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J Timsit

Publications and source records attributed to J Timsit.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Etiopathogenesis of type 1 diabetes mellitus].

Type 1 diabetes mellitus results from an autoimmune disease which specifically destroys the pancreatic beta cells. The disease presents a multigenic susceptibility and the activation of autoreactive T lymphocytes plays a major role in its pathogenesis. Environmental factors may initiate or modulate the immune response. Several mechanisms are probably involved in the ultimate beta cell destruction. The antigens which are first recognized by the immune system are still unknown. Humoral and cellular specific markers of the disease can be detected long before the onset of diabetes. Understanding the mechanisms which trigger the disease should allow a treatment of the autoimmune disease before the clinical expression of diabetes.

Autoimmune Diseases↗
PubMed1996

Contribution of DRB1*04 variants to predisposition to or protection from insulin dependent diabetes mellitus is independent of dq.

Certain DQ alpha/beta dimeric molecules have been shown to play a major role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB1*0302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB1*04 subtypes on the susceptibility encoded by DQ alleles is possible, since not all DRB1*04-DQB1*0302 haplotypes are associated with the disease. The distribution of DRB1*04 subtypes was analysed in 240 DR4-positive Caucasian IDDM patients and 110 DR4-positive healthy controls using allele-specific hybridization after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB1*0302 allele which was found in the majority of patients (94.2% vs 64.7% in controls, Odd's ratio OR = 8.8, P < 0.0001), differences between DRB1*04 variants persisted after the effect of the DQB1 locus was removed by matching patients and controls for DQB1*0302. Thus, the DRB1*0402 allele conferred a strong IDDM-predisposing effect (OR = 3.1, P < 0.02) which was highly significant in the absence of DR3 on the second haplotype (OR = 5.6, P < 0.0001) but was not visible among DR3/4 heterozygote individuals. Conversely, the DRB1*0404 allele conferred a strong protective effect (OR = 0.26, P < 0.0001) which was dominant even in the presence of the associated high risk DR3 haplotype (OR = 0.21, P < 0.03). These data indicate that DQ molecules are not the sole contributors to the DR4-associated IDDM predisposition, and that peculiar DR4 subtypes play a significant role in susceptibility to or protection from the disease. DRB1*0402 differs from DRB1*0404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate with the genetic linkage of IDDM predisposition.

Alleles↗
PubMed1996

Absence of primary association between DM gene polymorphism and insulin-dependent diabetes mellitus or celiac disease.

The DMA and DMB genes encode class II-like heterodimetric molecules located in a specialized endocytic compartment, where they facilitate efficient loading of antigenic peptides on HLA class II molecules. Both genes are located within the MHC class II region and present a limited allelic polymorphism. Here we report the distribution of DM alleles in a group of 75 IDDM patients, 72 CD patients, and 162 random controls. We found a pronounced decreased frequency of DMA*0102 in both patient groups relative to controls. This difference was, however, mainly secondary to a strong negative linkage disequilibrium (LD) between this allele and the IDDM and CD-associated DRB1*03 allele. The DMB phenotype frequencies were similar in CD patients and controls. By contrast, we observed a decreased frequency of DMB*0101 and an increased frequency of DMB*0102 and DMB*0104 in IDDM patients. These differences disappeared when matching individuals for DRB1*03 or DRB1*04 alleles, which was in accordance with strong negative LD between DMB*0101 and DRB1*04 or DQB1*0302 alleles, and positive LD between DMB*0104 and DQB1*0201. Our data suggest that the apparent associations of IDDM or CD with given DM alleles are mostly secondary to primary associations with alleles at the DRB and DQB loci.

