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Biomedical subjects

H Lestradet

Publications and source records attributed to H Lestradet.

At least 37 records · Page 2Linked to original sources
PubMed1988

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in type 1 (insulin-dependent) diabetes.

Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOB1,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DR beta and DQ beta DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n = 58), B18,DR3 (n = 62) or other DR3 haplotypes (Bx, DR3, n = 70), the haplotype segments C4AQOB1,DR3 (n = 41) or C4A3BQO,DR3 (n = 52) and the C4 null alleles C4AQO (N = 48) or C4BQO (n = 112) alone. The B8,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p less than 0.01, less than 0.08 and less than 0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (p less than 0.02, less than 0.01 and less than 0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former patients (p less than 0.02, less than 0.02 and less than 0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Study of cis and trans interactions between extended HLA-haplotypes in insulin-dependent diabetes.

From the study of HLA, A, B, C, DR, Bf and C4A, C4B alleles in 287 insulin-dependent diabetes mellitus patients and 108 controls, comparisons were made between 424 diabetic and 216 normal extended haplotypes. In the "cis" situation (haplotype), the highest relative risks (RR) for IDDM were borne by multiloci allelic associations, mainly DR/complement alleles, rather than by DR3 or DR4 considered alone. Susceptibility was strongly associated with two extended haplotypes (Aw30, Cw5, B18, C4BQ0, C4A3, BfF1, DR3 and A2, Cw3, B15, C4Bx, C4A3, BfS, DR4) or their smaller segments. Two haplotypes, S31 associated with DR2 or DR5 and F31 associated with DRw6 or DR7 had a protective effect. In the "trans" situation (opposite haplotype) the large excess of DR3/DR4 heterozygotes was not the only distortion observed. An excess of DR1 (57%) and of C4BQ0 (40%) was noted among non DR3, non DR4 haplotypes in diabetics compared to normal individuals (26% and 23%, respectively, P less than 0.01, 0.05). Homozygotes for DR3 or DR4 were not increased, and other homozygotes were decreased compared to controls. The protective antigens HLA DR2, DR5 and DR7 seemed not to be distributed randomly: their putative protective effect was not observed in the case of combination with DR1 or a B18, DR3 haplotype. DR2 was never found homozygous or combined with DR5. These results suggest that susceptibility to IDDM is generated by both cis and trans interactions between genes or gene products of the HLA region.

Alleles↗
PubMed1987

A Gm haplotype study in relation with HLA-DR in 155 insulin-dependent diabetic patients and their affected and non affected siblings.

In order to assess interaction between HLA and Gm for susceptibility to IDDM, the families of 155 IDDM probands were typed for HLA class I, II, III antigens and 16 Gm allotypes (including G2m23). Haplotypes were obtained for both systems. Individuals bearing the equivocal haplotype Gm (formula; see text) were excluded. The frequencies of the 6 Gm haplotypes detected were comparable in IDDM patients, sibling controls and unrelated controls. The number of Gm haplotypes was compatible with random segregation whether or not the HLA genotype was taken into account. However, analysis of the HLA-DR allelic combinations showed an increase of the uncommon haplotype Gm (formula; see text) in IDDM patients bearing DR3 in the absence of DR4 (Gm (formula; see text) phenotype frequency 43% vs 24% in other allelic combinations, p less than 0.04). When 21 diabetic and 154 non diabetic siblings of the probands were compared, the combined presence of DR3/ non 4 and Gm (formula; see text) was observed in 7 (33%) affected and 11 (7%) unaffected siblings (p less than 0.001), conferring a relative risk of 6.4 to siblings who bear both markers. All DR3/non 4 positive affected siblings (7/7) also carried Gm (formula; see text) compared with 27% (11/41) of unaffected siblings (p less than 0.001). This result suggests, that in spite of the absence of segregation distortion, interaction between Gm and HLA gene products may play a role in the familial penetrance of IDDM.

Adolescent↗
PubMed1986

[Artificial pancreas in diabetic children].

The current artificial pancreases, which are not wearable, are mainly used for physiological research. However, they may also become useful tools for clinical or therapeutic investigations in diabetes mellitus. This is clearly demonstrated by our own experience of the Biostator in 300 young diabetics. The steady state regulation of plasma glucose offers a wide range of possible investigations: clinical, such as measuring insulin activity in states of insulin resistance, urinary excretion of glucose and renal threshold; therapeutic, like evaluating the hypoglycemic activity of commercial insulins, or alternative routes of insulin administration, such as the peritoneum; physiopathological, for better evaluation of metabolic alterations in diabetes by measuring the turnover of various substrates. Experience of the artificial pancreas also appears to be crucial for a better handling of the many problems involved in the design of future wearable or implantable devices.

Adolescent↗
PubMed1986

[Influence of glucose on the conversion of galactose into galactitol in the young adult].

