Metab 2021 02 6;23(2):391-403. Epub 2020 Nov 6.

Département d'Endocrinologie, Diabétologie et Nutrition, L'Institut du Thorax, INSERM, CNRS, University of Nantes, CHU Nantes, Nantes, France.

Aim: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D).

Methods: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status.

Results: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m , reference group), 726 (36.9%) overweight (25-29.9 kg/m ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m ) and 314 (16.0%) with class II/III obesity (≥35 kg/m ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years.

Conclusions: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.
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http://dx.doi.org/10.1111/dom.14228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675375PMC
February 2021

Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline.

J Clin Endocrinol Metab 2020 12;105(12)

Department of Internal Medicine, University of Kentucky, Lexington, Kentucky.

Objective: This guideline will provide the practicing endocrinologist with an approach to the assessment and treatment of dyslipidemia in patients with endocrine diseases, with the objective of preventing cardiovascular (CV) events and triglyceride-induced pancreatitis. The guideline reviews data on dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) risk in patients with endocrine disorders and discusses the evidence for the correction of dyslipidemia by treatment of the endocrine disease. The guideline also addresses whether treatment of the endocrine disease reduces ASCVD risk.

Conclusion: This guideline focuses on lipid and lipoprotein abnormalities associated with endocrine diseases, including diabetes mellitus, and whether treatment of the endocrine disorder improves not only the lipid abnormalities, but also CV outcomes. Based on the available evidence, recommendations are made for the assessment and management of dyslipidemia in patients with endocrine diseases.
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http://dx.doi.org/10.1210/clinem/dgaa674DOI Listing
December 2020

Efficacy and Safety of the Duodeno-Jejunal Bypass Liner in Patients With Metabolic Syndrome: A Multicenter Randomized Controlled Trial (ENDOMETAB).

Ann Surg 2020 11;272(5):696-702

University Lille, Inserm, CHU Lille, Institut Pasteur Lille U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, Integrated Center of Obesity, Lille, France.

Objective: The aim of this study was to compare the efficacy and safety of 12-month implantation of a duodeno-jejunal bypass liner (DJBL) with conventional medical care in patients with metabolic syndrome (MS).

Summary Background Data: DJBL is an endoscopic device for treating obesity and related disorders. The persistence of favorable results after 6 months has not been tested in a controlled study.

Methods: We conducted a multicenter randomized controlled trial, stratified by center and diabetes status. The primary endpoint was the remission of MS at 12 months. The secondary endpoints included body mass index (BMI), glucose control, blood pressure, and lipids, assessed at 12 months after implantation, and again, at 12 months after the removal of the DJBL. Up to 174 subjects were planned to be randomized into either the DJBL or the control arm at a 2:1 ratio, respectively. Study enrollment was discontinued by the Scientific Monitoring Committee due to the early termination of the ENDO trial (NCT01728116) by the US Food and Drug Administration. The study was terminated after withdrawal of the device's European Conformity marking by the European Medicines Agency, and an interim analysis was performed.

Results: A total of 82 patients were enrolled (67.5% female, 48.8% with diabetes). At 12 months after randomization, the primary endpoint was met in 6 (12%) DJBL patients and 3 (10%) controls (P = 0.72). Patients in the DJBL group experienced greater BMI loss [mean adjusted difference (95% confidence interval, CI) -3.1 kg/m (-4.4 to -1.9) kg/m, P < 0.001] and HbA1c change [mean adjusted difference -0.5% (95% CI -0.9 to -0.2); P < 0.001] than those in the control group. No difference remained statistically significant at 12 months after the removal of the DJBL. In the DJBL group, 39% of patients experienced at least one device-related serious adverse event, which was classified as Grade III Dindo-Clavien in 22%, and required premature device explantation in 16%.

Conclusions: The present study showed a transient clinical benefit of DJBL, which was only apparent at 1 year, when the device was still in situ, and was obtained at the risk of serious device-related adverse events in 39% of patients. These results do not support the routine use of DJBL for weight loss and glucose control in patients with MS.
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http://dx.doi.org/10.1097/SLA.0000000000004339DOI Listing
November 2020

SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia.

