Accumulation of Triglyceride-Rich Lipoprotein in Subjects With Abdominal Obesity
The Biguanides and the Prevention of the Risk of Obesity (BIGPRO) 1 Study
Abstract—The present study represents a new insight into the Biguanides and the Prevention of the Risk of Obesity (BIGPRO) 1 study population at inclusion. This population, selected basically on the basis of a high waist-to-hip ratio (≥0.95 for men and ≥0.80 for women), is supposed to represent a group of patients with insulin resistance. The present study was undergone to establish whether apolipoprotein C-III (apoC-III) and apolipoprotein E (apoE) associated with apo B (apoC-III LpB and apoE LpB, respectively), considered to be markers of remnant accumulation, play a role in the hypertriglyceridemia associated with insulin resistance and whether they are related to other biological abnormalities frequently observed in this syndrome. In this population, the concentration of the markers of remnant accumulation increases with triglyceride levels. Therefore, correlation studies were realized to assess the relative effect of insulin and the markers of remnant accumulation on triglyceride plasma level. As a first attempt, a simple correlation analysis revealed that insulin is positively related to the markers of remnant accumulation only in hypertriglyceridemic patients (triglycerides ≥1.7 mmol/L). To assess the independent contribution of these markers, insulin, and other parameters related to the plasma triglyceride concentration, a stepwise multiple regression analysis was run. Results revealed that insulin and the markers of remnant accumulation (specifically, apoE LpB) are independent contributors to the plasma triglyceride concentration. Markers of the endothelial damage, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor, which are often increased in the case of insulin resistance, were tested for their correlation with the markers of remnant accumulation. Plasminogen activator inhibitor-1 is positively correlated with these markers only in hypertriglyceridemic male subjects. It is concluded that increased insulin levels found in insulin resistance syndrome are associated with an increased production of triglyceride-rich lipoproteins enriched in apoC-III and apoE. The accumulation of these remnants and/or their abnormal composition in apoC-III and apoE could be an explanation for the development of hypertriglyceridemia in this syndrome.
- insulin resistance syndrome
- central fat distribution
- triglyceride-rich lipoproteins
- lipoprotein particles
↵1 The BIGPRO study group and clinical centers are listed in the Appendix.
- Received July 17, 2000.
- Accepted September 11, 2000.
Insulin resistance syndrome includes a constellation of clinical and biological anomalies, clustering in subjects with upper body fat distribution who often exhibit insulin resistance at the cell level.1 2 3 4 Among these anomalies are hyperinsulinemia, glucose intolerance, elevated blood pressure, impaired fibrinolytic activity, and a dyslipidemic profile characterized by a high plasma triglyceride concentration and a low HDL cholesterol level.5 6 Triglyceride-rich lipoproteins (TGRLs) represent a mixture of particles in which apoC-III and apoE are present in multiple copies.7 During the lipolytic process, most apoCs and apoEs are transferred to HDL.8 9 10 11 In addition, apoC-III inhibits lipolysis,12 13 14 and apoE plays a role in the clearance of lipoproteins by their receptor pathway.15 16 17 18 19 20 Therefore, several mechanisms (ie, influx of TGRL and HDL into the circulation, the lipolytic process, and lipoprotein receptor activities) appear to be important in the determination of apoC-III and apoE plasma levels and their distribution among plasma lipoproteins. The benefit of measuring apoC-III and apoE in plasma lipoproteins has been evaluated in several clinical studies using different methodological approaches.20 21 22 23 24 25 26 First, Alaupovic20 demonstrated a strong relation between the apoC-III ratio (apoC-III in non-apoB lipoproteins/apoC-III in apoB lipoproteins) and lipoprotein lipase activity. Second, in 2 coronary angiographic trials, the Cholesterol Lowering Atherosclerosis Study (CLAS)24 and the Monitored Atherosclerosis Regression Study (MARS),25 an increase in the apoC-III level in apoB-containing lipoproteins (LpBs) appeared to be associated with the progression of coronary lesions, whereas an increase in the apoC-III level in non–apoB-containing lipoproteins (Lp non-Bs) was associated with a less extensive progression. Third, 2 clinical studies23 26 of patients suffering from cardiovascular diseases have indicated that apoC-III and/or apoE in the different lipoprotein fractions is related to the risk of disease. In nondiabetic patients, apoC-III in LpBs was positively correlated with the coronary score determined by angiography, whereas the apoC-III ratio was negatively correlated with the same score.26 In the Etude Cas-Temoins sur l’Infarctus du Myocarde (ECTIM) study,23 the apoC-III ratio differed strongly and was independent of cholesterol, triglycerides, HDL cholesterol, apoA-I, and apoB for the 2 populations at contrasting risk for myocardial infarction, with the population at higher risk presenting the lower apoC-III ratio. In the same study, subjects suffering from myocardial infarction had higher apoC-III and apoE in LpBs than did control subjects.
