Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes.

Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.

The polymorphism Arg585Gln in the gene of the sterol regulatory element binding protein-1 (SREBP-1) is not a determinant of ketosis prone type 2 diabetes (KPD) in Africans.

AIM: Ketosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene (SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD. METHODS: We examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test). RESULTS: There were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P=0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former (P=0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion. CONCLUSION: The results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.

[Propositions for the standardized expression of HbA 1c results]. / Propositions pour l'expression standardisée des résultats d'HbA 1c.

The 2007 international consensus about the standardization of HbA(1c) determination and expression of results is progressively implemented in most countries. In France, a common working group of the Société française de biologie clinique (SFBC) and the Société francophone de diabétologie (SFD) has expressed the following recommendations. HbA(1c) results are expressed in percentage of total hemoglobin and in mmol HbA(1c)/mol Hb, but are not converted into estimated average glucose. A table indicating the correspondence between HbA(1c) and estimated average glucose may be given with the results, subject to precautions of interpretation at the individual level.

Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France.

CONTEXT: Hypoglycaemia from antihyperglycaemic drugs may have a significant impact on patients' health-related quality of life. Combination use of metformin and a sulphonylurea has become increasingly common; yet, the impact of hypoglycaemia on quality of life in these patients is not well documented. OBJECTIVE: To examine patient-reported experience of hypoglycaemia, worry about hypoglycaemic symptoms and the impact of hypoglycaemia on patients' quality of life associated with use of sulphonylurea co-administered with metformin. DESIGN: This was an observational, cross-sectional, multi-centre study. SETTING: A total of 98 primary care centres in France during October to December 2005. PATIENTS: A total of 400 patients with type 2 diabetes, who were > or = 35 years old and who had been treated with metformin and a sulphonylurea for at least 6 months, completed questionnaires during their usual primary care office visit. MAIN OUTCOME MEASURES: Frequency and severity of hypoglycaemic symptoms in the past 6 months, the Worry subscale of the Hypoglycaemic Fear Survey-II (HFS-II) and the EuroQol-5 Dimensions (EQ-5D) questionnaire. RESULTS: A total of 136 (34%) patients reported experiencing hypoglycaemia, of whom 78 (58%) experienced mild, 40 (30%) experienced moderate and 16 (12%) experienced severe or very severe symptoms. Mean score on the HFS-II Worry scale was higher for patients who reported having hypoglycaemia than for those who did not (19.0 vs. 10.2; p < 0.0001) and increased with severity of hypoglycaemic symptoms. In linear regression analyses, more severe symptoms of hypoglycaemia were significantly associated with higher scores on the HFS-II Worry scale (p = 0.0162) among patients with hypoglycaemic symptoms. Summary scores on the EQ-5D were lower for patients who reported hypoglycaemia than for those who did not (p = 0.0001) and, in multivariate analysis, the experience of hypoglycaemia was negatively associated with the EQ-5D summary score (p < 0.0001). CONCLUSION: The occurrence and severity of hypoglycaemic symptoms were associated with increased patient worry about hypoglycaemia and lower health-related quality of life among type 2 diabetic patients being treated with both metformin and a sulphonylurea.

Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by Octreotide and Pegvisomant.

We describe the first case of a 36 year-old male patient with a somatotropin and thyreotropin secreting pituitary adenoma, co-treated by a long-acting releasing somatostatin analog (Octreotide) and a GH receptor antagonist (Pegvisomant). The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by MRI. The co-treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies.

Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin.

Remission from insulin dependency in insulin-treated recent-onset type I (insulin-dependent) diabetic patients can result from a partial recovery of insulin secretion, an improvement in tissue sensitivity to insulin, or both. The same hypothesis must be analyzed when remission occurs in cyclosporin A (CsA)-treated patients. In this study, plasma C-peptide levels were serially measured in the basal state and after stimulation in 219 recent-onset type I diabetic patients; 129 received CsA, and all patients were similarly monitored and insulin treated. The results were analyzed in view of the occurrence of remission. Remission was defined as good metabolic control in the absence of hypoglycemic treatment for greater than or equal to 1 mo. Remission occurred in 44% of the CsA-treated group and lasted for mean +/- SE 10.0 +/- 0.9 mo vs. 21.6% in the non-CsA-treated group with a duration of 4.4 +/- 0.8 mo. Plasma C-peptide levels were initially dramatically lower than normal in both groups in the basal and stimulated states. C-peptide levels increased significantly later, at 3 and 6 mo, in both groups. C-peptide values were proportional to the rates of remission in both groups. In the non-CsA-treated group, C-peptide levels later decreased, and these patients inexorably relapsed to insulin dependency. In contrast, in the CsA-treated group, the initial recovery in insulin secretory capacity was maintained over the 18-24 mo of the study. Furthermore, higher remission rates and longer-lasting remission were obtained in patients who reached higher C-peptide levels at the 3rd mo of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pattern of treatment among diabetic patients in France.