Atherosclerosis 2020 08 6;306:41-49. Epub 2020 Jul 6.

Aix Marseille University, INSERM, INRA, C2VN, Marseille, France; Department of Nutrition, Metabolic Diseases, Endocrinology, La Conception Hospital, Marseille, France. Electronic address:

Background And Aims: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population.

Methods: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population.

Results: We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively).

Conclusions: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.011DOI Listing
August 2020

Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice.

Arterioscler Thromb Vasc Biol 2020 09 16;40(9):2084-2094. Epub 2020 Jul 16.

From the L'institut du thorax, INSERM, CNRS, UNIV NANTES, France (D.G., F.M., A.A., W.D., X.P., L.A., B.C., C.L.).

Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific -deficient (i-) mouse model. PPL was measured in i- as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9 mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr mice. In contrast, i- mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in but not in mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated mice.

Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.
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http://dx.doi.org/10.1161/ATVBAHA.120.314194DOI Listing
September 2020

Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes.

J Exp Med 2020 10;217(10)

Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY.

Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
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http://dx.doi.org/10.1084/jem.20191261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537391PMC
October 2020

Lp(a) and calcific aortic valve stenosis: Direct LPA targeting or PCSK9-Lowering therapy?

Trends Cardiovasc Med 2020 Jul 2. Epub 2020 Jul 2.

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes F-44000, France.

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http://dx.doi.org/10.1016/j.tcm.2020.06.009DOI Listing
July 2020

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

Diabetologia 2020 08 29;63(8):1500-1515. Epub 2020 May 29.

Département Diabète et Endocrinologie, Hôpital Lariboisière, Assistance Publique Hôpitaux de Paris, Paris, France.

Aims/hypothesis: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown.

Methods: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation.

Results: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7.

Conclusions/interpretations: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days.

Trial Registration: clinicaltrials.gov NCT04324736.
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http://dx.doi.org/10.1007/s00125-020-05180-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256180PMC
August 2020

Acromegaly is associated with vertebral deformations but not vertebral fractures: Results of a cross-sectional monocentric study.

Joint Bone Spine 2020 Dec 16;87(6):618-624. Epub 2020 May 16.

Department of Rheumatology, CHU de Nantes, Nantes, France.

Objectives: Patients with acromegaly appear to be at increased risk of vertebral fractures despite normal bone mineral density. We investigated the prevalence of vertebral fractures in a cohort of acromegalic patients under 80 years of age.

Methods: Monocentric cross-sectional study performed at Nantes University Hospital from 1988 to 2018. Fifty patients (18 females, 32 males) with a median age of 52.3 years (range: 27-78) were included. Radiological vertebral fractures were evaluated on conventional lumbar and thoracic spine radiographs using Genant's semiquantitative fracture assessment. We studied qualitative abnormalities of the spine using three criteria: osteophytes, disc-space narrowing and wedge-shaped vertebrae. We analysed bone mineral density and endocrine status.

Results: Three patients (6%) had a vertebral fracture: one grade 1 and two grade 2 according to Genant's assessment, with two osteoporotic and one osteopenic patients. They had no unsubstituted pituitary deficiency. Considering the frank deformations (osteophyte or disc narrowing≥grade 2 or wedge-shaped), the thoracic spine was deformed in 22 patients (44%) and the lumbar spine in 21 patients (42%).

Conclusion: Acromegalic patients had a low prevalence of vertebral fractures but had a significant amount of vertebral deformations. We speculate that this high prevalence of frank deformations could explain the previously reported high prevalence of vertebral fractures.
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http://dx.doi.org/10.1016/j.jbspin.2020.04.020DOI Listing
December 2020

Efficacy of rituximab in patients with Graves' orbitopathy: a retrospective multicenter nationwide study.

Graefes Arch Clin Exp Ophthalmol 2020 Sep 13;258(9):2013-2021. Epub 2020 May 13.

Department of Ophthalmology, Hotel Dieu, CHU Nantes, 44093, Nantes Cedex 1, France.

