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J Timsit

Publications and source records attributed to J Timsit.

At least 91 records · Page 5Linked to original sources
PubMed1993

Presence of anti-insulin reaginic auto-antibodies of the IgG4 class in insulin-dependent (type I) diabetic patients before insulin therapy.

The autoimmune aetiology of type I diabetes has been well documented. We studied whether anti-insulin anaphylactic antibodies were present on the membrane of basophils from type I diabetics by the toluidine blue method (detecting basophil activation after stimulation by insulin). We observed that basophils of recently diagnosed insulin-dependent diabetic patients (n = 13) were statistically more frequently activated by insulin than basophils from noninsulin-dependent diabetics (p < 0.002, n = 8) or non-diabetic subjects (p < 0.05, n = 9). Basophils from normal donors were passively sensitized with plasma from insulin-dependent diabetics and could then be activated by insulin. This sensitization still occurred when using plasma previously heated to 56 degrees C, indicating that the sensitizing antibodies were not of the IgE class. When basophils from type I diabetics were preincubated with anti-IgG subclasses, only anti-IgG4 monoclonal antibodies inhibited the insulin-induced basophil activation. By contrast, preincubation with blocking concentrations of anti-IgG1-3 antibodies or desensitization of the IgE pathway did not modify basophil activation. These experiments strongly suggest the presence of anti-insulin antibodies of the IgG4 subclass in insulin-dependent diabetics before any insulin administration and provide a simple tool to complement the usual method of detecting auto-antibodies in diabetes.

Adult↗
PubMed1993

Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion.

Chronic growth hormone (GH) hypersecretion in rats leads to increased isometric force without affecting the unloaded shortening velocity of isolated cardiac papillary muscles, despite a marked isomyosin shift toward V3. To determine if alterations occurred at the level of the contractile proteins in rats bearing a GH-secreting tumor (GH rats), we examined the mechanical properties of skinned fibers to eliminate the early steps of the excitation-contraction coupling mechanism. We found that maximal active tension and stiffness at saturating calcium concentrations (pCa 4.5) were markedly higher in GH rats than in control rats (tension, 52.9 +/- 5.2 versus 38.1 +/- 4.6 mN.mm-2, p < 0.05; stiffness, 1,105 +/- 120 versus 685 +/- 88 mN.mm-2.microns-1, p < 0.01), whereas values at low calcium concentrations (pCa 9) were unchanged. In addition, the calcium sensitivity of the contractile proteins was slightly but significantly higher in GH rats than in control rats (delta pCa 0.04, p < 0.001). The crossbridge cycling rate, reflected by the response to quick length changes, was lower in GH rats than in control rats (62.0 +/- 2.6 versus 77.4 +/- 6.6 sec-1, p < 0.05), in good agreement with a decrease in the proportion of alpha-myosin heavy chains in the corresponding papillary muscles (45.5 +/- 2.0% versus 94.6 +/- 2.4%, p < 0.001). The changes in myosin heavy chain protein phenotype were paralleled by similar changes of the corresponding mRNAs, indicating that the latter occurred mainly at a pretranslational level. These results demonstrate that during chronic GH hypersecretion in rats, alterations at the myofibrillar level contribute to the increase in myocardial contractility observed in intact muscle.

Animals↗
PubMed1993

Chronic growth hormone (GH) hypersecretion induces reciprocal and reversible changes in mRNA levels from hypothalamic GH-releasing hormone and somatostatin neurons in the rat.

Effects of growth hormone (GH) hypersecretion on somatostatin-(SRIH) and GH-releasing hormone (GHRH) were studied by in situ hybridization and receptor autoradiography in rats bearing a GH-secreting tumor. 6 and 18 wk after tumor induction, animals displayed a sharp increase in body weight and GH plasma levels; pituitary GH content was reduced by 47 and 55%, while that of prolactin and thyrotropin was unchanged. At 18 wk, hypothalamic GHRH and SRIH levels had fallen by 84 and 52%, respectively. In parallel, the density of GHRH mRNA per arcuate neuron was reduced by 52 and 50% at 6 and 18 wk, while SRIH mRNA levels increased by 71 and 83% in the periventricular nucleus (with no alteration in the hilus of the dentate gyrus). The numbers of GHRH- and SRIH-synthetizing neurons in the hypothalamus were not altered in GH-hypersecreting rats. Resection of the tumor restored hypothalamic GHRH and SRIH mRNAs to control levels. GH hypersecretion did not modify 125I-SRIH binding sites on GHRH neurons. Thus, chronic GH hypersecretion affects the expression of the genes encoding for GHRH and SRIH. The effect is long lasting, not desensitizable and reversible.

Animals↗
PubMed1993

Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pituitary tumours.

