Prediabetes and deprivation: A couple at high risk of diabetes.

AIM: The higher prevalence of diabetes in deprived populations is well documented but little is known about the risk of diabetes associated with deprivation among pre-diabetic subjects. The aim of the study was to evaluate the risk of diabetes in a population of deprived pre-diabetic patients. METHODS: 2743 pre-diabetic subjects identified using the American Diabetes Association (ADA) criteria, 16 to 85 years old, 1656 non-deprived and 1087 deprived, had at least two health check-ups at an interval of 4.95 (2.04) vs 3.20 (1.71) years, P<0.0001, respectively. At the first visit, socioeconomic status was assessed using the EPICES score to differentiate deprived and non-deprived subjects. RESULTS: At the second visit, the prevalence of overt diabetes was 9.5% among deprived vs 5.1% in the non-deprived group (P<0.001). After adjustment on confounding factors, deprivation was found independently associated with occurrence of diabetes [1.70 (1.15-2.51), P=0.01]. Beyond social deprivation, Fasting Plasma Glucose and waist circumference were the main independent predictors of new-onset diabetes. CONCLUSION: After 4 years of follow-up, among subjects with prediabetes, prevalence of diabetes was twice as high among deprived compared with non-deprived subjects. Deprived populations with pre-diabetes may require specific public health approaches to avoid the occurrence of overt diabetes.

Impact of socioeconomic status on diabetes and cardiovascular risk factors: results of a large French survey.

AIM: This study examined the association between deprivation and diabetes in a large French population, and evaluated the impact of deprivation on diabetes after taking in account a number of confounding factors. METHODS: A total of 32,435 men and 16,378 women, aged 35 to 80 years, who had a health checkup at the "Centre d'Investigations Préventives et Cliniques" (IPC Centre: a preventive medical center in Paris, France), between January 2003 and December 2006, were evaluated. Socioeconomic deprivation was assessed using the EPICES score. The most deprived subjects were those in the fifth quintile of score distribution. RESULTS: Several cardiovascular risk markers increased significantly in deprived subjects. In both genders, deprivation was associated with deleterous health status and lifestyle habits. In women, BMI, central obesity and the metabolic syndrome were associated with deprivation. The prevalence of diabetes increased with deprivation level. Compared with the first quintile of EPICES score distribution, the prevalence of diabetes was three to eight times higher in the fifth quintile. After taking into account age, and biological, clinical and lifestyle parameters, the risk of diabetes onset (odds ratio) among deprived vs. non-deprived subjects was 2.54 (95% CI: 1.99-3.24) in men and 2.2 (95% CI: 1.44-3.35) in women. CONCLUSION: In the general French population, deprivation was associated with deleterious health status and lifestyle. Risk of diabetes increased linearly with deprivation level and, after taking into account various confounding factors, the risk of diabetes remained significantly higher among deprived subjects. Other factors such as nutrition should now be examined to explain the excess risk of diabetes among the most deprived people.

[Evaluation of the benefits brought by pregnancy planning in type 1 diabetes mellitus]. / Evaluation du bénéfice apporté par la programmation de la grossesse dans le diabète sucré de type 1.

Fetal mortality and morbidity remain dramatically increased in diabetic women. To evaluate the benefit of a preconceptional education combined with a good metabolic control, we compared the outcome of pregnancy in 2 groups of type I diabetic women: group A (n = 21) planned before conception versus group B (n = 40) not planned. Both groups were similar related to the type and duration of diabetes, its complications, age, body mass index and different factors of risk. In group A, HbA1C levels were < or = 3 SD of the normal mean of non diabetic values before conception and during the pregnancy course and > or = 3 SD in group B. We observed a significant reduction (p < 0.05) of the main adverse events regarding fetus outcome (fetal, perinatal and neonatal mortality, malformations) and obstetrical complications in the planned group. These data lead to the need of an extensive policy of early planification of pregnancy in diabetic women.

[Insulin resistance: from clinical diagnosis to molecular genetics. Implications in diabetes mellitus]. / La résistance à l'insuline: du diagnostic clinique à la génétique moléculaire. Implications dans le diabète sucré.