The levels of galactose and galactitol in the sera of 6 young adults after ingestion of 0.25 g/kg of galactose alone or with the same quantity of glucose were studied. The results showed that: glucose decreased significantly the galactosemia and galactitolemia observed after ingestion of galactose alone; repeated consumption on 4 consecutive days of galactose alone induced an increase in galactosemia, and more significantly in galactitolemia. The addition of glucose to galactose in the same conditions abolished these effects.

Adult↗
PubMed1986

[Risk factors in insulin-dependent diabetes].

The relative risks (RR) of the immunogenetic markers of insulin-dependent diabetes mellitus (IDDM) have been calculated in a population of 235 IDDM patients compared with a control population. The highest relative risk was that of subjects heterozygous DR3/DR4 (RR = 47, P less than 0.001) which was still more increased in those who carry this combination associated with the RFLP cluster DQR4 (RR = 72). Further, a sample of 51 secondary affected siblings of IDD index cases has been compared with 265 non affected siblings (one child of each family, excluding index cases). The highest risks have been found in addition to DR3/DR4, for DR3 alone and particularly for the combination C4BQ0, DR3 (RR = 9, p less than 0.001) suggesting a role for this peculiar association in the familial penetrance. In the group of siblings HLA-identical with the index case, only two factors showed some capacity of discriminating between affected and non affected siblings: HLA-DR3 and age (less than or equal to 10 years old at onset of IDDM in the index case) (p less than 0.01). In the group of haploidentical siblings, the combination DR3/DR4 and the associations C4BQ0, DR3 and BfF1, DR3 significantly increased the susceptibility for higher familial occurrence of the disease. If confirmed by additional family series, this scale of risk factors could be helpful in predicting risk of IDDM to siblings of diabetic children.

Diabetes Mellitus, Type 1↗
PubMed1986

[Renal diabetes. Apropos of 103 cases].

Three main concepts came out of this prospective study of 103 cases (51 girls and 52 boys) of renal diabetes followed up from 1955 to 1975 and reviewed in 1984: contrary to what is still sometimes written, renal diabetes does not evolve to diabetes mellitus; renal diabetes does not seem to progress over the years; the mode of genetic transmission, when present, which is rare, is obscure but it seems to occur in a recessive rather than a dominant fashion.

Adolescent↗
PubMed1986

Effects of HLA genotype, age and birth order on empirical risk estimates for insulin-dependent diabetes in siblings of diabetic children. An actuarial evaluation.

The incidence of insulin-dependent diabetes (IDDM) was evaluated as a function of time of follow-up among the 371 siblings of 193 diabetic children using actuarial methods and comparisons were carried out according to HLA genotype, sex, age and birth order. The following parameters appeared to be relevant for empirical discrimination in terms of the risk of recurrence of the disease among siblings: The number of HLA-haplotypes shared with the first affected sibling considered as the proband. Cumulative proportions 15 yr after onset of IDD in the proband were 35%, 20% and 3% in the case of 2, 1 and 0 haplotypes in common, respectively (p less than 0.02). The birth order. Cumulative risk estimates were 26% for sibs born after the proband and 11% for sibs born before the proband (p less than 0.001). The age. Risk estimates were 24% for sibs who were aged less than 10 yr at the time of the proband's onset and 5% in sibs aged greater than 10 yr (p less than 0.001). The joint analysis of birth order or age with HLA genotypes showed significantly higher risks for both identical and haplo-identical sibs with later birth order and/or younger age. Even though these results do not reflect true incidence rates because of retrospective recruitment of part of the material, the comparison of the risk figures points out the important role of some age-related effect, probably environmental, in addition to the genetic susceptibility borne by MHC genes.

Birth Order↗
PubMed1985

Whole body de novo amino acid synthesis in type I (insulin-dependent) diabetes studied with stable isotope-labeled leucine, alanine, and glycine.

Dynamic aspects of whole body alanine and glycine metabolism have been explored in insulin-dependent (type I) diabetic subjects. Using a primed, continuous intravenous (i.v.) infusion of [2H3]alanine and [15N]glycine given simultaneously with [1-13C]leucine, whole body alanine and glycine fluxes and their rates of de novo synthesis were measured in 6 diabetic young men. Subjects were studied in the postabsorptive state, after blood glucose was clamped overnight at 15.2 +/- 0.3 mM, and then, on the following night, at 5.9 +/- 0.2 mM (insulin infusion rates of 0.24 +/- 0.09 and 1.65 +/- 0.20 U/h, respectively). In the normoglycemic state, leucine, alanine, and glycine fluxes averaged 88 +/- 4, 378 +/- 39, and 155 +/- 8 mumol X kg-1 X h-1, respectively. Based on the leucine flux, alanine and glycine de novo synthesis rates were 264 +/- 36 and 67 +/- 8 mumol X kg-1 X h-1. In the hyperglycemic state, leucine flux increased 23% (P less than 0.01), alanine flux rose slightly (+5%) but significantly (P less than 0.05), while alanine de novo synthesis and glycine flux remained unchanged and glycine de novo synthesis decreased by 33% (P less than 0.001). These results show that small alterations in peripheral alanine inflow in the hyperglycemic state reflect increased proteolysis and suggest that increased circulating plasma glucose does not contribute to de novo alanine synthesis in the absence of adequate insulin effect and/or augmented glucose tissue uptake. These observations also reveal the importance of insulin in the maintenance of whole body leucine economy, since a lower rate of insulin administration was associated with an increased rate of leucine oxidation.