Celiac Disease↗
PubMed1995

HLA-associated heterogeneity of the humoral response to islet antigens in insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is associated with susceptibility HLA class II alleles. Islet cell antibodies (ICA), detected by indirect immunofluorescence on pancreas sections, represent the best marker of the disease. Autoantibodies to glutamic acid decarboxylase (GADA), one major islet antigen, do not totally account for ICA reactivity, suggesting heterogeneity of the anti-islet humoral response. In 97 patients with IDDM we have correlated ICA heterogeneity with clinical markers and DR and DQ alleles. ICA were found in 81% of the patients, and in 33% the serum blocked the binding to islet cells of reference sera with a granular fluorescence pattern. GADA were found in 62% of cases. Patients with high GADA titers and blocking sera were older at onset and less often had a family history of IDDM, suggesting that these antibodies might be a marker of slow progression to IDDM. ICAs were not associated with particular HLA DR or DQ alleles. Conversely, GADA were less frequent than ICA in DR4 subjects but not in the other groups. Moreover, among DR4 non-DR3 patients, GADA were found almost exclusively in DRB1*0401 patients but not in other DR4 subtypes. There was an association of GADA with DQ alleles but it was secondary to linkage disequilibrium between DR and DQ loci. In conclusion, the heterogeneity of the humoral response in IDDM is controlled by HLA class II genes and correlates with clinical heterogeneity.

Adolescent↗
PubMed1995

Family study of linkage disequilibrium between TAP2 transporter and HLA class II genes. Absence of TAP2 contribution to association with insulin-dependent diabetes mellitus.

The polymorphic TAP1 and TAP2 genes encode a transporter protein required for delivery of cytosolic peptides to class I molecules in the endoplasmic reticulum. Associations have been observed between TAP2 alleles and predisposition to autoimmune diseases such as IDDM but their interpretation has been complicated by the existence of LD between TAP2 and HLA class II loci, and conclusions are still contradictory. In order to precisely define LD on class II haplotypes, we performed an extensive familial analysis. A total of 466 individuals from 55 normal families and 49 IDDM multiplex families was studied, providing information on 420 independent haplotypes. The IDDM-predisposing DRB1*03 and DRB1*04 alleles were in strong negative LD with TAP2-B (delta = -0.035 and -0.034, respectively), and positive LD with TAP2-A (delta = + 0.055 and + 0.012). Positive LD was also found between TAP2-B and DRB1*01 and TAP2-C and DRB1*11 alleles. We then addressed the question of whether TAP2 is an independent additional IDDM-protective or predisposing genetic factor. No TAP2 effect was evidenced when considering DRB1*03 and/or 04 patients. A decreased TAP2-B phenotype frequency was observed in DRB1*03- and DRB1*04-negative IDDM patients compared with DRB1*03- and DRB1*04-negative normal controls (38.6% vs 63%, pc < 0.05), but was probably related to a combination of different weak LD between DRB1 and TAP2 alleles. It thus appears that there is no primary association between TAP2 alleles and IDDM. However, TAP polymorphism may allow us to define particular extended HLA haplotypes involved in susceptibility to autoimmune diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Effects of chronic octreotide treatment on GH secretory dynamics and tumor growth in rats bearing an ectopic somatotroph (GC) tumor.

The effects of octreotide, a long-acting somatostatin agonist selective of the sstr2/sstr3/sstr5 receptor subtypes, on ectopic GH secretion and tumor growth were investigated in Wistar-Furth female rats implanted with GH secreting (GC) cells which express mostly somatostatin receptors of the sstr1 and sstr2 subtypes. Octreotide dose dependently inhibited thymidine incorporation (-57%) and GH secretion (-41%) from GC cells in culture. In vivo, 6 weeks after GC cell implantation, plasma GH, IGF-1 and insulin levels were highly elevated. Cluster analysis of GH secretory dynamics revealed that GH secretion was less pulsatile in GC-implanted than in control animals. Furthermore, in GC-implanted animals, passive immunization either with SRIH or GHRH antisera, did not affect GH plasma levels. Three weeks after GC cell implantation, when tumors became palpable, octreotide (1 micrograms/h/kg BW) or saline was infused constantly for three weeks by osmotic minipumps. In octreotide treated rats, GH, IGF-1 and insulin levels were not different from sham-implanted animals and tumors weight were reduced by 80%. High affinity somatostatin binding sites were found in equivalent amounts on tumors from octreotide-treated or saline-treated animals. These findings indicate that GH secretion in GC-rats is mainly derived from the tumors and independent of hypothalamic control and that octreotide reduces both GH secretion and tumor growth. We conclude that the GC-implanted rat represents a good animal model to test the antisecretory and antitrophic properties of somatostatin analogs in vivo.

Animals↗
PubMed1995

Cyclosporin A does not delay insulin dependency in asymptomatic IDDM patients.