The present study was undergone to establish whether these markers of remnant accumulation play a role in the hypertriglyceridemia associated with insulin resistance and whether they are related to other biological abnormalities frequently observed in this syndrome.
Four hundred fifty-seven nondiabetic patients free of cardiovascular disease who were recruited from hospital outpatient clinics were included in the Biguanides and the Prevention of the Risk of Obesity (BIGPRO) 1 trial.27 Briefly, to be included in the present study, patients had to fulfill the following criteria: age 35 to 60 years for men and 40 to 65 years for women and a waist-to-hip ratio (WHR) ≥0.95 for men and ≥0.80 for women. However, patients presenting 1 of the following characteristics were excluded even if they met the inclusion criteria: diabetes (whether diagnosed before inclusion or by the oral glucose tolerance test at inclusion according to 1985 World Health Organization criteria, ie, fasting glucose ≥7.8 mmol/L or 2-hour glucose ≥11.1 mmol/L28 ), atheromatous cardiovascular disease (whether recognized before inclusion or detected by the ECG required for inclusion), impaired renal function (whether recognized before inclusion or by a plasma creatinine level [required for inclusion] ≥15 mg/L [130 μmol/L]), or serious illness (including mental illness, extensive chronic medical treatment, or chronic treatment by a drug containing metformin or by a lipid-lowering drug). In the studied population, 151 (33%) were men and 306 were women. The main criterion for patient selection was a high WHR. This was supposed to recruit a study population with insulin resistance.1 2 The detailed methodology and the primary results have already been published.27 The present study represents a new insight into the BIGPRO 1 population at inclusion.
Aliquots of blood samples drawn during the trial were immediately centrifuged, frozen, and sent to the central laboratories in Lille (INSERM U325) for glucose and lipid and apolipoprotein measurements and in Marseille (Endocrinology and Hematology Departments of La Timone Hospital) for insulin, blood coagulation, and fibrinolysis measurements. Blood was drawn with fluoride Vacutainer tubes for glucose and with EDTA Vacutainer tubes for lipids, apolipoproteins, and insulin. Plasma and serum were obtained after a 10-minute centrifugation at 3000g. Glucose, cholesterol, and triglycerides were measured by enzymatic methods (Boehringer-Mannheim) adapted to an automatic analyzer (Hitachi 717). HDL cholesterol was obtained by measurement of cholesterol with use of the same method that was used for total cholesterol after precipitation of non-HDL lipoproteins with sodium phosphotungstate/magnesium chloride (Boehringer-Mannheim). LDL cholesterol was estimated by use of the Friedewald formula29 for samples with triglyceride levels <4.56 mmol/L. ApoA-I and apoB were quantified by commercial reagent immunonephelometry (Behringwerke). Total plasma apoC-III and apoE levels and apoC-III and apoE in plasma devoid of apoB-containing lipoproteins (apoC-III Lp non-B and apoE Lp non-B) were measured by an electroimmunoassay using Hydragel LpC-III and LpE kits, respectively, supplied by Sebia. ApoC-III and apoE levels in apoB-containing lipoproteins (apoC-III LpB and apoE LpB) were obtained by calculating the difference between the results obtained in total plasma and in the Lp non-B lipoproteins. This methodology has been used previously, and its analytical performance and accuracy have been determined.23 Briefly, the complete immunoprecipitation of apoB-containing lipoproteins was checked for plasma samples of normolipidemic, hypercholesterolemic, hypertriglyceridemic, and mixed hyperlipidemic subjects (3 of each type) by measuring apoB in the supernatants after immunoprecipitation by use of an ELISA with a detection limit of 2.5 ng. The absence of coprecipitation of HDL was