Plasminogen activator inhibitor type-1 is an independent marker of metabolic disorders in young adults born small for gestational age.

BACKGROUND: Metabolic syndrome (MS) has been associated with being born small for gestational age (SGA). In epidemiological studies plasminogen activator inhibitor type-1 (PAI-1) levels have been associated with MS. Few studies have examined this association in subjects born SGA. PATIENTS AND METHODS: Five hundred and fifty-seven SGA adults (birth weight < 10th percentile) were compared with 671 subjects with a birth weight between the 25th and 75th percentiles (control group). MS was defined using the World Health Organization (WHO) definition. Active PAI-1 was measured on citrated plasma with bio-immunoassay. RESULTS: MS was more prevalent in the SGA group (8.7%) than in the control group (5.5%; P = 0.03). In both groups, PAI-1 concentrations were significantly correlated with waist circumference, plasma triglycerides, homeostatic model assessment-insulin resistance (HOMA-IR) and associated with male sex and MS. PAI-1 concentrations were significantly increased in the SGA group (12.2 ± 21.2 vs. 10.0 ± 13.5 IU mL⁻¹, P = 0.03) and this remained after adjustment of metabolic variables (P = 0.009). PAI-1 concentrations above 4.9 IU mL⁻¹ (= median of PAI-1 concentration in the control group) were present in 94% of the subjects with MS. Moreover, the adjusted odds ratio (OR) for having elevated PAI-1 was 1.48 (1.08; 1.95) in the SGA group in comparison with the control group (P = 0.005). CONCLUSIONS: PAI-1 plasma concentrations were significantly increased in SGA subjects independently of MS. These data suggest that elevation of PAI-1 concentrations might be an indication of an abnormal secretion at the level of the adipose tissue, endothelial cells or liver and implicated in metabolic disorders reported in SGA subjects.

Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age.

AIMS/HYPOTHESIS: Insulin resistance (IR) and the metabolic syndrome (MS) have been reported in adults as a consequence of being born small for gestational age (SGA). The process seems to be initiated early in life; however, little is known about the progression of MS and IR in young adults. We hypothesised that being born SGA would promote a greater progression over time of IR and MS, reflecting not only the gain in weight and fat mass but also the extension of the fetal programming process. METHODS: Participants were selected from a community-based cohort and born full-term either SGA (birthweight <10th percentile) or appropriate for gestational age (25th < birthweight < 75th percentile). A total of 1,308 individuals were prospectively followed between the ages of 22 and 30 years. RESULTS: At both ages, individuals born SGA were more insulin-resistant and showed a significantly higher prevalence of MS. Over the 8 year follow-up, the risk of developing MS was twofold higher in those SGA, after adjustment for gain in BMI, whereas the progression of IR was not significantly affected by the birth status. CONCLUSIONS/INTERPRETATION: Our data suggest that metabolic disorders in SGA individuals are amplified by the weight gain with time when adults, both probably resulting from fetal programming. Moreover, the modest increase in IR contrasts with the constant and much higher prevalence of MS.

Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B.

CONTEXT: Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy. OBJECTIVE: To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome. DESIGN AND SETTING: A university hospital-based prospective study from 2001 to 2008. SUBJECTS AND METHODS: Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening. RESULTS: Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC. CONCLUSION: Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

Birth weight and long-term metabolic outcomes: does the definition of smallness matter?

OBJECTIVE: To establish the role of individual definition of smallness at birth in the association between birth weight and long-term metabolic outcomes. METHODS: Lipid profile and oral glucose tolerance test were performed in young adults (22 years) born either small (SGA) or appropriate for gestational age (AGA). AGA/SGA were defined by both population-based and customized methods adjusting for individual maternal/pregnancy characteristics. 825 individuals were classified as AGA and 575 as SGA by both methods, 131 were SGA by the population-based method only (SGA(pop)) and 22 were SGA by the customized method only (SGA(cust)). RESULTS: SGA(cust) subjects had higher total cholesterol and triglyceride levels and lower high-density lipoprotein cholesterol concentrations than SGA(pop) and AGA subjects, however, insignificantly when adjusted for age, gender and body mass index. The homeostasis model assessment for insulin resistance (HOMA-IR) index was higher in the SGA(cust) (p = 0.05) and SGA(pop) (p = 0.02) versus the AGA group. Controlling for the HOMA-IR index, the insulinogenic index was significantly lower in the SGA(cust) versus SGA(pop) (p = 0.001) and AGA (p = 0.003) groups. In SGA(cust) individuals, the HOMA-IR index was clearly shifted to higher, while the insulinogenic index to lower tertiles of AGA distribution; SGA(pop) subjects had the HOMA-IR and insulinogenic index predominantly in the highest tertiles. CONCLUSIONS: Individualized birth weight standards allow to better identify subjects who failed to reach their genetic potential of intrauterine growth and are at higher risk of metabolic disturbances and impaired insulin secretion later in life.