OBJECTIVE: To measure the effects of cyclosporin A (CyA) with no insulin therapy on glucose tolerance and beta-cell function in the preclinical phase of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: beta-cell responses to the intravenous glucose tolerance test (IVGTT), hyperglycemic clamp, intravenous arginine, and intravenous glucagon were evaluated before and after a 6-month course of CyA in seven patients (mean age 19.6 years) with asymptomatic IDDM. RESULTS: Initial insulin secretory responses were severely decreased when the patients were compared with eight healthy control subjects: IVGTT (1 + 3 min): 106 +/- 16 vs. 884 +/- 190 pmol/l (P < 0.001); hyperglycemic clamp: 102 +/- 16 vs. 310 +/- 42 pmol/l (P < 0.001); intravenous arginine: 346 +/- 72 vs. 1104 +/- 168 pmol/l (P < 0.01); and intravenous glucagon: 170 +/- 37 vs. 247 +/- 35 pmol/l (NS). The beta-cell responses remained markedly abnormal after 6 months of CyA, although the response to intravenous glucose and oral glucose tolerance tests improved in three subjects. All the patients became insulin-dependent after 5-36 months. CONCLUSIONS: CyA alone is not a suitable treatment for asymptomatic IDDM. Earlier identification of subjects with substantial beta-cell secretory capacity and newer nontoxic intervention strategies are required for the prevention of IDDM.

Adolescent↗
PubMed1995

Anti-bovine serum albumin antibodies: genetic heterogeneity and clinical relevance in adult-onset IDDM.

OBJECTIVE: To evaluate the prevalence of anti-bovine serum albumin (BSA) antibodies in patients with adult-onset insulin-dependent diabetes mellitus (IDDM) and investigate a possible link between their presence and genetic susceptibility or resistance determined by human leukocyte antigen (HLA) complex. RESEARCH DESIGN AND METHODS: Sera from 60 recent-onset diabetic patients, 5 prediabetic subjects, and 102 healthy control subjects were tested using a radioimmunoprecipitation assay. HLA-DRB and -DQB alleles were determined by means of allele-specific oligonucleotide typing. Islet cell antibodies (ICAs) were assayed by indirect immunofluorescence. RESULTS: Levels of anti-BSA antibodies were significantly higher in IDDM patients (18.1 +/- 3.5%, n = 60) than in healthy control subjects (7.5 +/- 1.2%, n = 102) (P < 0.001), but in only 16.6% of IDDM patients (10 of 60) were the titers above the 95th percentile of control values. Anti-BSA antibody titers were higher in HLA-DR3 and/or -DR4 patients (23.4 +/- 4.9%, n = 41) compared with DR3 and/or DR4 control subjects (3.1 +/- 1.0%, n = 10) (P < 0.001). DR3 IDDM patients showed higher levels of anti-BSA antibodies (26.3 +/- 6.3%, n = 30) than non-DR3 patients (9.9 +/- 2.6%, n = 30) (P < 0.01) and healthy control subjects. Only two out of five prediabetic subjects had significant anti-BSA levels before clinical onset of diabetes. CONCLUSIONS: Our data confirm that antibodies to BSA are present in adult-onset IDDM patients, particularly in HLA-DR3-positive patients. However, the prevalence of anti-BSA antibodies was lower than previously reported in children, and there was a considerable overlap with healthy control subjects. Only two out of the five prediabetic patients demonstrated anti-BSA antibodies. Taken together, these results do not bring strong support to the clinical usefulness of anti-BSA antibodies as a relevant marker in diabetes prediction or diagnosis.

Adolescent↗
PubMed1995

[Eating disorders and metabolic balance in a population++ of young adults with insulin-dependent diabetes].

We have compared the prevalence of Eating Disorders in a population of 69 out-patients with Insulin-Dependent Diabetes Mellitus including a sample of diabetic young women (average year: 23 years) with two control populations (45 medicine out-patients and 54 girl students). The diabetic population didn't present no more eating disorders--measured by self-report questionnaires (EAT, BITE) than the control population. In a sample of 40 diabetic subjects--having participated in a diagnostic structured interview (LENTCA) based on DSM-III-R criteria: nobody has anorexia nervosa, one woman has bulimia nervosa, the lifetime prevalence of bulimia nervosa not otherwise specified was 21% for men and 43% for women. Bulimia Disorders--measured by self report questionnaire (BITE) and noncompliance were linked with poor glycemic control.

