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BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. METHODS: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. RESULTS: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). CONCLUSIONS: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.
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Proteína 3 Similar a la Angiopoyetina , Anticolesterolemiantes , LDL-Colesterol , Homocigoto , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/mortalidad , Masculino , Femenino , LDL-Colesterol/sangre , Adulto , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Eliminación de Componentes Sanguíneos , Biomarcadores/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Factores de Tiempo , Supervivencia sin Progresión , Adulto Joven , Resultado del Tratamiento , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , AdolescenteRESUMEN
Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.
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Autofagia , Calcio , Retículo Endoplásmico , Proteínas de la Membrana , Mitocondrias , Mitofagia , Animales , Mitofagia/fisiología , Humanos , Proteínas de la Membrana/metabolismo , Retículo Endoplásmico/metabolismo , Autofagia/fisiología , Ratones , Mitocondrias/metabolismo , Calcio/metabolismo , Síndrome de Wolfram/metabolismo , Síndrome de Wolfram/patología , Fibroblastos/metabolismo , Neuronas/metabolismoRESUMEN
BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.
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Adiponectina , Apolipoproteínas M , Resistencia a la Insulina , Humanos , Masculino , Apolipoproteínas M/sangre , Resistencia a la Insulina/fisiología , Adiponectina/sangre , Estudios Transversales , Persona de Mediana Edad , Adulto , Obesidad/sangre , Obesidad/metabolismo , Femenino , Adipocitos/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Biomarcadores/sangre , Tejido Adiposo/metabolismo , Apolipoproteínas/sangreRESUMEN
High blood levels of low-density lipoprotein (LDL)-cholesterol (LDL-C) are associated with atherosclerosis, mainly by promoting foam cell accumulation in vessels. As cholesterol is an essential component of cell plasma membranes and a regulator of several signaling pathways, LDL-C excess may have wider cardiovascular toxicity. We examined, in untreated hypercholesterolemia (HC) patients, selected regardless of the cause of LDL-C accumulation, and in healthy participants (HP), the expression of the adenosine A2A receptor (A2AR), an anti-inflammatory and vasodilatory protein with cholesterol-dependent modulation, and Flotillin-1, protein marker of cholesterol-enriched plasma membrane domains. Blood cardiovascular risk and inflammatory biomarkers were measured. A2AR and Flotillin-1 expression in peripheral blood mononuclear cells (PBMC) was lower in patients compared to HP and negatively correlated to LDL-C blood levels. No other differences were observed between the two groups apart from transferrin and ferritin concentrations. A2AR and Flotillin-1 proteins levels were positively correlated in the whole study population. Incubation of HP PBMCs with LDL-C caused a similar reduction in A2AR and Flotillin-1 expression. We suggest that LDL-C affects A2AR expression by impacting cholesterol-enriched membrane microdomains. Our results provide new insights into the molecular mechanisms underlying cholesterol toxicity, and may have important clinical implication for assessment and treatment of cardiovascular risk in HC.
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Enfermedades Cardiovasculares , Hipercolesterolemia , Proteínas de la Membrana , Humanos , LDL-Colesterol/metabolismo , Receptor de Adenosina A2A/metabolismo , Leucocitos Mononucleares/metabolismo , Adenosina , Factores de Riesgo , Colesterol , Proteínas Portadoras , Factores de Riesgo de Enfermedad Cardiaca , Microdominios de Membrana/metabolismoRESUMEN
Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals.