assessed by the absence of difference between plasma apoA-I and apoA-I in the supernatants. The within-day and between-day variances were also determined. For each parameter, the coefficients of variation were <10%. The accuracy of the assays was evaluated by mixing various quantities of VLDL and HDL to the infranatant (density 1.006 g/mL) of 3 corresponding hypertriglyceridemic plasma samples. Each fraction was quantified for apoC-III and apoE before and after mixing. The mean percentages of added apolipoproteins accounted for were 103.0% and 100.2% for apoC-III and apoE, respectively. Plasma insulin was determined by radioimmunoassay with use of a commercially available kit (CIS-Bio Industrie). In this assay, the cross-reactivity of proinsulin is 1:4 on a molar basis. For determination of hemostatic parameters, blood was collected on trisodium citrate (0.011 mol/L final concentration) in the presence of platelet inhibitors (Diatube, Diagnostica Stago) and immediately cooled on ice. Plasminogen activator inhibitor type 1 (PAI-1) activity was determined by using a commercially available kit (Biopool) according to the method of Ericksson et al.30 PAI-1 antigen, tissue plasminogen activator (tPA) antigen, and von Willebrand factor (vWF) were evaluated by ELISA with kits from Diagnostica Stago, according to the method of Declerck et al31 for PAI-1 antigen and Holvoet et al32 for tPA antigen.
All statistical analyses were performed with the use of SAS software (SAS Institute Inc). For the following variables (age, triglycerides, hemostatic variables, and insulin), which were not normally distributed, the concentrations in the different groups are shown as geometric means and 95% CIs. The apoC-III and apoE ratios had a nonparametric distribution; therefore, results are presented as median and 5th to 95th percentiles. The sex and triglyceride effects on the different clinical and biological parameters were evaluated by a 2-way ANOVA, except for apoC-III and apoE ratios, for which a nonparametric rank test by sex was run. Because a significant interaction was observed for HDL cholesterol, a 1-way ANOVA by sex was also run for this parameter. Simple correlations were expressed as the Spearman rank coefficients. The relationship between the logarithm of triglyceride concentrations and the other variables was evaluated in a stepwise multiple regression analysis.
Characteristics of the Studied Population
For the aim of the present study, the subjects of the BIGPRO 1 study who had all parameters of interest measured (n=431) at inclusion were divided into 2 subgroups according to their triglyceride concentrations: <1.7 mmol/L (normal triglyceride concentration), 265 patients; ≥1.7 mmol/L (high triglyceride concentration), 166 patients. The main clinical and biological characteristics of the population are presented in Tables 1⇓ and 2⇓. These results indicate that hypertriglyceridemic patients are also characterized by higher levels of cholesterol and LDL cholesterol, whereas their HDL cholesterol levels are lower than those in normotriglyceridemic patients. These changes in their lipid profiles are related to an increase in apoC-III LpB and apoE LpB and also to a more modest increase in the concentration of apoC-III Lp non-B and apoE Lp non-B. Therefore, a tendency toward a decrease in apoC-III and apoE ratios (apoC-III Lp non-B/apoC-III LpB and apoE Lp non-B/apoE Lp B, respectively) is observed, but the statistical significance is obtained only for the apoC-III ratio in women. The hypertriglyceridemic subgroup is also characterized by an increase in plasma glucose and insulin as well as in PAI-1 activity or PAI-1 antigen, tPA antigen, and vWF, specifically in women for the latter. In addition, ANOVA revealed a clear triglyceride effect for all these parameters, whereas a significant sex effect was demonstrated for WHR, glucose, insulin, apoC-III Lp non-B, and tPA antigen.