Adult↗
PubMed1994

IDDM: an islet or an immune disease?

Insulin-dependent diabetes develops as a consequence of the selective destruction of insulin-producing cells by an autoimmune reaction. However, the precise series of events which trigger anti-islet autoreactive T cells is still being investigated. Major issues will need to be raised before a comprehensive view of the anti-islet autoimmune reaction can be delineated. These include defining the primary site of activation of autoreactive lymphocytes and exploring hypotheses to explain the chronicity of the diabetes process. These issues all relate with the more general dilemma of the actual role of the islets of Langerhans in breaking self tolerance to beta-cell antigens. By studying non-obese diabetic mice deprived of beta cells following a single injection of a high dose of alloxan at 3 weeks of age, we recently obtained evidence that the activation of autoreactive T cells requires the presence of target islet cells in order to develop.

Animals↗
PubMed1994

Remission of proteinuria following correction of hyperlipidemia in NIDDM patients with nondiabetic glomerulopathy.

OBJECTIVE: Animal studies suggest that hyperlipidemia may play a direct role in glomerular damage. In patients with non-insulin-dependent diabetes mellitus (NIDDM), dyslipidemia occurs early in the course of nephropathy and may be involved in the progression of renal disease. CASES: We report on two young NIDDM patients with marked hyperlipidemia and proteinuria, in whom renal biopsy demonstrated nondiabetic glomerulopathy. In both cases, the decrease in blood lipid levels was associated with a major decrease in proteinuria. Episodes of hyperlipidemia were associated with a resumption of heavy proteinuria in one patient with serum triglyceride levels and proteinuria being closely correlated. CONCLUSIONS: These two cases suggest that hyperlipidemia has an important role in the pathogenesis of glomerular disease.

Adult↗
PubMed1994

The kidney in cyclosporin A-treated diabetic patients: a long-term clinicopathological study.

This was an analysis of the renal investigations performed in 248 cyclosporin A (CyA)-treated patients who had recent-onset type I insulin-dependent diabetes mellitus (IDDM) to assess the clinicopathological relationships, risk factors and predictive indices of CyA nephrotoxicity, and renal function observed with different CyA treatment regimens. There were four different protocols, using initial CyA dosages ranging from 7.5 to 10 mg/kg/day, with dose modification according to serum creatinine concentration, which was measured regularly in some patients for up to 9 years after starting treatment. Kidney biopsies were obtained from 125 patients (74 adults and 51 children) who had received only CyA for an average duration of 13 months before biopsy and had no other sources of renal injury at this stage of IDDM. Of these patients, 58% showed normal or minimal changes on biopsy, 26% showed slight abnormalities, and 16% showed medium-grade (grade III nephropathy) abnormalities. Lesion severity was related to the degree of interstitial fibrosis and tubular atrophy which, in turn, was related to the use of high maximum CyA dosages. Patients' age, and excessive CyA dose and blood trough levels were the main risk factors, and serum creatinine increase was the best predictive factor of CyA-induced nephropathy. However, CyA-induced renal dysfunction was essentially reversible on dosage reduction, and morphological changes were not followed by progressive renal insufficiency when CyA doses were low and adjusted according to serum creatinine levels. We conclude that, at present, it is recommended that low-dose CyA in combination with other non-nephrotoxic immunosuppressive strategies be used in patients with IDDM.

Adult↗
PubMed1993

[Octreotide, analog of somatostatin. Pharmacological properties and therapeutic applications in pituitary endocrine tumors].

Octreotide, the first somatostatin analogue developed, has pharmacological properties (it inhibits pituitary GH and TSH secretion, pancreatic and digestive tract endocrine secretion and various gastrointestinal functions) which are qualitatively similar to those of the natural 14 amino acids peptide. Enzymatic structural modification had resulted in a peptide which is very resistant to degradation and has a 90-110 min half-life permitting subcutaneous administration. Following a subcutaneous injection of 50 to 100 micrograms, absorption is rapid and complete. The peak plasma concentration is obtained within 20 to 30 minutes. The drug is degraded mostly in the liver. Among pituitary tumours, GH- and TSH-secreting adenomas constitute the primary indication. Octreotide has been widely tested in the treatment of acromegaly; 50 to 80 percent of patients with that disease respond to a discontinuous administration (usually 3 subcutaneous injections per day), and the IGF1 level is normalized in 50 percent of the cases. No long-term desensitization and no rebound phenomenon after drug withdrawal have been observed. Clinical improvement is obvious, even in cases with partial response to treatment. The dose required to obtain maximum response may vary from one patient to another, and resistance to the peptide has been observed in a few patients. This resistance does not seem to be related solely to the absence of somatostatin receptors on the tumours. The principal side-effect of octreotide treatment is the occurrence of gallstones. In some patients, continuous subcutaneous injection gives a better result with a lower dose. Other ways of administration (nasal or oral) have been tested or are being evaluated.