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Hiperlipidemias , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
OBJECTIVE: Prognostic models in patients living with diabetes allow physicians to estimate individual risk based on medical records and biological results. Clinical risk factors are not always all available to evaluate these models so that they may be complemented with models from claims databases. The objective of this study was to develop, validate and compare models predicting the annual risk of severe complications and mortality in patients living with type 2 diabetes (T2D) from a national claims data. RESEARCH DESIGN AND METHODS: Adult patients with T2D were identified in a national medical claims database through their history of treatments or hospitalizations. Prognostic models were developed using logistic regression (LR), random forest (RF) and neural network (NN) to predict annual risk of outcome: severe cardiovascular (CV) complications, other severe T2D-related complications, and all-cause mortality. Risk factors included demographics, comorbidities, the adjusted Diabetes Severity and Comorbidity Index (aDSCI) and diabetes medications. Model performance was assessed using discrimination (C-statistics), balanced accuracy, sensibility and specificity. RESULTS: A total of 22,708 patients with T2D were identified, with mean age of 68 years and average duration of T2D of 9.7 years. Age, aDSCI, disease duration, diabetes medications and chronic cardiovascular disease were the most important predictors for all outcomes. Discrimination with C-statistic ranged from 0.715 to 0.786 for severe CV complications, from 0.670 to 0.847 for other severe complications and from 0.814 to 0.860 for all-cause mortality, with RF having consistently the highest discrimination. CONCLUSION: The proposed models reliably predict severe complications and mortality in patients with T2D, without requiring medical records or biological measures. These predictions could be used by payers to alert primary care providers and high-risk patients living with T2D.
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BACKGROUND: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. METHODS: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. RESULTS: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P<0.0001) and were 2 years older (46.9±16.8 versus 44.7±15.9 years old, P=0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%-170%; P=0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06-3.11; P=0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39-5.51; P=0.004) when compared with paternal inheritance in multivariate analysis. CONCLUSIONS: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.
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Aterosclerosis , Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Humanos , Adulto , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Calcio , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Estudios Retrospectivos , Herencia Materna , Aterosclerosis/epidemiología , Aterosclerosis/genética , Aterosclerosis/complicaciones , Mutación , Factores de RiesgoRESUMEN
INTRODUCTION: Obesity and its co-morbidities, including type 2 diabetes (T2DM) and dyslipidemia, are accompanied by excess cardiovascular morbi-mortality. Aside from excess low density lipoprotein-cholesterol (LDL-C), atherogenic dyslipidemia (AD), mainly characterized by elevated triglycerides and decreased high density lipoprotein-cholesterol (HDL-C) levels, is often present in T2DM obese patients. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), has become a reference treatment in that population. However, the respective effects of RYGB vs SG on lipid metabolism in T2DM patients have been rarely studied. METHODS: A meta-analysis of randomized controlled trials, comparing the effects of RGYBG vs SG on lipid metabolism 12 months after surgery in T2DM patients, was performed. RESULTS: Four studies including a total of 298 patients (151 patients in the RYGB and 147 patients in the SG group) were examined. Despite a greater decrease in body mass index and greater improvement in glycemic control in RYGB compared to SG. RYGB vs SG was more effective in reducing total cholesterol, LDL-C, and non-HDL-C levels (mean difference [MD] -26.10 mg/dL, 95 % CI -38.88 to -13.50, p<0.00001; [MD] -20.10 mg/dL, 95 % CI -27.90 to -12.20, p<0.00001 and MD 31.90 mg/dl, 95 % CI -46.90 to -16.80, p<0.00001, respectively). CONCLUSIONS: The superiority of RYGB vs SG in reducing LDL-C, with an effect comparable to a moderate-intensity statin, suggests RYBG should be favored in hypercholesterolemic T2DM patients in order to further reduce cardiovascular risk.