Relationship Between Markers of Remnant Accumulation and Insulin
To establish whether the hyperinsulinemia found in patients suffering from insulin resistance was related to the accumulation of plasma triglycerides and remnants of TGRLs, Spearman correlation coefficients were calculated between serum insulin levels and the various markers of remnant accumulation. The results of these simple statistics are presented in Table 3⇓. Insulin serum concentration is highly correlated with triglycerides in both subgroups of female patients, whereas the correlation tends toward significance in male hypertriglyceridemic patients only. In contrast, insulin is positively correlated with apoC-III LpB and apoE LpB in only the hypertriglyceridemic patients of both sexes. No relation was found between insulin concentration and apoC-III Lp non-B or apoE Lp non-B. Therefore, a negative correlation is observed between insulin and the ratio of apoC-III Lp non-B to apoC-III LpB in the groups of patients of both sexes with high triglyceride concentrations.
Determinants of Plasma Triglyceride Concentration
To assess the independent contribution of the markers of remnant accumulation, insulin, and other parameters related to the plasma triglyceride concentration, a stepwise multiple regression analysis was carried out for each sex by use of age, body mass index, WHR, insulin, apoB, apoE LpB, apoE Lp non-B, apoC-III LpB, and apoC-III Lp non-B. Detail of the results obtained with this regression model are given in Table 4⇓. All parameters introduced in the model are positively associated with the plasma triglyceride concentration. Besides insulin, apoB and apoE LpB appear to be the main contributors of this concentration.
Relationship Between Markers of Remnant Accumulation and Markers of Fibrinolysis and Endothelial Damage
Spearman correlation coefficients between triglycerides, apoC-III LpB or apoE LpB, and the main markers of fibrinolysis and endothelial damage, namely, PAI-1 activity and antigen, tPA antigen, and vWF, are presented in Table 5⇓. Markers of fibrinolysis and PAI-1 activity and antigen are positively correlated with apoC-III LpB and apoE LpB only in the subgroup of hypertriglyceridemic male patients. Contrasting with these results, a positive correlation is observed between these markers and triglycerides in women, whatever the level of serum triglycerides, whereas male normotriglyceridemic patients do not exhibit any relation between these parameters. A positive correlation is also observed between tPA antigen and triglycerides in the normotriglyceridemic female group. vWF is negatively correlated with triglycerides in both sexes when the serum level of triglycerides is >1.7 mmol/L.
A dyslipidemic profile, characterized by a high plasma triglyceride concentration and a low HDL cholesterol level, is frequently observed in the insulin resistance syndrome.5 6 However, TGRLs represent a mixture of particles in which apoC-III and apoE are present in multiple copies. The content of apoC-III LpB and apoE LpB and the distribution of these apolipoproteins between apoB-containing and non–apoB-containing lipoproteins have been suggested to represent good markers of the TGRL remnant accumulation.20 In addition, several studies have suggested that these markers may be related to the increase in cardiovascular risk, which is usually associated with abnormalities in the metabolism of lipoproteins.23 24 25 The present study was undergone to establish whether these markers of remnant accumulation play a role in the hypertriglyceridemia associated with insulin resistance and whether they are related to other biological abnormalities frequently observed in this syndrome. The present study represents a new insight into the population of the BIGPRO 1 trial at inclusion, the main results of which have already been published.28 Among the 431 middle-aged subjects with upper body obesity included in this trial who had all lipid and hemostatic parameters measured, 38.5% had triglyceride serum concentrations >1.7 mmol/L and were considered to be hypertriglyceridemic. This cutoff point may be discussed inasmuch as there is no real consensus concerning triglycerides at the present time. It was chosen for 2 reasons. First, the recommendations for the management of lipid disorders of diabetic patients indicate that a triglyceride level of ≥1.7 mmol/L should be considered for therapeutics.33 Second, the International Task Force for the prevention of coronary heart disease recommends that particular note be taken of a triglyceride level of 1.7 to 4.5 mmol/L for the assessment of the global risk of cardiovascular disease.34 As shown in Tables 1⇑ and 2⇑, hypertriglyceridemic patients have higher plasma levels of glucose and insulin. These results confirm that hypertriglyceridemic patients present a more pronounced insulin resistance syndrome than do normotriglyceridemic patients. The other lipid abnormalities observed in the insulin resistance syndrome are also more pronounced, with lower HDL cholesterol and higher LDL cholesterol