Insulin resistance is observed in several diseases such as non insulin dependent diabetes mellitus (NIDDM) or polycystic ovarian syndrome (PCOS). To understand genetic determinism of this abnormality we have developed a multidisciplinary approach including selection of phenotypes with insulin resistance confirmed in vivo by minimal model of Bergman and characterization of cellular defects in insulin action on circulating erythrocytes and monocytes. Exploration of variability in candidate genes by direct sequencing in some genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gene associated with major defects in insulin binding or kinase activity. In other rare genetic syndromes or patients affected by NIDDM or PCOS defects appear to be located at post-receptor level, where IRS (insulin receptor substrate) genes are the most attractive candidates. Prevalence of some allelic variants suggested a potential role of IRS genes in insulin resistance, although their involvement in the pathogenesis of NIDDM remains controversial. Genotype-phenotype correlations in first degree relatives of an index case caring the Type A syndrome, suggested that association of allelic variants of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synergistic effects, to phenotypic expression of defects in signal transduction. These mechanisms through genetic epistasis, involving several genes in insulin action, fit better with the polygenic nature of current forms of NIDDM and represent a good model in the study of pathogenesis of insulin resistance.

TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates.

OBJECTIVE: We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease. DESIGN: Open non-randomized prospective study. SETTING: University Hospital of Montpellier, France. SUBJECTS: Sixty-six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3'-triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow-up. The remaining 48 patients were available for analysis of both remission and relapse. RESULTS: The median duration of therapy was 18 months (range, 4-41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups. CONCLUSION: TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.

Influences of weight, body fat patterning and nutrition on the management of PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity that is defined as the association of hyperandrogenism with chronic anovulation in women without specific underlying diseases of the adrenal or pituitary glands. PCOS is also associated with a metabolic disturbance (insulin resistance). The nature of the complex interrelation of obesity, insulin resistance and endocrine abnormalities in PCOS remains unresolved. However, several studies link obesity, body fat distribution and nutritional habitus with the hormonal and metabolic profiles of PCOS. Moreover, intervention studies have suggested that reducing weight and/or hyperinsulinaemia either by diet alone or by a combination of diet and drugs improves hirsutism, fertility and the hormonal and metabolic profiles of PCOS. In fact, the evaluation of nutritional factors in PCOS is helpful for the screening of metabolic abnormalities and the management of women with PCOS. A point of particular interest in the management of PCOS is that the choice of contraception remains difficult in these high cardiovascular risk women. The impact of pills with ethinyl oestradiol on weight, body fat distribution and carbohydrate metabolism in women with PCOS has not been thoroughly evaluated. The lack of prospective studies to evaluate long-term metabolic and cardiovascular tolerance necessitates care and the assessment of other hormonal possibilities.

Identification of two novel insulin receptor mutations, Asp59Gly and Leu62Pro, in type A syndrome of extreme insulin resistance.

To elucidate genetic determinants of insulin resistance, we investigated insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) genes, in vitro IR function and in vivo insulin sensitivity in a family with Type A syndrome. Two missense IR mutations (Asp59Gly and Leu62Pro) found in the proband, resulted in reduction by 90% of insulin binding to erythrocytes, decreased receptor autophosphorylation and a dramatic reduction of insulin sensitivity. The proband and mother were heterozygote for Gly972Arg IRS-1 variant. Asp59Gly mutation, also carried by proband's brother with no consequence on insulin sensitivity, was inherited from the mother who is diabetic and insulin resistant and Leu62Pro was from the father. We conclude that severity of insulin resistance in the proband may be explained by the genetic condition of compound heterozygote for IR mutations while severe insulin resistance in the mother raises the possibility that other genetic factors, like IRS-1 polymorphisms, may contribute to the phenotypic expression of IR mutations.

Protein kinase C alpha and tumorigenesis of the endocrine gland.

A point mutation in the protein kinase C alpha (PKC alpha) gene has been discovered in a subpopulation of human pituitary tumors characterized by their invasive phenotype. Here we show that: (1) thyroid tumors can express the PKC alpha mutation detected in a subpopulation of follicular adenomas and carcinomas, and (2) mutated PKC alpha has modified enzymatic properties as compared to wild-type PKC alpha. It has lost its capacity to phosphorylate the S17R substrate and exhibits a higher sensitivity to degradation as compared to wild-type PKC alpha. In conclusion, the presence of the PKC alpha mutant in tumors other than pituitary tumors and the observation that the presence of the point mutation induces changes in PKC alpha properties suggest the involvement of this mutant in tumorigenesis.

[Iodine deficiency in the Cirque of Salazie (Reunion Island). Analysis of nutritional causes and study of their consequences]. / Mise en evidence d'une carence iodée dans le Cirque de Salazie (Ille de la Réunion). Analyse de ses causes nutritionnelles et etude de ses conséquences.

