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Biomedical subjects

J C Carel

Publications and source records attributed to J C Carel.

At least 19 recordsLinked to original sources
PubMed2006

Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents.

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappaB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.

Active Transport, Cell Nucleus↗
PubMed2005

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

Adolescent↗
PubMed2003

Destruction of conditional insulinoma cell lines in NOD mice: a role for autoimmunity.

AIMS/HYPOTHESIS: betaTC-tet (H2(k)) is a conditional insulinoma cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Transgenic expression of several proteins implicated in the apoptotic pathways increase the resistance of betaTC-tet cells in vitro. We tested in vivo the sensitivity of the cells to rejection and the protective effect of genetic alterations in NOD mice. METHODS: betaTC-tet cells and genetically engineered lines expressing Bcl-2 (CDM3D), a dominant negative mutant of MyD88 or SOCS-1 were transplanted in diabetic female NOD mice or in male NOD mice with diabetes induced by high-dose streptozotocin. Survival of functional cell grafts in NOD-scid mice was also analyzed after transfer of splenocytes from diabetic NOD mice. Autoreactive T-cell hybridomas and splenocytes from diabetic NOD mice were stimulated by betaTC-tet cells. RESULTS: betaTC-tet cells and genetically engineered cell lines were all similarly rejected in diabetic NOD mice and in NOD-scid mice after splenocyte transfer. In 3- to 6-week-old male NOD mice treated with high-dose streptozotocin, the cells temporarily survived, in contrast with C57BL/6 mice treated with high-dose streptozotocin (indefinite survival) and untreated 3- to 6-week-old male NOD mice (rejection). The protective effect of high-dose streptozotocin was lost in older male NOD mice. betaTC-tet cells did not stimulate autoreactive T-cell hybridomas, but induced IL-2 secretion by splenocytes from diabetic NOD mice. CONCLUSION/INTERPRETATION: The autoimmune process seems to play an important role in the destruction of betaTC-tet cells in NOD mice. Genetic manipulations intended at increasing the resistance of beta cells were inefficient. Similar approaches should be tested in vivo as well as in vitro. High dose streptozotocin influences immune rejection and should be used with caution.

Animals↗
PubMed2002

Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results.

OBJECTIVE: The small number of boys present in most studies on final height (FH) after gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP) offers difficulties in the evaluation of the effects of treatment on FH in males. METHOD: We therefore combined FH data from The Netherlands, Italy and France to study the effect of GnRHa treatment in a large group of 26 boys with CPP. RESULTS: The mean chronological age at the start of treatment was 7.6 +/- 2.0 (SD) years, bone age (BA) was 11.0 +/- 2.1 years. All boys were treated with depot formulations of the GnRHa triptorelin with established gonadal suppression for a mean treatment period of 4.7 +/- 2.1 years. FH was 172.9 +/- 6.6 cm. FH standard deviation score (SDS) was -0.66 +/- 1.22, not significantly different from the target height SDS of -0.23 +/- 0.75. FH-SDS was significantly lower in the subgroup of 12 patients with organic CPP compared to patients with idiopathic CPP (-1.34 +/- 1.06 vs. -0.08 +/- 1.06, respectively; p = 0.01), but no difference in height gain was observed. The mean estimated height gain, defined as the difference between predicted and actual adult height was 6.2 +/- 8.7 cm using the average tables of Bayley and Pinneau, and 0.3 +/- 8.6 cm using the BA advance adjusted tables. Regional differences in height gain were observed between the different countries, reflecting different local practices. CONCLUSION: We conclude that GnRHa treatment in boys results in a FH close to target height.

Antineoplastic Agents, Hormonal↗
PubMed2000

Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabète Insuline Orale group.

BACKGROUND: Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. METHODS: We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy. Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. FINDINGS: Baseline C-peptide and haemoglobin A1c concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A1c concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. INTERPRETATION: At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function.

Administration, Oral↗
PubMed2000

Effects of prolonged administration of ultralente insulin on fasting and postbreakfast beta-cell function in normal adults.

Treatment with small doses of subcutaneous insulin is being investigated as a possible approach to prevent type 1 diabetes in humans. The mechanism of prophylactic insulin therapy could involve the inhibition of beta-cell secretory activity and/or the initiation of an active immunoregulatory process. To evaluate the pure metabolic effect of exogenous insulin, the present study assessed whether daily subcutaneous administration of ultralente insulin alters beta-cell function in normal adults. Fourteen healthy adults were randomized to receive 0.2 U/kg x d ultralente insulin (Ultratard; Novo Nordisk, Bagsvaerd, Denmark) or placebo subcutaneously once daily for 30 days. Plasma glucose, C-peptide, and insulin concentrations were measured in the fasting state and 1 hour after a standardized breakfast, during treatment and during a recovery period of 10 days. Insulin administration induced a 15% to 40% decrease of fasting plasma C-peptide. In contrast, postbreakfast plasma C-peptide increased by 40% to 90% in subjects receiving insulin. Fasting and postbreakfast C-peptide concentrations were significantly different between groups during the injection period after adjustment for baseline concentrations (P < .05, ANOVA with repeated measures). These alterations disappeared 3 days after cessation of insulin treatment. The present regimen of exogenous insulin alters endogenous insulin secretion in normal subjects. Instead of the expected beta-cell rest, the effect appeared to be dual, with insulin secretion decreasing in the basal state and increasing after meals.