levels in hypertriglyceridemic patients. In these patients, hypertriglyceridemia is apparently accompanied by an increase in lipoprotein particles containing apoB and apoC-III or apoB and apoE (apoC-III LpB and apoE LpB), with a significant effect of triglycerides on these levels for both sexes. As the lipolysis of these lipoprotein particles proceeds, through the action of lipoprotein lipase, most of the apoC-III and some of the apoE molecules are transferred to HDL.8 9 10 This process explains the parallel increase in apoC-III Lp non-B and apoE Lp non-B observed in the hypertriglyceridemic patients. However, it is most probable that the lipolytic process is not efficient enough to clear the excess of apoC-III or apoE bound to apoB, inasmuch as the apoC-III Lp non-B/apoC-III LpB or apoE Lp non-B/apoE LpB ratios tend to be decreased in hypertriglyceridemic patients, although the triglycerides have a statistically significant effect only in women for the apoC-III ratio. In addition to these lipoprotein abnormalities, impaired fibrinolysis appears to be more pronounced in hypertriglyceridemic patients, as assessed by the increase in PAI-1 activity and antigen in the HTG groups. An increase in tPA antigen is observed in hypertriglyceridemic subjects of both sexes, whereas vWF appears to increase in hypertriglyceridemic women. tPA antigen and vWF are mainly secreted by the endothelial cells and are considered to be markers of endothelial damage.35 36 However, the tPA antigen level is also considered to reflect the plasma fibrinolytic activity because this immunologic measurement quantifies mainly the circulating PAI-1/tPA complexes.37 Therefore, the increase in tPA antigen in the hypertriglyceridemic subgroup would reflect the increase in circulating PAI-1 rather than endothelial damage per se.
Surprisingly, although the insulin level is positively correlated with triglycerides in both subgroups of patients, at least in women, significant correlations are observed with the different markers of remnant accumulation only in the case of hypertriglyceridemia. These correlations are positive with apoC-III LpB and apoE LpB, whereas they are negative with the apoC-III ratio. This observation suggests that hyperinsulinemia could lead to different lipoprotein abnormalities: an increase in serum TGRLs with a normal composition in apoC-III and apoE or the combination of quantitative and qualitative abnormalities with an accumulation of TGRLs substantially richer in apoC-III and apoE. In the first case, the patient would remain “relatively normotriglyceridemic”; in the second case, the patient would become hypertriglyceridemic. In the latter case, it is suggested that hyperinsulinemia may lead to a decrease in the lipolytic process through lipoprotein lipase, because the ratio of apoC-III Lp non-B to apoC-III LpB is negatively correlated with the insulin level. In other words, it may be hypothesized that insulin would stimulate the hepatic production of TGRLs rich in apoC-III and apoE and that the development of hypertriglyceridemia depends on the capability of the lipolytic process to adapt to this overloading. Hypertriglyceridemia appears to be a crude marker of visceral obesity and of insulin resistance in nondiabetic subjects.38 Therefore, it is not surprising to find that hyperinsulinemia is associated with an increased production of TGRLs enriched with apoC-III and apoE, with the visceral adipose cells providing the substrates for this production. Actually, it has recently been shown that visceral adipose tissue is associated with the postprandial triglyceride responses in both sexes.39 40 However, we cannot completely exclude a direct effect of insulin itself on the apoC-III and apoE production.
To estimate the relative contribution of insulin and other factors (including these markers of remnant accumulation) to the triglyceride serum level, a stepwise multiple regression was run in the entire male and female populations, with triglycerides as the explained variable. As shown in Table 4⇑, all variables included in the model are associated with the plasma triglyceride concentration. However, apoE LpB, apoE Lp non-B, and apoC-III Lp non-B (in women only for the latter) are significant contributors to triglyceridemia, independently of insulin and apoB. This suggests that not only the number of apoB-containing particles but also the relative enrichment of TGRL in apoE (ie, the number of apoE molecules per particle) determine the serum level of triglycerides. It has been shown previously that hypertriglyceridemia, accompanied by low HDL cholesterol levels, is associated with features of the insulin resistance syndrome.41 Also, HDL cholesterol has been reported to be more closely associated with various features of the insulin resistance syndrome, particularly the triglyceride level.42 In the present study, we suggest that in addition to HDL cholesterol, the apoE (and possibly the apoC-III) content of HDL particles is a good determinant of the triglyceride level in patients suffering from this syndrome.