Randomized subjects (n = 294), (35 young children, 6-30 months old--91 children 8.6 +/- 0.7 years, 116 teenagers 13.2 +/- 1.9 y--52 young women 28.5 +/- 6.1 y) leaving in a mountainous area of Reunion Island (Cirque de Salazie) were evaluated according to the following: a questionnaire related to food intake, cervical palpation for thyroid size evaluation and collections of urine and foods (natural and mineral water, breast and commercial milk and salt) for iodine measurement. Neonatal TSH of 308 new borns in Salazie were compared to TSH of 300 new-borns of Lille (France). The prevalence of goiter increases with age (0% in young children, 12.1% in children, 23.3% in teenagers, 38.4% in women) whereas median urinary iodine (microgram/dl) decreases in the same groups (12-7.8-5.6-4.2). The intake of milk and dairy products significantly decreases from children to adults. Neonatal TSH values are significantly higher in Salazie than in Lille (p < 0.005). Natural and mineral water, breast milk and salt contain little iodine. In conclusion iodine deficiency is present in this area of Reunion Island with a significant increment of neonatal TSH values.

Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.

We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

Insulin underdelivery from implanted pumps using peritoneal route. Determinant role of insulin pump compatibility.

OBJECTIVE: To evaluate the incidence and investigate determinants of insulin underdelivery events occurring with implanted pumps using peritoneal route from a 103 patient-year experiment. RESEARCH DESIGN AND METHODS: Of the MiniMed (MIP 2001) pumps implanted in 47 type I diabetic patients, 70 were refilled quarterly with four successive batches (A, B, C, D) of U400 Hoechst 21 PH neutral insulin during a 3-year study period. Any reduction of insulin flow rate > 15% was considered as abnormal insulin delivery. Diagnosis of the cause of underdelivery was established according to the response to the following steps: 1) 0.01 mol/l NaOH rinse of pump circuits to solubilize insulin aggregates, 2) surgical examination and replacement of blocked catheters, and 3) postsurgical 0.01 mol/l NaOH rinse of pump. Step 2 was selected first if the increase of insulin requirements or reduction of flow rate were > 50%. Relative contributions of insulin and the implanted system to underdelivery events were analyzed. RESULTS: There were 76 episodes of insulin underdelivery that occurred during the study, resulting in an incidence of 74 events per 100 patient-years. Of 52 NaOH pump rinses, 30 restored normal flow rate. Surgery, performed after rinse failure (n = 22) or as the first step (n = 24), disclosed catheter blockages due to tip obstructions in 28 cases and omental encapsulations in 18 other cases. Five combined severe reductions of pump flow rate requiring pump replacements were diagnosed during surgery, and additional NaOH rinses had to be performed after catheter change in 12 other cases. Analysis of the incidence of underdelivery events indicated that both pump- and catheter-related problems were significantly increased while implanted systems infused batches B, C, and D versus batch A (P < 0.01), whereas the duration of pump implantation had no significant influence. CONCLUSIONS: Underdelivery events constitute serious limiting obstacles to prolonged peritoneal insulin infusion from implanted pumps. Progress in insulin pump compatibility is expected to reduce their occurrence and, thus, to improve the feasibility of this treatment.

[Iodine consumption in France. National results of the Thyromobile project in a population of schoolchildren aged 6-14 years]. / Apport iodé en France. Résultats nationaux du projet Thyromobile dans une population d'enfants scolarisés de 6 à 14 ans.

The "Thyromobile" project was initiated to update information on iodine supply in school-children aged 6-14 years in Europe. It involved 4 places in France: Lorraine, Rhône-Alpes, Languedoc-Roussillon, Midi-Pyrénées. Schools of the three former places had been investigated in 1986 during the Mornex's study whereas in the latter they had never been investigated in the past. With a mobile unit, all children (n = 1522) had a thyroid echography performed by the same trained investigator, and urinary iodine concentration was determined in 1458 of them. The mean +/- SD of urinary iodine concentration was 13.0 +/- 7.4 micrograms/dl, but 38% of urinary iodine concentrations were below 10 micrograms/dl and 10% were under 5 micrograms/dl. The prevalence of goitre was 4.1% in boys and 3.1% in girls. There was a negative correlation between urinary iodine concentration and thyroid volume (p < 0.001). Therefore, the results of the "Thyromobile" project show that the places, investigated in France, are not in an area of endemic goitre due to iodine deficiency. However, other epidemiological studies must be done to provide further information about iodine supply in all parts of France.

[Evolution of blood glucose control and retinopathy during long-term treatment of insulin-dependent diabetes mellitus with intraperitoneal infusion of insulin]. / Evolution du contrôle glycémique et de la rétinopathie au cours d'un traitement prolongé du diabète sucré insulinodépendant par infusion intrapéritonéale d'insuline.

