Amandine Nguyen

Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment

Objective— High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). Approach and Results— Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L-[3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). Conclusions— We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.

Major changes in the sphingophospholipidome of HDL in non-diabetic patients with metabolic syndrome

OBJECTIVE Phospholipids and sphingolipids play a critical role in the protective effects of HDL against atherosclerosis. These properties are impaired in patients with metabolic syndrome, before the development of diabetes. We thus investigated whether HDL from patients with metabolic syndrome but normal fasting glycaemia present abnormalities in their sphingophospholipid profile. METHODS Using liquid chromatography/tandem mass spectrometry, we quantified the different species of the main phospholipids and sphingolipids in the HDL2 and HDL3 from 26 obese patients with metabolic syndrome but normal fasting glycaemia and 50 controls. RESULTS Phosphatidylcholines, when expressed as the relative amount compared with total phospholipids and sphingolipids, were similar in both HDL2 and HDL3 in the two groups. Lysophosphatidylcholines were 41% (p = 0.0002) and 86% (p < 0.0001) higher in HDL2 and HDL3, respectively, from patients with metabolic syndrome than in those from controls. Phosphatidylinositols were also higher in HDL2 and HDL3 (respectively, +60 and + 103% (p < 0.0001)). In contrast, both HDL2 and HDL3 from patients with metabolic syndrome showed lower proportions of phosphatidylethanolamine-based plasmalogens (respectively -78 and -73%, p < 0.0001), phosphatidylcholine-based plasmalogens (respectively -44 and -53%, p < 0.0001), d18:1-sphingosine-1-phosphate (respectively -52 and -38%, p < 0.0001) and sphingomyelins (respectively -19% (p < 0.0001) and -24% (p = 0.0006)), than did controls. Moreover, we observed a decrease in C18:2 fatty acid-containing phospholipids and an increase in C20:4 fatty acid-containing phospholipids. CONCLUSION The sphingophospholipidome of HDL from normoglycaemic obese patients with metabolic syndrome is profoundly modified, before the dysregulation of glycaemia. Most of the changes observed have pejorative effect in terms of vascular protection.

Detection of glucose metabolism disorders in coronary patients enrolled in cardiac rehabilitation: Is glycated haemoglobin useful? Data from the prospective REHABDIAB study:

Introduction Diabetes and pre-diabetes are highly prevalent in patients with a history of acute coronary syndrome. This is why screening for glucose metabolism disorders is recommended in patients following an acute coronary syndrome. The aim of our study was to determine whether glycated haemoglobin alone compared with the oral glucose tolerance test could allow effective screening for glucose metabolism disorders in acute coronary syndrome patients undergoing cardiac rehabilitation. Patients and methods Among 347 patients with a recent history of acute coronary syndrome enrolled in our cardiac rehabilitation centre, 267 patients without previously known diabetes were recruited for this prospective study with performance of both oral glucose tolerance test and glycated haemoglobin measurement. The patients were divided into three groups: newly diagnosed diabetes mellitus, pre-diabetes and normoglycaemia according to the oral glucose tolerance test and glycated haemoglobin results. The results obtained with glycated haemoglobin were compared with those obtained with the oral glucose tolerance test, considered as the reference. Results For the diagnosis of diabetes, glycated haemoglobin had a sensitivity of 72% and a specificity of 100%. Positive and negative predictive values were high at 100% and 96%, respectively. However, for the diagnosis of pre-diabetes the sensitivity of glycated haemoglobin was low at 64% as were the specificity (53%) and the positive predictive values (37%). Glycated haemoglobin overdiagnosed pre-diabetes (52% vs 30%, p < 0.0001). For the diagnosis of normoglycaemia, the sensitivity of glycated haemoglobin was also low (48%). Conclusion According to our study, glycated haemoglobin has low sensitivity and specificity for the detection of pre-diabetes in patients with coronary disease enrolled in cardiac rehabilitation, and glycated haemoglobin over-diagnoses pre-diabetes in comparison with the oral glucose tolerance test.

Liver Fat Content in People with Pituitary Diseases: Influence of Serum IGF1 Levels

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome, and type 2 diabetes. NAFLD is also seen in patients with endocrinopathies. However, the relationship between endocrine diseases and the development of NAFLD is not well known. In this study, we set out to determine whether liver fat content (LFC) was associated with IGF1 levels in people with pituitary diseases (PD). Eighty-nine patients with pituitary diseases and 74 healthy controls were included in this study. LFC was measured using MRI. Hepatic steatosis was defined as LFC>5.5%. Patients with PD were older, and had a higher BMI than healthy controls. LFC was significantly higher in people with PD than in controls (6.5% vs. 3.2%; p<0.001). LFC was negatively associated with the IGF1 level. The prevalence of steatosis was higher in PD patients than in controls (36.3% vs. 14.8%; p=0.002). In multivariate analysis, which included patients and controls, the predictive variables for steatosis were age, BMI and IGF1 levels, whereas the presence of pituitary diseases and gender were not associated with steatosis. Our data showed that LFC was strongly associated with IGF1 levels. These results suggest that steatosis associated with PD is probably a consequence of a low IGF1 level in these patients.

Unexpected adverse effect of metyrapone: A case report

Hypercortisolism, or Cushings syndrome, is a disease which can be treated surgically or with medications such as mitotane, ketoconazole or metyrapone. However, the use of metyrapone is not common, and the adverse effects are not well known. A metyrapone overdose is usually associated with gastro-intestinal symptoms and signs of adrenal failure. To our knowledge, no other side effects have been reported in connection with an ingestion of high doses of metyrapone. This article is protected by copyright. All rights reserved.