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.

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.

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.

Relationship between first-phase insulin secretion and age, HLA, islet cell antibody status, and development of type I diabetes in 220 juvenile first-degree relatives of diabetic patients.

OBJECTIVE: To assess the adequacy of the first-phase insulin response for predicting development of insulin-dependent diabetes. RESEARCH DESIGN AND METHODS: Determinations were made of 1- and 3-min insulin responses to glucose (0.5 g/kg i.v.), islet cell antibodies (ICAs), insulin autoantibodies (IAAs), and HLA. We studied 220 first-degree relatives (aged 3-29 yr) of diabetic patients; 75 underwent two or more tests. RESULTS: At the first test, insulin responses correlated with age in ICA- children less than or equal to 11 yr old (r = 0.46, p less than 0.001). Individual responses varied widely in all ages, and low values were common (5th percentile: 108 pM in children less than 5 yr old, 180 pM thereafter). No correlation was found between insulin responses and IAAs or HLA. The responses of 15 ICA+ subjects were not significantly different from those of ICA- subjects after excluding the influence of age. At subsequent tests, ICA+ and ICA- subjects displayed distinct changes; the mean +/- SE insulin response increased in ICA- subjects from 619.2 +/- 40.8 to 716.4 +/- 50.4 pM (P less than 0.001) but declined in ICA+ subjects from 403.2 +/- 91.8 to 313.8 +/- 67.2 pM (P less than 0.02). During follow-up, 5 of 9 (56%) consistently ICA+ siblings developed diabetes or impaired glucose tolerance compared with 1 of 54 (2%) consistently ICA- subjects. The sensitivity and specificity of two or more low insulin responses (300 pM) for predicting progression to diabetes were 60 and 96%, respectively; the predictive value was 43%. The highest predictive value (75%) was achieved by the combination consistently ICA+, consistently low insulin response, and HLA-DR3/4. However, in no subject could the time of onset of diabetes be deduced from the decline of the insulin response. CONCLUSIONS: Consecutive intravenous glucose tolerance tests are a useful complement for predicting progression to diabetes but not its onset.

Susceptibility to type 1 diabetes in the Senegalese population is linked to HLA-DQ and not TAP and LMP genes.

OBJECTIVE: To investigate the frequency of the transporter associated with antigen processing (TAP) and large multifunctional protease (LMP) alleles and their role in the susceptibility to type 1 diabetes, in comparison with the well-known HLA-DQ alleles susceptibility, in Senegalese subjects. RESEARCH DESIGN AND METHODS: Three loci in the TAP/LMP region were analyzed in 92 type 1 diabetic subjects and 117 nondiabetic control subjects by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: No association was found between the studied polymorphisms of TAP1, TAP2, and LMP2 and type 1 diabetes in the Senegalese population, in contrast to the HLA-DQA1 and DQB1 genes, which were associated with type 1 diabetes. CONCLUSIONS: Diabetogenic genes in the class II HLA region are located near the DQA1 and DQB1 loci rather than the TAP and LMP loci.

HLA-DQ beta 1 typing and non-Asp57 alleles in the aborigine population of Senegal.

OBJECTIVE: To investigate, in Senegalese subjects, the frequency of human leukocyte antigen (HLA)-DQ beta 1 alleles and their role in susceptibility to insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: HLA-DQ beta 1 typing was done in 55 IDDM subjects and 118 nondiabetic control subjects by means of polymerase chain reaction restriction fragment length polymorphism. RESULTS: Alleles bearing a codon for an Asp residue at position 57 in the DQ beta-chain were associated with a significantly lower risk of IDDM. Alleles 0201 and 0302 (Ala57) were positively associated with diabetes, but allele 0501 (Val57) was less frequent in IDDM subjects than in control subjects. CONCLUSIONS: HLA-DQ beta 1 alleles may be genetic susceptibility markers for IDDM in the Senegalese population, as they are in Caucasian populations.

Pancreatic hormone expression in the murine thymus: localization in dendritic cells and macrophages.

The expression of preproinsulin (ppIns), proglucagon, prosomatostatin, and propancreatic polypeptide was investigated in thymic extracts, thymic cells, and thymic cell lines from C57BL/6 mice by RT-PCR. The expression of pancreatic hormones was similar in thymic extracts taken from neonatal and 2-, 4-, and 8-week-old animals, but was decreased in 20-week-old animals. Pancreatic hormone expression was not observed in mouse liver, salivary gland, or spleen. Analysis of thymic cell populations revealed a 10- to 20-fold enrichment in expression of all hormones in low buoyant density cells. No expression was detected in high buoyant density cells (predominantly thymocytes) or in thymic epithelial cell lines, primary cultures of epithelial cells, or peripheral macrophages. In addition, immunoreactive insulin, measured by specific RIA, was detectable in the low buoyant density population, but not in high buoyant density cells. The enriched cell population was depleted of contaminating lymphocytes and sorted based on reactivity to the cell surface markers F4/80 (macrophage) or N418 (dendritic cells). Cells gated for N418 demonstrated expression for ppIns, but not the other pancreatic hormones. Conversely, expression for proglucagon, prosomatostatin, and propancreatic polypeptide, but not ppIns, was detected in F4/80-gated cells. Our data indicate that pancreatic endocrine hormones are differentially expressed by dendritic cells and macrophages in a normal mice.