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Diabetes Mellitus Tipo 2 , Dislipidemias , Derivación Gástrica , Obesidad Mórbida , LDL-Colesterol , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/cirugía , Dislipidemias/complicaciones , Gastrectomía , Humanos , Obesidad/complicaciones , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Resultado del TratamientoRESUMEN
Lipoprotein(a) is an apolipoprotein B100-containing low-density lipoprotein-like particle that is rich in cholesterol, and is associated with a second major protein, apolipoprotein(a). Apolipoprotein(a) possesses structural similarity to plasminogen but lacks fibrinolytic activity. As a consequence of its composite structure, lipoprotein(a) may: (1) elicit a prothrombotic/antifibrinolytic action favouring clot stability; and (2) enhance atherosclerosis progression via its propensity for retention in the arterial intima, with deposition of its cholesterol load at sites of plaque formation. Equally, lipoprotein(a) may induce inflammation and calcification in the aortic leaflet valve interstitium, leading to calcific aortic valve stenosis. Experimental, epidemiological and genetic evidence support the contention that elevated concentrations of lipoprotein(a) are causally related to atherothrombotic risk and equally to calcific aortic valve stenosis. The plasma concentration of lipoprotein(a) is principally determined by genetic factors, is not influenced by dietary habits, remains essentially constant over the lifetime of a given individual and is the most powerful variable for prediction of lipoprotein(a)-associated cardiovascular risk. However, major interindividual variations (up to 1000-fold) are characteristic of lipoprotein(a) concentrations. In this context, lipoprotein(a) assays, although currently insufficiently standardized, are of considerable interest, not only in stratifying cardiovascular risk, but equally in the clinical follow-up of patients treated with novel lipid-lowering therapies targeted at lipoprotein(a) (e.g. antiapolipoprotein(a) antisense oligonucleotides and small interfering ribonucleic acids) that markedly reduce circulating lipoprotein(a) concentrations. We recommend that lipoprotein(a) be measured once in subjects at high cardiovascular risk with premature coronary heart disease, in familial hypercholesterolaemia, in those with a family history of coronary heart disease and in those with recurrent coronary heart disease despite lipid-lowering treatment. Because of its clinical relevance, the cost of lipoprotein(a) testing should be covered by social security and health authorities.
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Aterosclerosis , Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Consenso , Humanos , Lipoproteína(a) , Factores de RiesgoRESUMEN
Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p < 0.001), asymmetric-dimethylarginine (+105%, p < 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24-33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6-17) and 36% (95%CI: 27-45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.
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BACKGROUND: Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. OBJECTIVE: We aimed to examine the direct and/or indirect role of GH on TRL metabolism. METHODS: We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. RESULTS: After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. CONCLUSION: In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.
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Enfermedad de la Arteria Coronaria/etiología , Dislipidemias/etiología , Hormona del Crecimiento/fisiología , Intestinos/metabolismo , Lipoproteínas/sangre , Lipoproteínas/metabolismo , Hígado/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo , Adulto , Causas de Muerte , Enfermedad de la Arteria Coronaria/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Hormona del Crecimiento/deficiencia , Humanos , Resistencia a la Insulina/fisiología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismoRESUMEN
BACKGROUND: Hyperglycemia is the most common side-effect of phosphatidylinositol 3-kinase (PI3K) inhibitors that are approved for the treatment of some advanced or metastatic breast cancers. This side-effect is likely due to the central role of PI3K in insulin signalling. Here we report the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to manage severe hyperglycemia. CASE PRESENTATION: We describe a 74-year-old woman who developed severe uncontrolled hyperglycemia after commencing alpelisib, a new oral PI3K inhibitor indicated for a metastatic breast cancer, despite taking oral anti-diabetic drugs, metformin and vildagliptin, combined with intravenous insulin infusion of up to 250 units/day. The introduction of the SGLT2 inhibitor dapagliflozin rapidly improved blood glucose with a drastic reduction in insulin dosage, from 250 to 12 units/day, and without significant side-effects. CONCLUSIONS: We report the successful management of hyperglycemia induced by alpelisib using a SGLT2 inhibitor without the need to discontinue effective cancer treatment.