Because fibrinolysis is impaired in insulin resistance, we studied the relationship between the markers of fibrinolysis and endothelial damage and the main markers of remnant accumulation: apoC-III LpB and apoE LpB. Although the correlations classically found43 44 45 between the markers of fibrinolysis or endothelial damage and triglycerides are observed in both subgroups of female patients, positive correlations are observed between PAI-1 activity or PAI-1 antigen and triglycerides as well as the 2 markers of remnant accumulation only in the hypertriglyceridemic subgroup of male patients. In vitro, it has been shown that VLDLs stimulate the production of PAI-1 by hepatic cells and endothelial cells.46 47 However, no study has been performed so far to establish the influence of the relative content in apoC-III and apoE of these lipoproteins on the production of PAI-1 by cells. It may be hypothesized that in the hypertriglyceridemic subgroup, an additional effect on the production of PAI-1 is observed because of the increased number of apoC-III and apoE molecules in TGRLs. However, the observed sex difference in the effect of the apoC-III and apoE composition of TGRLs on these markers of fibrinolysis should be studied further. The absence of a relationship between vWF and the different markers of remnant accumulation and the negative effect of triglycerides on vWF remain difficult to explain. Because vWF and tPA antigen are considered to be markers of endothelial damage,35 36 it may be suspected that the apoC-III and apoE content of TGRLs does not have a direct effect on the endothelium. Therefore, the weak positive but not significant relationship between these parameters and tPA antigen would be the consequence of their effect on PAI-137 rather than a direct effect on the endothelium.
In conclusion, the present study has demonstrated that increased insulin levels found in insulin resistance syndrome are associated with an increased production of TGRLs enriched in apoC-III and apoE. The accumulation of these remnants and/or their abnormal composition in apoC-III and apoE could be an explanation for the development of hypertriglyceridemia in this syndrome. Because these markers of remnant accumulation have been found to be cardiovascular risk markers,23 24 25 26 this phenomenon could be part of the explanation for the increased risk in patients suffering from insulin resistance. The benefit of measuring these markers for a more precise evaluation of the cardiovascular risk for subjects with insulin resistance syndrome should be further studied.
BIGPRO Study Group
The BIGPRO study group includes the following: Michel Safar, MD, Chairman (INSERM U337, Paris); Eveline Eschwège, MD, M. Aline Charles, MD, MPH, Annick Fontbonne, MD, PhD, and Patricia Lavoine, (INSERM U21-258, Villejuif); Jean-Marie Bard, PhD, and Jean-Charles Fruchart, PhD (INSERM U325, Lille); Gilles Bouvenot, MD, Charles Caulin, MD, Pierre Grandmottet, MD, and Patrice Queneau, MD (National Pedagogic Association for the Teaching of Therapeutics, APNET, Paris, France); Bernard Bégaud, MD (School of Medicine, University of Bordeaux); Irène Juhan-Vague, MD, PhD, and Philippe Vague, MD, PhD (University of Marseille); Philippe André, MD, and Françoise Isnard, MD (LIPHA, Lyon, France); and Jean-Marie Cohen, MD (OPEN/ROME, Paris, France).