Among somatostatin analogues, octreotide is the most extensively studied. Its pharmacodynamic properties are similar to those of somatostatin, with a wide spectrum of inhibitory effects on anterior pituitary function, pancreas and gut endocrine secretions, and gastrointestinal functions. Compared with the somatostatin, octreotide is highly resistant to enzymatic degradation and has a prolonged plasma half-life of about 100 minutes in humans, allowing its use in the long term treatment of various pathological conditions. Differential effects of octreotide on endocrine secretions such as growth hormone (GH) and insulin in healthy volunteers, as well as variable efficacy in the treatment of endocrine tumours, may relate to the distribution of somatostatin receptor subtypes. The volume of distribution of octreotide ranges from 18 to 30L. Calculated serum distribution half-life ranges from 72 to 98 minutes. In blood, octreotide is mainly distributed in the plasma, 65% being bound to lipoproteins. After subcutaneous injection, absorption appears rapid and complete and bioavailability is about 100%. Mean peak plasma concentrations are between 2 and 4 micrograms/L in patients receiving 50 to 100 micrograms. Peak concentrations are reached within 20 to 30 minutes and are 20 to 40% of corresponding values after intravenous injection. Peak concentrations and values for areas under the plasma concentration-time curve linearly correlate with the dosage. The elimination half-life is about 90 to 110 minutes. Total clearance in healthy individuals is about 160 ml/min (9.6 L/h). Hepatic metabolism of octreotide is extensive (30 to 40%) and about 11 to 20% of the dose is excreted unchanged in the urine. Among pituitary tumours, GH- and thyrotrophin-secreting adenomas are the most sensitive to octreotide. Octreotide has been widely used in the treatment of acromegaly. 50 to 80% of the patients respond to daily multiple subcutaneous injections with insulin-like growth factor-1 (IGF1) levels being normalised in about 40 to 50% of them. Neither desensitisation with long term therapy nor rebound phenomena after octreotide withdrawal have been noticed in these studies. Even in patients with partial response, clinical symptoms improved. Octreotide daily dosages needed to achieve optimum responses may vary greatly from one patient to another. In a minority of patients complete resistance to octreotide was observed and was not always related to the absence of somatostatin receptors in the tumour. The wide spectrum of effects of octreotide in humans accounts for adverse effects seen during long term treatment, primarily cholelithiasis. Other modes of administration are efficient.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1993

Aberrant distribution of CD4 and CD8 lymphocyte subsets in recent-onset IDDM patients. Effect of cyclosporin.

The monoclonal antibodies 2H4 and 4B4 are specifically directed against CD45RA and CD29 antigens, respectively, which are expressed on both CD4+ and CD8+ lymphocytes. We used them to monitor the distribution of these T-cell subsets in 19 recent-onset IDDM patients (26 +/- 7 yr of age [mean +/- SD throughout]) receiving cyclosporin, and who had been treated with insulin for < 1 mo. Blood samples were examined before starting cyclosporin and after 3 and 9-12 mo of therapy. CD45RA and CD29 are expressed on distinct subsets of CD4+ T-cells, whereas in both healthy subjects and IDDM patients, 2H4 and 4B4 labeling does not always differentiate two distinct CD8+ populations. Various proportions of double-labeled CD8+ CD45RA+ CD29+ cells were detected in 59% of IDDM patients and 70% of healthy control subjects. Before cyclosporin treatment, recent-onset IDDM patients had a significantly lower proportion of CD4+CD29+ cells than the healthy control subjects (42 +/- 11 vs. 52 +/- 9%, P < 0.004). This imbalance corresponded to a significant increase in the CD4+ CD45RA+/CD4+ CD29+ ratio in the IDDM patients (1.37 +/- 0.93 vs. 0.78 +/- 0.36, P < 0.014). Independent of the presence of double-labeled cells, the proportion of CD8+ lymphocytes expressing CD45RA was significantly higher in the patients than in control subjects (72 +/- 15 vs. 57 +/- 15%, P < 0.004). The mean density of the CD45RA antigen (but not that of CD29) on both CD4+ and CD8+ cells was significantly higher in the IDDM patients before treatment than in the healthy control subjects. Cyclosporin induced complete or partial remission of the disease in 12 of 19 patients at 4-6 mo of treatment, but did not correct the imbalance between the regulatory T-cell subsets, regardless of clinical effectiveness. Cyclosporin use was associated with a significant decrease in CD45RA antigen density on both CD4+ and CD8+ T-cells.

Adult↗
PubMed1992

[Immunotherapy of type 1 diabetes].

Insulin-dependent diabetes mellitus is the late consequence of a chronic autoimmune disease directed to the B islet cell, that begins long before the hyperglycemic state. Experimental evidence suggests a central pathogenic role for autoreactive T lymphocytes. Immunointervention studies, particularly those using cyclosporin, have shown that it is possible to stop B cell destruction, even at the late stage of overt diabetes. New therapeutic approaches will be focused on the use of specific agents such as monoclonal antibodies and immunotoxins, and on earlier interventions allowed by the detection of genetic and immunological markers of prediabetes.