Acromegaly↗
PubMed1993

[Diabetic thoracoabdominal neuropathy. Clinical and electrophysiological study with evaluation of the autonomic nervous system].

We report on eight patients with diabetic thoracoabdominal neuropathy in whom careful evaluation of peripheral and autonomic nervous system function was performed. All patients had non insulin-dependent diabetes mellitus of 10.5 +/- 6.7 years mean (+/- SD) known duration with poor glycemic control. Thoracic (n = 7) or abdominal (n = 1) pain of sudden onset involved several adjacent dermatomal segments and was bilateral and asymmetrical in 7/8 patients. Four patients had hypoesthesia in the painful zone and six presented with significant weight loss (6.2 +/- 4.3 kg) which reversed after the relief of pain. Truncal electromyogram was abnormal in 7/7 patients. Nerve damage was not limited to thoracic nerves since electrophysiological studies evidenced distal polyneuropathy in all patients. The autonomic nervous system was also involved. Sympathetic skin response was abnormal in 7/7 patients and autonomic cardiovascular function tests demonstrated cardiac denervation in 5/5 patients. In 4/4 patients a marked relief of pain was noted within one week with amitriptyline treatment. This report confirms the characteristic clinical presentation of diabetic thoracoabdominal neuropathy. Moreover, it suggests that this neuropathy is part of a diffuse damage that also involves peripheral nerves of the limbs and autonomic nervous system.

Abdominal Pain↗
PubMed1993

Protection from insulin-dependent diabetes mellitus is linked to a peptide transporter gene.

HLA class II association with insulin-dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult-onset and 51 childhood-onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for the TAP2*0201 allele [relative risk (RR) = 0.3, corrected probability (pc) < 0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR = 3.4, pc < 0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR = 0.06, pc < 0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB1*0302 haplotypes predisposing effect (RR = 1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed by chi 2 analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies (p < 0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to beta cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM prediction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Proliferation and Na+/H+ antiport activity in human fibroblasts from type I diabetic patients with nephropathy.

To investigate whether constitutive alterations of the Na+/H+ antiport or of cell proliferation control mechanisms are implicated in development of nephropathy in insulin-dependent diabetics (IDD), skin fibroblasts from controls, recent-onset IDD with normal or high glomerular filtration rates, and IDD with proteinuria were cultured by explant technique. The Na+/H+ antiport activity was studied using the pH sensitive fluorescent dye BCECF. The cell growth capacity was investigated by determination of cell DNA doubling time and by nuclear [3H]thymidine incorporation in response to serum. The Na+/H+ antiport activity and fibroblast growth capacity did not differ between fibroblasts from controls and IDD patients, suggesting the absence of a genetic alteration of the Na+/H+ antiport in the development of diabetic nephropathy.

Adult↗
PubMed1993

Erythrocyte Na+/Li+ countertransport and glomerular hyperfiltration in insulin-dependent diabetics.

Erythrocyte Na+/Li+ countertransport activity was investigated in 11 controls and 22 recent onset type I (insulin-dependent) diabetic patients with normal and high glomerular filtration rates. No differences in Vmax were observed in hyperfiltering compared to normofiltering patients or controls. The Na+/Li+ activity was correlated with blood glucose levels in insulin-dependent diabetics showing good glycemic control. Total cholesterol and triglyceride concentrations were similar among the three groups. In conclusion, enhanced Na+/Li+ countertransport activity is not associated, in our case, with diabetic condition per se and with early glomerular hyperfiltration and cannot be used as a marker of renal involvement in recent onset insulin-dependent diabetics.

Adult↗