Purpose: The clinical utility of rituximab (RTX) in Graves' orbitopathy (GO) treatment remains controversial since the discrepant results from 2 prospective randomized studies (Stan M et al. J Clin Endocrinol Metab 2015; Salvi M et al. J Clin Endocrinol Metab 2015). The aim of this study was to assess in real life the characteristics and the clinical outcomes of patients with GO treated with RTX in cases of corticosteroid resistance or corticosteroid dependence.

Methods: Multicenter French retrospective study including patients with moderate-to-severe GO requiring second-line treatment with RTX. Patients were classified according to three main baseline characteristics: clinical inflammation (CAS ≥ 3), oculomotor limitation, and visual dysfunction. Patients were considered as responders if, at 24 weeks (week 24), at least 1 of these 3 parameters improved with no worsening elsewhere.

Results: Forty patients were included (65% smokers, 38% dysthyroidism). Thirty-two patients were treated with RTX alone (one patient excluded owing to side effects): 64.5% had favorable responses at week 24 and significant reduction in baseline CAS (3.29 ± 1.6) at 12 weeks (1.93 ± 1.1; P < 0.001) and at week 24 (1.59 ± 1.1; P < 0.001); reduction in anti-TSH receptor antibodies at week 24 (P < 0.01); and significant improvement of visual acuity (P = 0.04) and ocular hypertonia (P = 0.04) at week 12, but no improvement in oculomotor dysfunction. Eight patients needed emergency treatment with concomitant RTX and orbital decompression, with favorable outcome for 5 patients. Predictive factors for a poor response to RTX were low baseline CAS, smoker, and baseline ocular hypertonia. All patients reported good tolerance except one serious side effect (a cytokine release syndrome).

Conclusions: The efficiency results of RTX in reducing CAS in this cohort are just between those of Stan and Salvi. This could be explained by our delay before treatment initiation, quicker than Stan but longer than Salvi. RTX appears to be effective as a second-line treatment for the inflammatory component of GO, especially if the disease is highly active and recent.
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http://dx.doi.org/10.1007/s00417-020-04651-6DOI Listing
September 2020

A high-throughput mass spectrometry-based assay for large-scale profiling of circulating human apolipoproteins.

J Lipid Res 2020 07 13;61(7):1128-1139. Epub 2020 May 13.

NUN, INRA, CHU Nantes, UMR 1280, PhAN, IMAD, CRNH-O, Nantes, France; CRNH-O Mass Spectrometry Core Facility, Nantes, France.

Apolipoproteins govern lipoprotein metabolism and are promising biomarkers of metabolic and cardiovascular diseases. Unlike immunoassays, MS enables the quantification and phenotyping of multiple apolipoproteins. Hence, here, we aimed to develop a LC-MS/MS assay that can simultaneously quantitate 18 human apolipoproteins [A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a)] and determined apoE, apoL1, and apo(a) phenotypes in human plasma and serum samples. The plasma and serum apolipoproteins were trypsin digested through an optimized procedure and peptides were extracted and analyzed by LC-MS/MS. The method was validated according to standard guidelines in samples spiked with known peptide amounts. The LC-MS/MS results were compared with those obtained with other techniques, and reproducibility, dilution effects, and stabilities were also assessed. Peptide markers were successfully selected for targeted apolipoprotein quantification and phenotyping. After optimization, the assay was validated for linearity, lower limits of quantification, accuracy (biases: -14.8% to 12.1%), intra-assay variability [coefficients of variation (CVs): 1.5-14.2%], and inter-assay repeatability (CVs: 4.1-14.3%). Bland-Altman plots indicated no major statistically significant differences between LC-MS/MS and other techniques. The LC-MS/MS results were reproducible over five repeated experiments (CVs: 1.8-13.7%), and we identified marked differences among the plasma and serum samples. The LC-MS/MS assay developed here is rapid, requires only small sampling volumes, and incurs reasonable costs, thus making it amenable for a wide range of studies of apolipoprotein metabolism. We also highlight how this assay can be implemented in laboratories.
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http://dx.doi.org/10.1194/jlr.D120000835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328037PMC
July 2020