Adolescent↗
PubMed1984

Segregation of HLA-DR2 among affected and non-affected offspring of 66 families with type 1 (insulin-dependent) diabetes.

Segregation of HLA-DR2 among affected and unaffected offspring was studied in 66 HLA-genotypes families with Type 1 diabetes in whom at least one parent carried DR2. The frequency of DR2-positive parents (21%) was not different from that of control families (29%). Among the diabetic probands, the gene frequency of DR2 was significantly decreased compared with control subjects (0.05 versus 0.17, p less than 0.001) as were DR5 (0.07 versus 0.17, p less than 0.01) and DR7 (0.06 versus 0.13, p less than 0.003). Twenty probands carried DR2, in 11 or whom (55%) it was found in combination with either DR3 or DR4. The nine cases who carried another DR allele included one who was DR2 homozygous. Transmission of DR2 was reduced in affected offspring, and random in unaffected siblings, compared with the expected ratio. However, when the DR2 transmission was analysed separately for parents bearing DR2 with DR3, DR4 or another DR allele, it appeared that DR2 transmission to affected offspring was random when the parents carried neither DR3 or DR4, the transmission deficit being due to over-transmission of DR3 and DR4. The haplotype analysis showed that the haplotype A3, Cw7, B7, GfS, DR2, found in 19% of "non-diabetic" DR2 haplotypes was practically absent among "diabetic" DR2-haplotypes (4%). In conclusion, population and segregation analysis could not demonstrate a specific protective effect of DR2.

Diabetes Mellitus, Type 1↗
PubMed1984

Genetic polymorphism of the fourth component of complement and type 1 (insulin-dependent) diabetes.

The complement proteins, Bf, C2, C4A and C4B, are closely linked to HLA. In 74 propositi and their families, and 97 controls genotyped for HLA-A, -B, -C, DR, -Bf, a high incidence of the C4BQ0 variant was detected in the patient group (33% versus 12%, p less than 0.00001); C4BQ0 was more frequent in propositi than in non-affected siblings (40 out of 74 versus 36 out of 92, p less than 0.05). When comparing the distribution of the phenotype C4BQ0 in Type 1 diabetic patients and normal control subjects, the difference was significant in patients bearing DR3 or DR4 (56% and 25%, respectively, p less than 0.003). The main linkage disequilibria were observed among the 74 propositi: B18, BfF1, C4, A3, BQ0, DR3; B12, BfS, C4, A3, BQ0, DR4. The existence of a silent allele at the C4 B locus is known to be associated with a defective immune response.

Complement C4↗
PubMed1984

Evaluation of recurrence risk in siblings of diabetic children: importance of age and birth order in relation to HLA genotypes.

In order to identify factors other than the HLA-linked susceptibility involved in the risk to the siblings of diabetic children, we compared the age at onset, birth order and HLA genotypes in 23 IDD multiplex (Mx) families and 140 simplex (Sx) families. The results showed a relationship between age and recurrence risk in sibs. Probands (= 1st affected sibs) of Mx families were significantly younger at onset (5.8 +/- 0.8 yr) than probands of Sx families (9.0 +/- 0.4 yr, p less than 0.01). The 2nd affected sibs of Mx families, although affected at an older age (12.4 +/- 1.6 yr), had been significantly younger at the time of the proband's onset, than the siblings who have remained unaffected (6.2 +/- 1.2 vs 11.5 +/- 0.5 yr, p less than 0.01). Probands of Mx families were more often the first born and probands of Sx families, more often came later in the birth order (p less than 0.02). Prevalence of IDD was higher among siblings born after than among those born before the proband (12% vs 4%, p less than 0.002). The HLA haplotype distribution in unaffected siblings deviated from the random assortment in relation to birth order, showing an excess of HLA-identical sibs born before the proband and, inversely, an excess of non-identical sibs born after the proband. The results suggest that age-dependent factors are likely to increase the penetrance of HLA-linked IDD susceptibility. These factors could be related to the environmental insult. However, a genetically determined form of type I diabetes characterized by higher familial penetrance and earlier onset cannot be ruled out.

Age Factors↗