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BACKGROUND AND AIMS: Few studies distinguished the independent role of overweight/obesity or their associated-comorbidities in the evolution towards severe forms of COVID-19. Obesity as a unifying risk factor for severe COVID-19 is an emerging hypothesis. The aim of this study was to evaluate whether excessive body weight per se, was a risk factor for developing a severe form of COVID-19. PATIENTS AND METHODS: We included 131 patients hospitalized for COVID-19 pneumonia in a single center of the internal medicine department in Marseille, France. We recorded anthropometric and metabolic parameters such as fasting glycaemia, insulinemia, HOMA-IR, lipids, and all clinical criteria linked to SARS-CoV-2 infection at the admission. Excess body weight was defined by a BMIâ¯≥â¯25â¯kg/m2. The occurrence of a serious event was defined as a high-debit oxygen requirement over 6â¯L/min, admission into the intensive care unit, or death. RESULTS: Among 113 patients, two thirds (nâ¯=â¯76, 67%) had an excess body weight. The number of serious events was significantly higher in excess body weight patients compared to normal weight patients (respectively 25% vs 8%, pâ¯=â¯0.03) although excess body weight patients were younger (respectively 63.6 vs 70.3â¯years old, pâ¯=â¯0.01). In multivariate analyses, the excess body weight status was the only predictor for developing a serious event linked to SARS-CoV-2 infection, with an odds ratio at 5.6 (95% CI: 1.30-23.96; pâ¯=â¯0.02), independently of previous obesity associated comorbidities. There was a trend towards a positive association between the BMI (normal weight, overweight and obesity) and the risk of serious events linked to COVID-19, with a marked increase from 8.1% to 20% and 30.6% respectively (pâ¯=â¯0.05). CONCLUSION: Excess body weight was significantly associated with severe forms of the disease, independently of its classical associated comorbidities. Physicians and specialists in Public Health must be sensitized to better protect people with an excess body weight against SARS-CoV-2 infection.
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Peso Corporal/fisiología , COVID-19/diagnóstico , COVID-19/patología , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , COVID-19/epidemiología , COVID-19/etiología , Comorbilidad , Enfermedad Crítica , Femenino , Francia/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/epidemiología , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2/fisiología , Índice de Severidad de la EnfermedadRESUMEN
Many proteins are causative for inherited partial lipodystrophies, including lamins, the essential constituents of the nuclear envelope scaffold called the lamina. By performing high throughput sequencing on a panel of genes involved in lipodystrophies, we identified a heterozygous mutation in LMNB2 gene (c.700C > T p.(Arg234Trp)) in a female patient presenting early onset type II diabetes, hypertriglyceridemia, and android fat distribution. This mutation is rare in the general population (frequency 0.013% in GnomAD) and was predicted pathogenic by a set of pathogenicity prediction software. Patient-derived fibroblasts showed nuclear shape abnormalities and premature senescence features, which are two typical cellular phenotypes associated with laminopathies. Moreover, we observed an atypical aggregation of lamin B2 in nucleoplasm, which co-distributes with emerin and lamin A/C, along with an abnormal distribution of lamin A/C at the nuclear envelope. Finally, reducing lamin B2 expression level by siRNA targeted toward LMNB2 transcripts resulted in decreased nuclear anomalies and senescence-associated beta-galactosidase, suggesting a role of the mutated protein in the occurrence of the observed cellular phenotype. Altogether, these results suggest that mutations in lamin B2 could produce premature senescence and partial lipodystrophy features as observed with certain mutants of lamin A/C.
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Senescencia Celular/genética , Predisposición Genética a la Enfermedad , Lamina Tipo B/genética , Lipodistrofia/genética , Mutación/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Núcleo Celular/patología , Niño , Regulación hacia Abajo , Femenino , Humanos , Lamina Tipo B/química , Adulto JovenRESUMEN
CONTEXT: The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown. OBJECTIVE: The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population. METHODS: Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up. RESULTS: Patients with FCS were younger than those with MCS (34.3â ±â 13.6 vs 45.2â ±â 12.6 years, Pâ <â 0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least 1 episode of acute hypertriglyceridemic pancreatitis (AHP) (hazard ratio [HR]â =â 3.6; Pâ <â 0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HRâ =â 0.3; Pâ =â 0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (odds ratio [OR]â =â 22.8; Pâ <â 0.01 in FCS and ORâ =â 30.3; Pâ <â 0.01 in MCS). CONCLUSION: The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.
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Hiperlipoproteinemia Tipo I/epidemiología , Hiperlipoproteinemia Tipo I/etiología , Adulto , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Francia/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Hiperlipoproteinemia Tipo I/clasificación , Hiperlipoproteinemia Tipo I/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Síndrome , Factores de Tiempo , Adulto JovenRESUMEN
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 APOB (apolipoprotein B) and PCSK9 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%, P<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.