BIGPRO Clinical Centers
The BIGPRO centers include the following: Amiens, Regional University Hospital, Department of Internal Medicine (Head, J.P. Ducroix; Investigator, N. Vanwymeersch); Angers, Regional University Hospital, Department of Diabetology (Head, M. Marre; Investigator, M. Hallab); Besançon, J. Minjoz Regional University Hospital, Department of Endocrinology Diabetology (Head, J. Massol; Investigators, M. Grandmottet and V. Llorca); Bondy, Jean Verdier AP-HP University Hospital, Department of Endocrinology-Diabetology (Head, P. Attali; Investigators, P. Valensi and M. Attalah); Bordeaux, Saint-André Regional University Hospital, Department of Internal Medicine (Head, J. Paccalin; Investigator, C. Fromenteau); Brest, Morvan Regional University Hospital, Department of Internal Medicine (Head, D. Mottier; Investigator, L. Bressollette); Corbeil, Gilles-de-Corbeil Hospital, Department of Metabolic Diseases (Head, G. Charpentier; Investigators, C. Diaz and F. Goebel); Dijon, Bocage Regional University Hospital, Department of Endocrinology-Diabetology (Head, J.M. Brun; Investigator, J.M. Petit); Grau-du-Roi, Medical and Surgical Center, Department of Diabetology and Nutrition (Head, J.L. Richard; Investigator, S. Jureidini); Grenoble, Regional University Hospital, Department of Endocrinology (Head, S. Halimi; Investigator, C. Talantikit); Lille, Regional University Hospital, Department of Endocrinology-Diabetology (Head, P. Fossati) and Dr Borys’ private practice (Investigator, J.M. Borys); Lyon, Lyon Sud Regional University Hospital, Department of Internal Medicine (Head, D. Vital-Durand; Investigator, R. Nové-Josserand); Lyon, Lyon Sud Regional University Hospital, Department of Endocrinology-Diabetology (Head, J. Orgiazzi; Investigator, N. Chatenay-Laniel); Lyon, Edouard Herriot Regional University Hospital, Department of Nephrology (Head, M. Laville; Investigator, P. Morel); Lyon, Antiquaille Regional University Hospital, Department of Endocrinology (Head, F. Berthezène; Investigator, M.P. Larmaraud); Marseille, La Timone Regional University Hospital, Department of Endocrinology-Diabetology (Head, P. Vague; Investigator, C. Mattei); Nancy, Regional University Hospital, Department of Internal Medicine (Head, J. Schmitt; Investigator, D. Wahl); Nantes, Hôtel-Dieu Regional University Hospital, Department of Endocrinology-Diabetology (Head, B. Charbonnel; Investigator, P. Blanchard); Nîmes, Carémeau Hospital, Department of Internal Medicine (Head, J. Jourdan; Investigator, P. Guillot); Nîmes, Carémeau Hospital, Department of Medicine T (Head, M. Rodier; Investigator, C. Gouzes); Paris, Broussais AP-HP University Hospital, Department of Internal Medicine (Head, M. Safar; Investigators, B. Darné and F. Ferhaoui); Paris, Laënnec AP-HP University Hospital, Department of Internal Medicine (Head, F.C. Hugues; Investigator, C. Le Jeunne); Paris, Lariboisière AP-HP University Hospital, Emergency Department (Head, C. Caulin; Investigator, O. Chassany); Paris, Saint-Antoine AP-HP University Hospital, Department of Endocrinology (Head, P. Aubert; Investigator, L. Ponsoye); Poitiers, Regional University Hospital, Department of Endocrinology-Diabetology (Head, R. Maréchaud) and Dr Breux’s private practice (Investigator, M. Breux); Reims, Robert Debré Regional University Hospital, Department of Endocrinology (Head, M. Leutenegger; Investigator, H. Grulet); Rennes, Hôtel-Dieu Regional University Hospital, Department of Cardiology A (Head, J.C. Daubert; Investigators, F. Paillard and B. Bompais); Roubaix, Roubaix Hospital, Department of Metabolic Diseases (Head, J.L. Grenier; Investigators, P. Gross and F. Gentholz); Saint-Etienne, Bellevue Regional University Hospital, Department of Endocrinology (Head, B. Estour; Investigator, H. Villard); Saint-Laurent-du-Var, Arnaud Tzanck Institute, Department of Endocrinology-Diabetology (Head, N. Balarac; Investigator, N. Balarac); Toulouse, Purpan Regional University Hospital, Department of Internal Medicine (Head, B. Chamontin; Investigator, T. Brillac); and Tours, Bretonneau Regional University Hospital, Department of Internal Medicine (Head, J.L. Guilmot; Investigator, E. Diot).
This work was supported by grants from the LIPHA company (contract INSERM-LIPHA No. 90050) and from the National Health Insurance for Wage Earners (CNAMTS).
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