Impact of fetal growth restriction on body composition and hormonal status at birth in infants of small and appropriate weight for gestational age.

BACKGROUND: Fetal growth restriction (FGR) has been related to several health risks, which have been generally identified in small-for-gestational age (SGA) individuals. OBJECTIVE: To evaluate the impact of FGR on body composition and hormonal status in infants born either small- or appropriate-for-gestational age (AGA). METHODS: Fetal growth was assessed by ultrasound every 4 weeks from mid-gestation to birth in 248 high-risk pregnancies for SGA. Fetal growth velocity was calculated as change in the estimated fetal weight percentiles and FGR defined as its reduction by more than 20 percentiles from 22 gestational weeks to birth. Impact of FGR on body composition, cord insulin, IGF-I, IGF binding protein-3 (IGFBP-3), and cortisol concentrations was assessed in SGA and AGA newborns. RESULTS: Growth-retarded AGA infants showed significantly reduced birth weight, ponderal index, percentage of fat mass, and bone mineral density when compared with AGA newborns with stable intrauterine growth. Cord IGF-I and IGFBP-3 concentrations were significantly decreased in growth-retarded infants in both SGA and AGA groups. Cord insulin concentration was significantly lower and cord cortisol significantly higher in AGA infants with FGR versus AGA newborns with stable intrauterine growth. After adjustment for gestational age and gender, birth weight was directly related to fetal growth velocity and cord IGF-I concentration. The variation in infant's adiposity was best explained by fetal growth velocity and cord insulin concentration. CONCLUSIONS: FGR affects body composition and hormonal parameters in newborns with birth weight within the normal range, suggesting these individuals could be at similar metabolic risks as SGA. .

Inter-method variability in PTH measurement: implication for the care of CKD patients.

The National Kidney Foundation/Kidney-Dialysis Outcome Quality Initiative guidelines recommend to maintain the serum intact parathyroid hormone (PTH) concentration between 150 and 300 ng/l in chronic kidney disease (CKD) stage 5 patients. As these limits were derived from studies that used the Allegro intact PTH assay, we aimed to evaluate whether they were applicable to other PTH assays. We compared the PTH concentrations measured with 15 commercial immunoassays in 47 serum pools from dialysis patients, using the Allegro intact PTH assay as the reference. We also evaluated the recovery of graded amounts of synthetic 1-84 and 7-84 PTH added separately to a serum pool. Although the assays were highly correlated, the concentrations differed from one assay to another. The median bias between the tested assays and the Allegro intact PTH assay ranged from -44.9 to 123.0%. When the PTH concentrations were 150 or 300 ng/l with the Allegro intact PTH assay, they ranged with other assays from 83 to 323 ng/l and from 160 to 638 ng/l, respectively. The tested assays recognized 7-84 PTH with various cross-reactivities, whereas a given amount of 1-84 PTH was recovered differently by these assays. We found important inter-method variability in PTH results owing to both antibody specificity and standardization reasons. The unacceptable consequence is that opposite therapeutic attitudes may be reached in a single patient depending on the PTH assay used. We propose to use assay-specific decision limits for CKD patients, or to apply a correcting factor to the PTH results obtained with a given assay.

Low serum adiponectin levels in subjects born small for gestational age: impact on insulin sensitivity.

OBJECTIVE: Increasing evidence point to the role of the adipose tissue on the insulin resistance associated with reduced fetal growth. Since adiponectin, exclusively produced by the adipose tissue, exerts an important insulin-sensitizing activity, it appears critical to investigate the effect of being born small for gestational age (SGA) on adiponectin production in adulthood and its relationship with insulin sensitivity. SUBJECTS AND METHODS: Serum adiponectin concentrations were measured in 486 young adults born SGA, precisely selected on birth data, who were compared to 573 age-matched subjects born appropriate for gestational age (AGA). The relationship between serum adiponectin levels and insulin-resistance indices measured under OGTT were tested and compared between the two groups. RESULTS: The SGA group demonstrated significantly reduced serum adiponectin levels than controls (12.6 +/- 6.9 vs 13.2 +/- 6.4 microg/ml, P = 0.02) and the difference remained significant when the key regulatory factors were taken into account (P = 0.008). In the AGA group, fasting I/G taken as an insulin-resistance index negatively correlated with serum adiponectin concentrations (P = 0.02), while the relationship followed a U-shape with increased fasting I/G ratio despite high concentrations of serum adiponectin in the SGA group (P = 0.12). CONCLUSION: Subjects born SGA demonstrated significantly reduced serum adiponectin levels, which were not related to insulin-resistance indices in comparison to what observed in age-matched subjects born AGA. Although this defect in adiponectin production and in its insulin-sensitizing action remains to be elucidated at the molecular level, it strengthens the critical contribution of the adipose tissue in the metabolic complications associated with reduced fetal growth.