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.

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.

Insulin assays and reference values.

Insulin is produced by beta cells in pancreatic islets of Langherans via a complex process of proteolytic conversion. A precursor molecule, proinsulin, is transported to the Golgi apparatus where it is packed into secretory granules. Maturation of the secretory granules is associated with conversion of proinsulin to insulin and C-peptide by enzymatic cleavage. Secretion of insulin into the bloodstream is accompanied by the release of small amounts of proinsulins. Insulin immunoassays consist of radioimmunoassays using polyclonal antisera which cross-react with proinsulins, and two-site assays using monoclonal antibodies. These immunometric assays have led to improvements in specificity and sensitivity as compared to radioimmunoassays. To determine reference values and limits, insulinaemia must be measured in normoglycaemic subjects with a normal body weight. Moreover, as insulinaemia is most often measured during stimulation tests, reference values must also be determined for the most common tests such as the oral glucose tolerance test or the intravenous glucose tolerance test. We report the analytical characteristics of insulin assays and review reference values and their interpretation. Wide-scale use of insulin assays remains a subject of research rather than a diagnostic application. Spontaneous hypoglycaemia, a disorder which can be caused by hyperinsulinism, insulinoma, insulin autoimmune syndrome and non-insulin-mediated factors, is almost the only clinical indication for the measurement of plasma insulin. Diabetes is diagnosed solely on the basis of chronic hyperglycaemia. Thus, measurement of plasma insulin has no clinical value in the diagnosis or management of diabetic patients, with the exception of rare cases including the syndrome of severe insulin resistance and abnormalities in beta-cell secretory products. Otherwise, insulin measurement is used in experimental investigations to study the pathophysiology of various disorders, especially diabetes. The reference and range of plasma insulin values are not yet clearly established, and the range of concentrations reported in the literature remains unsatisfactory. There is a need to standardise results and thereby improve comparability among studies.

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.

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.

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.

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.

Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study.

OBJECTIVE: To investigate whether the association between low birth weight and increased risk of developing impaired glucose tolerance, insulin resistance, hypertriglyceridaemia, and hypertension in middle age is apparent by the age of 20 in people born small for gestational age. DESIGN: Regional cohort study. SETTING: Maternity registry, Haguenau, France. SUBJECTS: 236 full term singleton babies born small for gestational age (birth weight or length, or both, below third centile) during 1971-8 and 281 with normal birth weight (between 25th and 75th centile). All subjects were contacted and evaluated at a mean (SD) age of 20.6 (2.1) years. MAIN OUTCOME MEASURES: Adult height; concentrations of glucose, insulin, and proinsulin during an oral glucose tolerance test; lipid and fibrinogen concentrations; and blood pressure. RESULTS: After sex and target height were adjusted for, subjects who had been born small for gestational age were significantly shorter at age 20 than those with a normal birth weight (men 4.5 cm shorter (95% confidence interval 6.0 to 3.0 cm); women 3.94 cm shorter (5.2 to 2.7 cm)). After sex and body mass index were adjusted for, mean plasma glucose concentration 30 minutes after a glucose load, fasting insulin concentration (in women), and insulin and proinsulin concentrations 30 and 120 minutes after a glucose load were significantly higher in subjects who had been born small for gestational age than in those with a normal birth weight. Mean lipid and fibrinogen concentrations and blood pressure were not different between the two groups. CONCLUSIONS: Intrauterine growth retardation has long term consequences such as reduced final height Raised insulin and proinsulin concentrations are present in young adults born small for gestational age and could be markers of early changes in insulin sensitivity.

[Somatomedins]. / Les somatomédines.