To evaluate the efficacy on blood glucose control of long-term peritoneal insulin infusion and its consequences on the evolution of diabetic retinopathy, we analyzed retrospectively the values of glycosylated haemoglobin measured quarterly and the retinal angiograms obtained after 1, 5 and 9 years from seventeen insulin-dependent diabetic patients treated by this technique during 9.0 +/- 2.2 years. Blood glucose control was significantly improved from the first year of treatment (p < 0.01). Seventy-one per cent of patients had a level of glycosylated hemoglobin below one standard deviation of normal values after five years and ninety-two per cent of 12 patients treated up to nine years remained in the same near-normal range. Glycaemic excursions below 0.5 g/l and over 2 g/l were limited to 5-7% and 15-17% of four times-daily capillary glucose measurements respectively, along the whole IP insulin infusion period. Among 7 patients with no retinopathy (n = 1) or with mild to moderate nonproliferative retinopathy, requiring no specific ophthalmological treatment, (levels 20 to 40 on worse eye according to a simplified version of ETDRS classification, n = 6), 3 remained stable, 2 improved and 2 impaired although remaining under level 50 of the classification, after 5 to 9 years. Nine patients with severe nonproliferative (level 50, n = 1) or proliferative (level 65, n = 8) retinopathy, all treated by panretinal photocoagulation before initiation of IP treatment, improved and one patient with severe nonproliferative retinopathy, incompletely treated by laser photocoagulation, remained stable, after 5 to 9 years. No macular edematous reaction or impairment of existing macular edema occurred after panretinal photocoagulation under IP treatment. These data indicate that a sustained near-normal blood glucose control can be achieved under long-term peritoneal insulin infusion, without significant impairment of diabetic retinopathy when an initial ophthalmological evaluation, and a specific treatment if necessary, are performed.

The natural protein kinase C alpha mutant is present in human thyroid neoplasms.

An altered protein expression of Ca(2+)-dependent protein kinase C (PKC) isoforms and a point mutation in the PKC alpha cDNA (position 908 of the nucleotide sequence, position 294 of the amino acid sequence, substitution of an aspartic acid by a glycine) have been previously described in a subpopulation of human pituitary tumors. In this work, we screened 16 thyroid tissue samples (four follicular adenomas, five colloid adenomas, three papillary carcinomas, one follicular carcinoma and three normal tissues adjacent to the tumors) for the presence of the PKC alpha point mutation and for PKC alpha, beta 1, beta 2, epsilon and delta protein expression. Screening for the presence of the PKC alpha mutant was performed by a subcloning technic. The polymerase chain reaction products were generated using reverse-transcribed cDNAs, subcloned and sequenced (10 clones were routinely sequenced). The PKC alpha point mutation at position 908 of the cDNA sequence was found in four out of the nine adenomas and in the follicular carcinoma. It was neither detected in the papillary carcinomas nor in the adjacent normal tissues (one was the adjacent normal tissue of the follicular carcinoma; in this sample, genomic DNA and cDNA were used to look for the presence of the mutant), demonstrating the somatic nature of this mutant. Western blot analysis of PKC isoforms showed that the expression of all isoforms was higher in the thyroid neoplasms as compared with their adjacent normal tissue (n = 3). It was also higher in the samples containing the PKC mutant (two follicular adenomas, two colloid adenomas and the follicular carcinoma) as compared with the tumors where it was not detected (three papillary carcinomas and five adenomas). Samples could be ordered according to their increasing PKC expression as follows: normal adjacent tissue < follicular adenomas without PKC alpha mutant < or = papillary carcinoma < follicular adenomas with PKC mutant < follicular carcinoma with PKC mutant. In conclusion, the discovery of the PKC alpha mutant in thyroid neoplasms demonstrates that this mutant is not particular to human pituitary tumors where it was originally detected. It is a somatic mutation and its presence is concomitant with high levels of all of the PKC isoforms analysed. The presence of the PKC mutant in thyroid neoplasms raises the question of its importance in thyroid tumorigenesis.

Weight excess before pregnancy: complications and cost.

OBJECTIVE: To investigate the incidence of pregnancy complications and the cost of prenatal care in patients with pregravid overweight. DESIGN: Retrospective study of patients dispatched into four groups: normal weight, moderate overweight, obesity, massive obesity. SETTING: Department of Obstetrics and Gynecology of Montpellier. SUBJECTS: One hundred and twelve pregnancies among 89 overweight women, compared with 54 healthy normal weight controls. MAIN OUTCOME MEASURES: Incidence of maternal complications, complications of labor, duration of hospitalization. RESULTS: Hypertension, toxemia, gestational diabetes, insulin treatment, urinary tract infections and macrosomia were positively correlated with maternal pregravid weight excess. Mean duration of hospitalization and overall cost were also strongly related to maternal weight. Cesarean section rate increased only in morbidly obese women. No materno-fetal mortality was observed in our study. CONCLUSION: Even moderate overweight is a significant risk factor for obstetrical complications and needs a multidisciplinary antenatal management in order to prevent materno-fetal complications.