Smallness for gestational age is associated with persistent change in insulin-like growth factor I (IGF-I) and the ratio of IGF-I/IGF-binding protein-3 in adulthood.

CONTEXT: Implication of the IGF-IGF-binding protein (IGFBP) axis in the development of metabolic and cardiovascular diseases has been well documented. It has also been shown that an adverse intrauterine environment alters the IGF-IGFBP axis during childhood. OBJECTIVE: The objective of this study was to investigate whether these alterations persist into adulthood. DESIGN AND METHODS: Fasting serum IGF-I, IGFBP-3, and insulin concentrations were measured, and their determinants were analyzed in a cohort of young adult subjects (22 yr of age) born either small (SGA; n = 461) or appropriate (AGA; n = 568) for gestational age. RESULTS: In adulthood, subjects born SGA had significantly lower mean serum IGF-I (320 +/- 137 vs. 348 +/- 143 microg/liter; P = 0.0015), IGFBP-3 (4700 +/- 700 vs. 4800 +/- 800 microg/liter; P = 0.04), and IGF-I/IGFBP-3 ratio (0.067 +/- 0.026 vs. 0.072 +/- 0.025; P = 0.01) than those born AGA. The fasting IGF-I concentration and the IGF-I/IGFBP-3 ratio were significantly inversely associated with age, body mass index, smoking, and oral contraception and were positively related to birth weight and fasting insulin levels. The IGFBP-3 concentration was significantly negatively correlated to age and smoking and was positively related to insulin concentration and oral contraception. After adjustment for age, height, body mass index, gender, smoking, and oral contraception, the mean IGF-I concentration and the mean IGF-I/IGFBP-3 ratio remained significantly lower in the SGA compared with the AGA group (P = 0.003 and P = 0.01, respectively). CONCLUSIONS: Serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio are lower in adult subjects born SGA. Although the origin of this persisting alteration of the IGF-IGFBP axis in adulthood needs to be elucidated, its potential contribution to the long-term metabolic and cardiovascular complications associated with fetal growth restriction is important to consider in the future.

In situ lipolytic regulation in subjects born small for gestational age.

OBJECTIVE: Subjects born small for gestational age (SGA) who are prone to develop insulin resistance in adulthood display an abnormal development pattern of the adipose tissue during fetal and postnatal life. Since the lipolytic activity of the adipose tissue is critical in the development of insulin resistance, the purpose of this study was to investigate whether SGA itself might affect lipolysis regulation. STUDY DESIGN: We studied the effect of catecholamines, by local injection of isoproterenol, and the effect of insulin, using two-step infusion at 8 and 40 mU/m2/min, on the in situ lipolysis of the subcutaneous abdominal adipose tissue of 23 subjects born SGA and 23 born appropriate for gestational age (AGA), using the microdialysis technique. RESULTS: Under isoproterenol infusion, the increase in dialysate glycerol concentration was significantly 1.5-fold higher in the SGA than in the AGA group (P=0.02) and induced a 20% increase in the plasma FFA concentration (P=0.04), whereas no significant increase was observed in the AGA group. The antilipolytic action of insulin on dialysate glycerol concentration was similar in both groups throughout the insulin infusion. CONCLUSION: Subjects born SGA demonstrated a hyperlipolytic reactivity to catecholamines, which might be regarded as an additional deleterious component of the insulin resistance associated with SGA. In contrast, being born SGA does not directly affect the antilipolytic action of insulin, showing that it does not play a major role in causing the long-term metabolic complications associated with reduced fetal growth.

Dynamic change in adiposity from fetal to postnatal life is involved in the metabolic syndrome associated with reduced fetal growth.