Asunto(s)
Apolipoproteína B-100/genética , LDL-Colesterol/sangre , Hipobetalipoproteinemias/genética , Herencia Multifactorial , Mutación , Enfermedad del Hígado Graso no Alcohólico/etiología , Proproteína Convertasa 9/genética , Adulto , Biomarcadores/sangre , Regulación hacia Abajo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hipobetalipoproteinemias/sangre , Hipobetalipoproteinemias/complicaciones , Hipobetalipoproteinemias/diagnóstico , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Fenotipo , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
SCOPE: Cholesterol bioavailability displays a high interindividual variability, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explained a minor fraction of the variability of this complex phenotype. The aim is to identify a combination of SNPs associated with a significant part of the variability in cholesterol bioavailability. METHODS AND RESULTS: Thirty-nine healthy adult males are given a standard test snack containing 80 mg heptadeuterated (D7) cholesterol. The plasma D7-cholesterol concentration is measured at equilibrium 40 h after test snack intake. The D7-cholesterol response (D7-cholesterol/total cholesterol concentration) exhibits a relatively high interindividual variability (CV = 32%). The association of exonic SNPs in candidate genes (188 genes involved in or related to cholesterol metabolism) with the plasma D7-cholesterol response is assessed by univariate statistics followed by partial least squares regression. A significant model (p-value after cross-validation ANOVA = 1.64 × 10-7 ) that includes 8 SNPs (SOAT2-rs9658625, DNAH11-rs11768670, LIPC-rs690, MVK-rs2287218, GPAM-rs10787428, APOE-rs7412, CBS-rs234706, and WRN-rs1801196) explains 59.7% of the variance in cholesterol bioavailability (adjusted R²). CONCLUSION: Here a combination of SNPs is significantly associated with the variability in dietary cholesterol bioavailability in healthy adult males.
Asunto(s)
Colesterol/genética , Colesterol/farmacocinética , Polimorfismo de Nucleótido Simple , Adulto , Dineínas Axonemales , Disponibilidad Biológica , Humanos , Desequilibrio de Ligamiento , Masculino , Helicasa del Síndrome de WernerRESUMEN
OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.
Asunto(s)
Tejido Adiposo/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Pericardio/metabolismo , Plasmalógenos/metabolismo , Anciano , HDL-Colesterol/sangre , VLDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Femenino , Humanos , Lipidómica , Masculino , Persona de Mediana Edad , Grasa Subcutánea/metabolismoRESUMEN
BACKGROUND: Liver adenomatosis (LA) is a rare disease resulting from biallelic inactivation of the hepatocyte nuclear factor-1 alpha (HNF1A) gene, which induces the proliferation of adenoma cells in liver parenchyma. Liver adenomatosis has only been documented in case reports from patients carrying a HNF1A germline mutation. We have evaluated the frequency of LA among a large cohort of patients with HNF1A-maturity onset diabetes of the young (MODY), previously termed "MODY3," and herein describe its clinical, radiological, and pathological characteristics. METHODS: In all, 137 HNF1A-MODY subjects from 74 families were screened by liver ultrasonography in 13 centers, and 15 additional cases of LA were later included in the series. Liver adenomatosis was confirmed by liver computed tomography, magnetic resonance imaging (MRI), and/or histopathology. RESULTS: Among 137 carriers of an HNF1A mutation, 9 patients (6.5%) from seven families were diagnosed with LA. Diabetes mellitus was present in 87.5% of patients with LA. In 25% of patients, LA was diagnosed due to intra-abdominal or intratumoral bleeding. Liver biochemistry was near normal in all patients. Liver imaging showed adenomas of various sizes and numbers. On MRI, most nodules had the radiological characteristics of steatotic adenomas. Histopathological confirmation of LA was available in 13 cases, and these adenomas were mostly steatotic. Surgery was initially performed in 37.5% of patients, and liver disease progression was observed in 30%. No disease progression was observed in 14 pregnancies. CONCLUSIONS: The frequency of LA in a cohort of screened HNF1A-MODY patients and the high incidence of LA progression and/or hemorrhage warrants systematic screening for liver adenomatosis in HNF1A-MODY families.