Adult↗
PubMed2000

Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics.

Since 1981, GnRH agonist administration has been the treatment of choice for central precocious puberty. Continuous administration of the agonist, instead of permanently stimulating gonadotropin secretion, deeply suppresses LH and FSH levels and induces a marked inhibition of gonadal activity and regression of clinical symptoms. This inhibitory effect is due both to specific kinetic parameters relative to natural GnRH, and to marked alterations of the biosynthetic pathways of gonadotropin subunits. The half disappearance time of infused agonists is 3-10 fold that of natural GnRH. This means that the residence time of GnRH agonists is significantly longer than that of GnRH. The resistance of agonist to enzymatic degradation, mainly due to the substitution of a hydrophobic D-amino acid for glycine 6, is one of the factors involved in the increased availability of GnRH superagonists. The paradoxical effects of GnRH superagonists are still incompletely understood. In children long-term treated with depot formulations of triptorelin or leuprorelin, alpha-subunit secretion is markedly increased, and remains sensitive to exogenous GnRH, which demonstrates that the gonadotrophs are not totally desensitized. Despite the sustained stimulation of a-subunit secretion, no deleterious side effects, either during therapy or during post-therapy follow-up, have been reported in children treated with GnRH agonists. It should be noted that alpha-subunit responsiveness to exogenous GnRH decreases progressively after several years of treatment, although it is never completely abolished. On the other hand, LH beta-subunit secretion is suppressed as evidenced by radioimmunoassay of LH beta-subunit in serum chromatographic fractions from children treated with triptorelin. This differential pattern of secretion parallels that of mRNA levels in rat pituitary after in vivo exposure to triptorelin. Both pharmacodynamic and pharmacokinetic data can help diagnose the situations of resistance or escape. The lack of clinical effect of GnRH in the treatment of precocious puberty can be due to true resistance, or to an inappropriate injection schedule, or to abnormal metabolism. Measurement of serum alpha-subunit level, and, if needed, of serum agonist level, generally provides the answer.

Delayed-Action Preparations↗
PubMed2000

Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass.

Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.

Adipose Tissue↗
PubMed1999

T-cell response to proinsulin and insulin in type 1 and pretype 1 diabetes.

Insulin-dependent diabetes mellitus (IDDM) results from the selective destruction of pancreatic beta cells by a T cell-mediated autoimmune process. Insulin and proinsulin are the only known beta cell-specific autoantigens. Using short-term cultures of freshly isolated peripheral blood mononuclear cells, we evaluated T-cell responses to proinsulin and to insulin in IDDM patients and individuals at risk for IDDM. A proliferative T-cell response to proinsulin was observed in only 2 of 26 recent-onset IDDM subjects and 2 of 12 long-standing IDDM subjects and was associated with a proliferative response to insulin. In contrast, 5 of 13 islet cell autoantibody-positive first-degree relatives of IDDM patients showed a proliferative response to proinsulin alone, 3 of 13 to insulin alone, and 1 of 13 to both insulin and proinsulin. Overall, 9 of 13 ICA-positive first-degree relatives responded to either proinsulin or insulin. We observed an inverse relationship between antiinsulin antibodies and T-cell responses to insulin in ICA-positive first-degree relatives but not in long-standing IDDM patients. Our data indicate that proinsulin is a major antigen in IDDM and, further, illustrate the difference between the autoimmune response to insulin and the immune response to exogenous insulin.

Adolescent↗
PubMed1999

Gonadotropin releasing hormone agonist treatment for central precocious puberty.

Several methodological problems complicate the evaluation of final statural height (FH) benefit after treatment with gonadotropin releasing hormone (GnRH) agonists for central precocious puberty (CPP). Since no controlled study has been performed, we have to rely on indirect methods, comparison with predicted height or with historical controls. FH of 58 girls, uniformly treated with triptorelin slow release formulation (triptorelin-SR, Decapeptyl((R))) for CPP were compared with predicted height before treatment and with FH of an historical group of patients not treated with GnRH agonist. The comparison with predicted height revealed an improvement of 4.8 +/- 5.8 cm; comparison with the historical control group showed a mean improvement of 8.3 cm. The post-treatment growth spurt (DeltaFH - height at the end of treatment) was a strong predictor of FH in multivariate analysis. The data suggest that continuing treatment beyond the age of 11 in girls does not improve and could actually decrease FH.

Body Height↗
PubMed1999

Lack of effect of GnRH agonists on final height in girls with advanced puberty: a randomized long-term pilot study.

GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 +/- 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 +/- 4.3 cm (+0.6 SDS) in group I, 136.1 +/- 4.2 cm (+0.8 SDS) in group II, with target height 157.6 +/- 4.3 cm (group I) and 157.8 +/- 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 +/- 3.9 cm and 155.2 +/- 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 +/- 4.0 cm) and untreated girls (156.1 +/- 5.3 cm) (NS).

Age Determination by Skeleton↗
PubMed1999

Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency.

Deficiency of protein Gs (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright's hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with Gs deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

Blood Glucose↗