AIMS/HYPOTHESIS: The aims of this study were to establish the role of insulin resistance in the metabolic syndrome associated with restricted fetal growth and to characterise the fetal and postnatal determinants responsible for the long-term metabolic outcome. METHODS: The study population consisted of adults selected on birth data from a maternity registry and born either small for gestational age (SGA) (n=734, birthweight

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission.

AIMS: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years. METHODS: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity). PATIENTS: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity. RESULTS: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls. CONCLUSIONS: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.

[Recommendations for the standardization of growth hormone assays]. / Recommandations pour l'harmonisation des techniques de dosage sérique d'hormone de croissance.

The diagnosis of growth hormone (GH) deficiency is based on the GH biological response to pharmacological stimulation tests. The cut-off value defining normality is the same whatever the GH assay used. In a group of the French Society for Clinical Biology (SFBC), we have evaluated whether differences between the GH concentrations obtained with the 9 commercial GH assays available in France exist or not. The study samples consisted of 72 serum pools and serial dilutions of the recombinant GH 22 kDa international standard, IS 98/574. These dilutions were performed by using 3 different diluents: the specific diluent provided by the manufacturers and thus different from one assay to another, serum without GH and heparin plasma without GH. Despite being calibrated against the same international standard, the different assays proposed variable conversion factors between microg and mIU, and we decided to express the results in mIU. The GH concentrations obtained for the 72 serum pools with the 9 assays were highly correlated, but absolute concentrations were significantly different from one assay to another. In particular, the ratio between the concentrations measured with both assays giving the lowest and highest concentration in the same sample respectively was about 50%. In the recovery test executed by adding the international standard, the slope of the regression curve describing the relationship between expected and measured concentrations was different of 1 in all but one assay. Furthermore, for a given assay and a given expected concentration, the measured values were sometimes different by up to 30% depending on the diluent used. These results led us to advise the manufacturers to calibrate their assays against the recombinant GH international standard, IS 98/574, to take into account the matrix effect detected in our study and to use the official conversion factor of 3 mIU/microg. Waiting for this new calibration, it is recommended that the results should be expressed in mIU/L and that serum samples should be used for the measurement of GH instead of plasma samples.

Anti-Müllerian hormone levels in serum from human foetuses and children: pattern and clinical interest.

Serum anti-Müllerian hormone (AMH) determination has been used to investigate gonadal development and abnormal sexual differentiation, but until recently, it was based on assays developed by specialized laboratories. A short time ago, a sensitive assay kit was developed commercially (Immunotech-Beckman Coulter) for clinical use. With this method, we established usual levels of serum AMH in fetuses, newborns, and pre-pubertal children, and evaluated the clinical value of this assay. AMH measurement required only 25 microl of sample and could be performed within 3 h. In females, AMH emerged after birth at low levels (median: 4 ng/ml). In males, AMH levels remained stable during fetal life (median: 44.4 ng/ml), peaked in the first months of life to reach a median of 124.7 ng/ml, then fell with wide individual variations. Cord blood AMH levels at birth may be useful to investigate ambiguous genitalia suspected prenatally. In children with isolated microphallus or hypospadias, decreased AMH values are in favor of testis dysfunction. When testes cannot be palpated, a single determination of serum AMH levels can distinguish between anorchia and cryptorchidism.

Absorption and efficiency of insulin after oral administration of insulin-loaded nanocapsules in diabetic rats.

Poly(isobutylcyanoacrylate) nanocapsules have been shown to decrease the blood glucose level after oral administration to streptozotocin-induced diabetic fasted rats after 2 days [Diabetes 37 (1988) 246]. Yet, the absorption of insulin in the blood of rats has not been characterised. The aim of this work was to evaluate the biological activity of insulin given orally as nanocapsules. Humalog-loaded nanocapsules (50 IU/kg) were administered by gavage to streptozotocin-induced diabetic rats. Thirty minutes to 1 h after oral administration, significant levels of human insulin were detected in rat plasma. However, the concentrations were very heterogenous from one rat to another and no decrease of glycemia could be observed. In addition, parenteral injection of insulin in solution showed that high levels of the protein are necessary to decrease blood glucose concentration in diabetic rats. These concentrations were not reached after oral administration. The same dose of insulin decreased glycemia by 50% in normal rats and by only 25% in diabetics. This suggested that an insulino-resistance was developed by streptozotocin-induced diabetic rats.

Biochemical investigation of foetal and neonatal thyroid function using the ACS-180SE analyser: clinical application.