Diabetes Mellitus, Type 1↗
PubMed1992

Islet cell antibody heterogeneity among type 1 (insulin-dependent) diabetic patients.

Conventional detection of islet cell antibodies is based on indirect immunofluorescence performed on frozen human pancreas sections. The number and nature of epitopes recognized by antibodies detected by such techniques are unknown. To determine the existence of heterogeneous fluorescence patterns of islet cell antibodies on pancreatic sections, we selected two sera showing a distinctive granular fluorescence. We then tested random sera from patients with Type 1 (insulin-dependent) diabetes mellitus for their ability to block ultimate binding of fluorescein isothiocyanate-labelled immunoglobulins purified from these two sera with a characteristic granular pattern. Among 102 subjects with recent-onset Type 1 diabetes, 79 had detectable anti-islet cell antibodies; 21 showed complete blockade of the binding to islets of granular fluorescein isothiocyanate-labelled immunoglobulins. The majority of these 21 patients were women carrying a DR3 non-DR4 DQB1*0201 allele, with under-representation of DRB1*0402 and 0405. Discrimination between islet cell antigenic specificities may help in identifying islet cell autoantibodies in autoimmune Type 1 diabetes.

Adult↗
PubMed1992

Pancreas and islet transplantation in man.

The results of pancreas transplantation have greatly improved, the overall patient and graft 1-year survival rates now being 89 and 62%, respectively. A technically successful graft ensures a near-normal glucose metabolism in most cases, and improves the patient's quality of life. However, pancreas transplantation is not a life-saving procedure and because of the necessary permanent immunosuppression it is usually performed in patients in whom a kidney transplant is needed or has been previously established. In such patients the other diabetic chronic complications are often advanced and limit the potential benefit of pancreas transplantation, but it seems premature to extend the indications to early stage diabetes. Islet transplantation has many potential advantages, mainly the possibilities of immune alteration and immune protection of the transplant that could allow transplantation to be performed without immunosuppression and the use of xenogenic tissue. Major limiting factors are the high numbers of islets necessary to ensure insulin independence and the low yield of islet isolation from adult pancreas. Encouraging, albeit preliminary results have been recently reported in man.

Diabetes Complications↗
PubMed1992

Effects of octreotide on lipid metabolism in acromegaly.

Hypertriglyceridemia is the most frequent modification of lipid metabolism observed in acromegaly. The somatostatin analog, octreotide (Sandostatin), widely used in the treatment of acromegaly, is able to produce a decrease in levels of growth hormone (GH), insulin, and Insulin-like Growth Factor 1 (IGF1). We have attempted to evaluate the influence of this treatment on the lipid status of acromegalic patients. Seventeen patients with active acromegaly were treated with octreotide, 100 to 500 micrograms/injection subcutaneously three times daily. The levels of fasting serum triglycerides (TG), total cholesterol, High Density Lipoprotein (HDL) cholesterol and IGF1, as well as mean plasma GH and insulin levels during a diurnal profile, were evaluated before and after three months of octreotide therapy. GH, insulin and IGF1 decreased by 61%, 42% and 36% respectively (p less than 0.05). Mean levels (+/- SEM) of TG and total cholesterol fell from 2.2 +/- 0.4 mmol/l to 1.6 +/- 0.3 mmol/l (p less than 0.05) and 6.4 +/- 0.39 mmol/l to 5.6 +/- 0.27 mmol/l (p greater than 0.05), respectively. There was no correlation between triglyceride decrease and hormonal changes or clinical status (BMI, age, sex). In conclusion, the administration of octreotide over a three month period to acromegalic patients is associated with a decrease in TG levels.

Acromegaly↗
PubMed1992

Resistance to somatostatin (SRIH) analog therapy in acromegaly. Re-evaluation of the correlation between the SRIH receptor status of the pituitary tumor and the in vivo inhibition of GH secretion in response to SRIH analog.

The development of a long-acting somatostatin (SRIH) analog (octreotide, Sandoz) has been a major breakthrough in the treatment of acromegaly. However, in 20-30% of the patients, growth hormone (GH) plasma levels remain elevated (> 10 micrograms/l) despite treatment with octreotide. This raised the concept of resistance to SRIH analog therapy in acromegaly. Indeed, in vivo response to SRIH analogs varies greatly among acromegalic patients. According to the reviews in the literature and our own autoradiographic data, no direct correlation can be established between the GH response to octreotide and the number or affinity of the SRIH receptors located on the tumor. In our series a greater density of SRIH receptors is present on tumors from patients very sensitive to the SRIH agonist. A subset of patients resistant to octreotide could result from a very low density of SRIH receptor although this type of GH-secreting tumor constitutes certainly a rare case. A subset of GH-secreting pituitary tumors can be characterized by a mutation on the alpha subunit of the guanine nucleotide-dependent protein coupled to the stimulation of adenylate cyclase (G alpha s). This mutation results in a high basal adenylate cyclase activity and a low GHRH-stimulated activity. However, when the adenomas are separated according to their basal adenylate cyclase activity, SRIH is able to decrease cAMP levels in both types of tumor. In addition, in our series no direct correlation is observed between the SRIH inhibition of adenylate cyclase and the amount of SRIH-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1992

Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.