Somatomedins or insulin-like growth factors (IGFs) are two polypeptides (IGF I and IGF II) whose structure shows great homology with proinsulin. Mostly synthetized by the liver but also by many tissues, they circulate in blood bound to specific binding proteins (IGFBPs). IGFBP3, a 120 to 150 kDa complex, carries over 95% of blood IGFs and its production is stimulated by growth hormone (hGH). On the contrary, IGFBP1, a 40 to 50 kDa protein, increases in case of hGH-deficiency. An IGFBP of 34 kDa, which is the major BP in cerebrospinal fluid but also present in blood, shows a great affinity for IGF II whereas the others BPs show similar affinities for both IGFs. Little is known about the other BP, IGFBP2. Two receptors can be found in most tissues: type 1, which binds IGFs and insulin, type 2, which binds IGF II preferentially to IGF I but not insulin. Type 1 IGF receptor has structural and enzymatic (phosphorylation of one of its own sub-units) similarities with the insulin receptor and mediates the action of IGF I. Type 2 receptor has an homology with the bovine cation-dependent mannose-6-phosphate receptor and has no known function. Liver production of IGF I is mainly under the control of hGH and other factors such as diet; other tissues are less or not at all under the control of hGH. The blood levels of IGF I raise from birth to the end of puberty, then decrease and remain almost stable during adulthood. The activity of IGF I on skeletal growth is well established and the determination of its plasma levels by radioimmunoassay is of great clinical utility in the diagnosis of growth disorders. IGF I levels in blood are high in case of acromegaly, low in hGH-deficiency, undernutrition, hypothyroidy and renal failure. IGF I acts in an autocrine/paracrine way and probably endocrine sometimes. How IGF II synthesis is regulated is not well known, in any case, IGF II has no effect on growth and the regulation of its secretion is hardly influenced by hGH, its blood levels remain unchanged in acromegaly and are irregularly diminished in hGH-deficiency. Moreover, IGF I and II promote cellular growth and differentiation. This activity could be of great importance during fetal life.

[Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in nutritional status]. / Hormone de croissance (GH) et insulin-like growth factor 1 (IGF 1) dans les états nutritionnels.

Nutrition plays a pivotal role in the regulation of growth hormone (GH) and insulin-like growth factor 1 (IGF 1) secretions; GH and IGF 1 in turn significantly influence the use of nutrients in humans and animals. Fasting, and caloric or protein restriction increase circulating values of GH and decrease those of IGF 1. These findings strongly suggest peripheral growth hormone resistance. Mechanisms accounting for this GH refractoriness could be a marked reduction in GH receptors, a decrease in binding of GH to its receptor, or post-receptor phenomena. Peripheral refractoriness to IGF 1 has also been described during caloric intake restriction. Metabolic effects of GH and IGF 1 are strongly dependent on a protein anabolic mechanism, and modifications of circulating levels of these hormones could be explained as an adaptation to the nutritional microenvironment of the cells. Because of the potent anabolic effects of GH and IGF 1 on protein metabolism, several authors have proposed treating severe catabolic states with GH or IGF 1. In humans both hormones seem to enhance protein anabolism but only for short periods. Secondary effects are mainly hypoglycemia with IGF 1 and hyperglycemia with GH. The combination of GH + IGF 1 could be a suitable approach to obtain a synergistic effect on protein metabolism and achieve normal blood glucose concentrations.

[Determination of plasma proinsulins, insulin and C-peptide]. / Dosage des proinsulines, insuline et peptide-C plasmatiques.

Insulin is synthesized from a precursor, proinsulin, then converted in the beta cell by sequential limited proteolysis into insulin and C-peptide, which are stored in secretory granules derived from the Golgi apparatus. Since this process is incomplete, some intact and partially processed proinsulins (split proinsulins) remain trapped in the granules and enter the circulation with insulin and C-peptide. As proinsulins are present in low concentration in serum and show structural homology with insulin and C-peptide, only two-site immunoassays using monoclonal antibodies can achieve sensitive and specific measurements of their intact and split forms. Insulin radioimmunoassays using polyclonal antibodies are not specific since such antibodies cross-react with proinsulins. Two-site immunoassays using monoclonal antibodies improve the specificity and the sensitivity of insulin determination. C-Peptide concentration is measured by radioimmunoassays using polyclonal antibodies which cross-react with proinsulins.

[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.

[HLA-markers and diabetic retinopathy in the Senegalese population]. / Marqueurs HLA et rétinopathie diabétique dans la population Sénégalaise.

Patients with IDDM often develop severe forms of retinopathy, supposed to be associated to risk factors such as hypertension, poor glycemic control and nephropathy. A controversial intervention of a genetic marker was evoked so as some diabetic patients have retinopathy in the absence of known risk factors. HLA-DR and DQ markers were compared in two groups of patients with IDDM respectively constituted of patients with and without severe retinopathy. HLA typing was carried out by polymerase chain reaction (PCR) and restriction fragments of length polymorphism (RFLP). DR9 (p < 10(-4); O.R. = 8.36) and DQA1*0301 (p < 0.05; O.R = 2.92) alleles were positively associated to diabetic retinopathy, at the opposite of DR3 (p < 10(-3); O.R: 0.01) and DQA1* (p < 10(-9); O.R = 0.15). Furthermore, among the genotypes previously considered as risk markers of IDDM in senegalese people, only DR4: DQA1*0301:DQB1*0302/DR9: DQA1*0301: DQB1*0201 was often observed in retinopathy.