Despite sonographic detection of foetal goitre, uncertainty persists in the initial diagnosis of thyrotoxicosis and hypothyroidism. The aim of this study was to establish foetal and neonatal iodothyronine and thyrotrophin reference values for the ACS-180SE analyser. From 22 to 36 weeks of gestation, median foetal serum free thyroxine (FT4) levels increased from 6.0 pmol/L to 143 pmol/L, while free tri-iodothyronine (FT3) levels increased from 0.7 pmol/L to 1.9 pmol/L and mean thyrotrophin (TSH) levels remained stable (10.2 +/- 3.8mU/L; n = 33). At birth, concentrations were independent of gender and gestational age. Among the 10 cases of sonographically detected foetal goitre, serum TSH and FT4 were measured in five, showing hypothyroidism (3/5) or hyperthyroidism (2/5). Cord blood TSH levels reflected the efficacy of prenatal therapy. Measurement of foetal FT4 and TSH can be used to confirm foetal thyroid dysfunction, whereas treatment efficacy can be assessed sonographically and confirmed by measurement of TSH assay at birth.

Utility of insulin-like growth factor-I and its binding protein assays.

Insulin-like growth factor-I circulates in serum either in free form or bound to insulin-like growth factor-binding proteins that modulate its bioavailability. Insulin-like growth factor-binding proteins interfere with insulin-like growth factor-I assay, which remains technically difficult. Many assays have been developed, but their results are somewhat discordant. The choice of separation method, standard and tracer considerably influences the results. The circulating concentration of insulin-like growth factor-I, however, is clearly dependent on nutritional status, and total levels are a valuable marker of nutritional status. The clinical utility of free insulin-like growth factor-I assay and simultaneous assay, in the same sample, of total insulin-like growth factor-I and its binding proteins (reflecting the bioavailable insulin-like growth factor-I fraction), remains to be evaluated.

Hemodynamic, metabolic and hormonal responses to oral glibenclamide in patients with cirrhosis receiving glucose.

BACKGROUND: In patients with cirrhosis, glucose may induce splanchnic and renal vasodilation. Since the antidiabetic sulfonylurea glibenclamide is known to induce splanchnic and renal vasoconstriction in portal hypertensive animals, this drug may inhibit glucose-induced hemodynamic responses in patients with cirrhosis. The aim of the present study was to investigate, in patients with cirrhosis, the short-term effects of glibenclamide on hemodynamic and humoral responses to glucose. METHODS: Patients were randomly assigned to receive either glibenclamide (5-mg tablet) or a placebo. All patients received an infusion of 10% glucose (62.5 ml/h for 12 h) that was started at the same time as glibenclamide or placebo administration. Studies were performed prior to and 90 min after glibenclamide or placebo. RESULTS: Glibenclamide (i.e. glibenclamide plus glucose) significantly increased plasma insulin concentrations and glycemia while placebo (i.e. glucose alone) significantly increased glycemia but did not change plasma insulin levels. Glibenclamide did not significantly change the hepatic venous pressure gradient while this value was significantly increased following glucose alone. Glibenclamide did not significantly change renal blood flow and glomerular filtration rate while glucose alone significantly increased renal blood flow without affecting the glomerular filtration rate. Glibenclamide significantly decreased cardiac index while glucose alone did not change this value. CONCLUSIONS: In patients with cirrhosis receiving glucose, glibenclamide blunted glucose-induced splanchnic and renal vasodilation. In addition, glibenclamide per se induced a decrease in cardiac index. These findings should be taken into account when glibenclamide is administered to patients with cirrhosis and type 2 diabetes.

No evidence for a major beta-cell dysfunction in young adults born with intra-uterine growth retardation.