The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.

Adolescent↗
PubMed1992

Growth hormone and insulin-like growth factor-I stimulate hormonal function and proliferation of thymic epithelial cells.

We have investigated the role of GH and insulin-like growth factor-I (IGF-I) in controlling the secretion of thymulin, a hormone produced by thymic epithelial cells (TEC). Thymulin plasma concentrations (mean +/- SD) were increased in 21 patients with acromegaly compared to those in 30 controls, as assessed by bioassay (4.24 +/- 0.97 vs. 2.67 +/- 0.87; P less than 0.001) and RIA (561 +/- 241 vs. 315 +/- 113 pg/L; P less than 0.01). Good correlations were observed between plasma levels of thymulin and IGF-I (P less than 0.001). In vitro experiments demonstrated that both recombinant human GH and IGF-I significantly increased thymulin production in culture supernatants of normal human TEC and a rat TEC line. In parallel, IGF-I also significantly stimulated the proliferation of human TEC, as measured by bromodeoxyuridine incorporation. Additionally, the stimulatory effect of GH on thymulin production was abrogated by both an anti-IGF-I antibody and an anti-IGF-I receptor antibody. These results support a role for GH and IGF-I in the control of thymic hormonal function in man and suggest that the effect of GH may be mediated by local secretion of IGF-I within the thymus.

Acromegaly↗
PubMed1992

[Metabolic markers of type I prediabetes].

Studies of the early metabolic alterations of type 1 diabetes aim at the quantification of the residual beta cell mass and its rate of destruction, as well as identifying predictive markers of insulin dependency. The first phase of insulin secretion during the intravenous glucose tolerance test has been mostly investigated. The test is satisfactorily reproducible provided it is standardized. The age and the insulin sensitivity of the subject should be taken into account when interpreting the results. Moreover, functional phenomenon that may be reversible may take part in the observed alterations of insulin secretion. The abolition of the first phase of insulin secretion always precedes insulin dependency, and has a good positive predictive value in subjects with anti-islet cell antibodies. However, some pre-diabetic subjects already have a low first phase insulin response from the first examination, which does not favour the hypothesis of a linear beta cell destruction and points to the heterogeneity of this stage of the disease. Conversely, profound metabolic alterations have been described with no progression towards insulin dependency, suggesting remission of the autoimmune process. The predictive value of the alterations of insulin secretion using other stimulus will be assessed by ongoing studies.

Biomarkers↗
PubMed1992

TAP1 and TAP2 transporter genes and predisposition to insulin dependent diabetes mellitus.

Genetic control of insulin dependent diabetes mellitus (IDDM) is mainly dependent on HLA genes in the major histocompatibility complex (MHC). The participation of TAP1 and TAP2 genes, located in the MHC region and coding for antigenic peptide transporters, was investigated in 116 IDDM patients and 98 normal controls using oligotyping after DNA amplification. The TAP2-B allele had a dominant protective effect, additive to that of the DR2 haplotype but antagonist to the susceptibility associated with the DR3 and/or DR4 haplotypes. The TAP2-A allele, in the homozygous state, had a predisposing effect. TAP1 allelic distribution did not differ among IDDM patients and controls. These data argue in favour of the role of peptide transporter gene in diabetogenesis.

Adult↗
PubMed1992

Effects of chronic growth hormone excess on cardiac contractility and myosin phenotype in the rat.

The effects of chronic growth hormone (GH) hypersecretion on intrinsic contractile properties of the myocardium were studied in rats bearing a GH-secreting tumour. Body weight and heart weight increased, but no true cardiac hypertrophy was observed. The maximum active force of left ventricular papillary muscle was increased, and the maximum shortening velocity of the unloaded muscle was unaltered. This was despite a marked shift of the myosin isoforms towards the low ATPase activity V3 form, which was associated with a similar shift of myosin mRNAs. Total ATPase activity, measured on frozen sections, was unaltered suggesting, together with the results of the mechanical study, an increase in the number of active enzymatic sites. Studies performed on skinned fibres confirmed the increased myocardial contractility, thus suggesting that myocardial adaptation to chronic GH excess occurred, at least in part, at the level of the myofibrillar contractile apparatus.

Animals↗