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Biomedical subjects

J Timsit

Publications and source records attributed to J Timsit.

At least 19 recordsLinked to original sources
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↗
PubMed1991

[Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications].

Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.

Autoantibodies↗
PubMed1990

Cardiovascular effects of the somatostatin analog octreotide in acromegaly.

OBJECTIVE: To determine the cardiovascular effects of the somatostatin analog octreotide in patients with acromegaly. DESIGN: Prospective nonrandomized study. SETTING: Referral-based endocrinology clinic. PATIENTS: Seven patients with active acromegaly, three of whom had refractory congestive heart failure. The other four patients were free of symptoms associated with heart failure. INTERVENTIONS: All patients were treated with octreotide, 100 to 500 micrograms subcutaneously three times daily. The three patients with heart failure continued to receive cardiovascular therapy (angiotensin converting enzyme inhibitors, digitalis, diuretics). MEASUREMENTS AND MAIN RESULTS: During octreotide therapy, patients showed a rapid decrease in growth hormone and insulin-like growth factor 1 (IGF-1): Mean levels (+/- SD) fell from 28.1 +/- 32.7 micrograms/L to 5.2 +/- 8.3 micrograms/L and 740 +/- 126 micrograms/L to 372 +/- 64 micrograms/L, respectively (P less than 0.025). Plasma volume returned to normal and heart rate decreased significantly. In the four patients without heart failure, right-heart catheterization done before and after 3 months of octreotide therapy showed an 18.3% +/- 11% reduction in stroke volume and a return to normal of the cardiac index. The three patients with congestive heart failure, evaluated before and after 40 days and up to 2 years of therapy, showed a dramatic clinical improvement that was associated with an increase in stroke volume (by 24% to 51%). In these patients, the cardiac index remained in the normal range, filling pressures were markedly decreased, and pulmonary wedge pressure returned to normal. This improvement was sustained for up to 3 years in the two patients with heart failure who were receiving long-term treatment. CONCLUSION: The rapid and sustained cardiac improvement seen in our patients shows that octreotide therapy for patients with acromegaly may be highly beneficial, even in those patients with advanced cardiac failure.

Acromegaly↗