The association between low birth weight and the later development of type 2 diabetes is well established. It has been hypothesized that in utero undernutrition may affect pancreatic beta-cell development, leading to an impaired beta-cell function in adulthood. We have previously demonstrated that intrauterine growth retardation (IUGR) is associated with insulin-resistance early in adulthood. The aim of this study was to test whether IUGR would affect beta-cell function in young adults. Twelve 25-yr-old insulin-resistant subjects with IUGR were matched for age gender and body mass index (BMI) to 13 controls. All of them had normal glucose tolerance. Mean fasting plasma glucose did not significantly differ between the group with IUGR and the control group (97 +/- 7 vs. 98 +/- 4 mg/dL; p = 0.83). Blood glucose was maintained at 124.8 +/- 6.5 vs. 126.2 +/- 7.5 mg/dL above the basal glycemia in the IUGR and control groups (p = 0.64) throughout the hyperglycemic clamp. Serum insulin concentrations did not significantly differ between the group with IUGR and the control group either during the first (0-10 min) phase (311 +/- 252 vs. 248 +/- 184 pmol/L, p = 0.85) or during the second (80-100 min) phase (575 +/- 284 vs. 559 +/- 413 pmol/L, p = 0.72). C-peptide concentrations were similar in both groups during the two phases (2.35 +/- 1.44 vs. 2.59 +/- 1.10 nmol/L, p = 0.39 and 4.86 +/- 1.36 vs. 4.96 +/- 1.41 nmol/L, p = 0.91). In conclusion, our data do not argue in favor of an impairment of beta-cell function at 25 yr of age as a consequence of in utero undernutrition, but rather suggest that insulin resistance might be the primary defect responsible for the development of metabolic disorders associated with IUGR in adulthood.

Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women.

It was recently suggested that precocious pubarche associated with subsequent functional ovarian hyperandrogenism and hyperinsulinemia could have a common origin in reduced fetal growth. We previously reported that young women born with intrauterine growth retardation (IUGR: birth weight less than the third percentile) were hyperinsulinemic and less insulin sensitive than women born with normal birth weight. The aim of the present study was to investigate whether these IUGR-born women demonstrated hyperandrogenism compared with controls. Our study population was composed of 130 IUGR-born women and 150 controls, of similar age (20.6 +/- 3.2 vs. 20.4 +/- 2.0 yr). Hormonal contraception in terms of frequency and medication, including antiandrogenic therapy, was identical in the 2 groups. After adjustment for hormonal contraception, being born with IUGR had no independent effect on serum androgen concentrations. In women who were not receiving hormonal contraception, no statistical differences were found between IUGR-born women (n = 67) and controls (n = 64) for delta4-androstenedione (2.26 +/- 0.68 vs. 2.24 +/- 0.55 ng/mL; P = 0.76), dehydroepiandrosterone sulfate (2294 +/- 1117 vs. 2489 +/- 1235 ng/mL; P = 0.24), testosterone (0.82 +/- 0.85 vs. 0.70 +/- 0.26 ng/mL; P = 0.80), or serum sex hormone-binding protein concentrations (45.5 +/- 28.2 vs. 53.1 +/- 30.3 nmol/L; P = 0.27). In both IUGR and control groups, sex hormone-binding protein correlated negatively with fasting insulin (r = -0.23; P = 0.03 and r = -0.26; P = 0.05), but serum androgen levels did not correlate with insulin. In summary, hyperinsulinemia observed in young women born with IUGR is not associated with hyperandrogenism. Consequently, our results do not support the hypothesis of a common in utero programming of hyperandrogenism and hyperinsulinemia.

Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART).

This study assessed glucose tolerance, insulin sensitivity and lipid parameters in HIV-infected patients presenting with lipodystrophy during HAART including protease inhibitors. Fourteen consecutive patients from Rothschild Hospital treated with HAART and presenting with marked facial lipoatrophy were evaluated. A 75 g oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, proinsulin and free fatty acids at T0, 30, 60, 90 and 120 min was performed. Lipid parameters (triglycerides, cholesterol, apolipoproteins A1 and B) were studied as well as nutritional and inflammatory markers (albumin, prealbumin, transferrin, haptoglobin, orosomucoid, C-reactive protein), endocrine and cytokine parameters (thyrotropin, cortisol, leptin, interleukin-6), HIV viral load and CD4-lymphocyte count. These patients were compared with 20 non-lipodystrophic protease inhibitor-treated patients. The measurements performed during OGTT showed that among the 14 lipodystrophic patients, 11 (79%) presented with diabetes (5 patients) or normal glucose tolerance but with insulin resistance (6 patients). This frequency was strikingly different in the group of nonlipodystrophic patients, which included only 4 (20%) presenting with diabetes (1 patient), or impaired glucose tolerance (2 patients), or normal glucose tolerance but with insulin resistance (1 patient). Hypertriglyceridaemia was present in 11 lipodystrophic (79%) versus 7 nonlipodystrophic patients (35%). Nutritional and endocrine measurements were normal. An abnormal processing of proinsulin to insulin was excluded. Thus, lipodystrophy during HAART was associated with diabetes, insulin resistance and hypertriglyceridaemia. Diabetes, diagnosed by basal and/or 120 min-OGTT glycaemia, seems more frequent than previously described. The therapeutic consequences of these results deserve evaluation in clinical trials.