Both the treatment pattern and the degree of metabolic control were estimated from a sample of 1172 French diabetic patients. The subjects were recruited from 80 medical-analysis laboratories scattered throughout the country, where they came for biologic blood sample tests. Patients had to be diagnosed as having diabetes, give consent for additional blood sampling, and fill out a short self-questionnaire. Glycosylated hemoglobin A1c (HbA1c) was centrally determined by liquid chromatography (normal range 3.5-6.3%). We found 135 patients (11.5%) who were not drug treated or treated with diet alone, 862 (73.5%) treated with oral agents, and 175 (15.0%) treated with insulin. Among the latter, 79 (6.7%) were defined as true insulin-dependent diabetes mellitus (IDDM) patients. Among patients receiving no drug or a slight dosage or oral agents, 47% were found to be in the normal range of HbA1c. On the other hand, among the patients intensively treated with oral agents or secondarily with insulin, less than half were under fair control (HbA1c less than 7.5%). These results are in agreement with previous estimates of treatment distribution derived from national drug sales data. They provide evidence regarding the particular features of diabetes in France, i.e., low prevalence of IDDM, low consumption of insulin, high consumption of oral agents. The finding of a large proportion of normal HbA1c values in non-insulin-dependent diabetic patients suggests a state of overdiagnosis linked to the use of nonspecific criteria of diagnosis in large-scale screening.

Androgen excess in women with acne alone compared with women with acne and/or hirsutism.

Acne is known to be one of the features of hyperandrogenism. The aim of the present work was to study women with persistent acne and without other evidence of hyperandrogenism, such as hirsutism, alopecia, or irregular menses. Among 87 female patients with acne and/or hirsutism, we defined three groups: group 1 (n = 29), patients having treatment-resistant acne without menstrual disturbance, alopecia, or hirsutism; group 2 (n = 27), patients with acne and hirsutism; and group 3 (n = 31), patients with hirsutism alone. Clinical chemistry criteria for hyperandrogenism were based on elevated values of one or more of the following parameters: plasma testosterone, delta-4-androstenedione, dehydroepiandrosterone, urinary 5 alpha-androstane 3 alpha-17 beta-diol, and 17-ketosteroids (with chromatography). Plasma and urine samples were drawn between the 18th and 25th days of the cycle. Among group 1 patients, we found 25 subjects (86%) with hyperandrogenism, according to these laboratory criteria. The etiologies were: polycystic ovary syndrome (36%), adrenal hypersecretion (40%, of which 12% showed secondary polycystic ovaries), isolated increase in 5 alpha-androstane 3 alpha-17 beta-diol (20%), and hyperandrogenism without diagnosis (4%). The parameters were found to be more elevated in these patients than in a control group of 30 normal volunteer women. In groups 2 and 3, the findings were essentially the same as in group 1, except for increased levels of testosterone and the testosterone/SHBG ratio. Furthermore, it was evident that persistent acne may be an isolated sign of hyperandrogenism.

Effect of oral isotretinoin treatment on skin androgen receptor levels in male acneic patients.

An oral daily dose (mean +/- SD, 0.75 +/- 0.05 mg/kg) of isotretinoin was administered for 3 months to six male patients with acne (scores of 4 and 5 according to Rosenfield). The therapy resulted in complete resolution of acne in four patients and improved acne significantly (score 1) in two patients. In accordance with recent findings, no change in serum testosterone and significant decreases in 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol glucosiduronate, and androsterone glucosiduronate levels were observed after treatment. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after 3 months of isotretinoin treatment. The treatment did not modify the binding affinity constant of skin androgen receptor (0.44 vs. 0.32 nmol/L), but it did induce a 2.6-fold decrease in its binding capacity constant (62 vs. 24 fmol/mg cytosolic protein), as assessed by Scatchard plot and confirmed immunologically by Western blot analysis. These data clearly showed that skin androgen receptor was sensitive to oral isotretinoin administration in acneic patients. The decrease in skin androgen receptor levels (this study) and the recently reported suppression of skin 5 alpha-dihydrotestosterone production by isotretinoin treatment appeared consistent with the involvement of androgen receptor and 5 alpha-dihydrotestosterone in the pathogenesis of acne. Indeed, sebum production is under androgen control, and an abnormal response of the pilosebaceous unit to androgens appears to be implicated in the pathogenesis of acne. These observations were consistent with the absence of sebum in complete androgen-insensitive patients and normal sebum production in male pseudohermaphrodites.

Increased plasma 21-deoxycorticosterone (21-DB) levels in late-onset adrenal 21-hydroxylase deficiency suggest a mild defect of the mineralocorticoid pathway.

Plasma 21-deoxycorticosterone (21-DB) concentrations were measured before (basal) and 1 h after ACTH stimulation in a population of 34 normal subjects, 18 patients with the late-onset form of congenital adrenal hyperplasia (LO-CAH) due to 21-hydroxylase deficiency, and 19 LOCAH heterozygotes. For comparison, plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were determined simultaneously in the same subjects. Plasma 21-DB concentrations as well as those of 21-DOF did not vary significantly as a function of age, sex, or phase of the menstrual cycle, in contrast to plasma 17-OHP. The mean plasma 21-DB concentrations in normal subjects (adult men, follicular and luteal phase women, and children) were 19.0 +/- 9.5 (+/- SD) pmol/L before and 73.2 +/- 31.0 after ACTH stimulation. In the LOCAH patient group, the mean post-ACTH plasma 21-DB concentration was 1736.0 +/- 1243.0 pmol/L, and all values were above the highest post-ACTH value (148.2 pmol/L) in the normal subjects. Similarly, in the LOCAH patients the post-ACTH plasma 21-DOF concentration was 33.7 +/- 20.3 nmol/L, and the post-ACTH plasma 17-OHP value was 134.0 +/- 70.6 nmol/L; all LOCAH patients had supranormal responses to ACTH. However, 38.9%, 11.2% and 16.7% of the basal plasma 21-DB, 21-DOF, and 17-OHP values in the LOCAH patients overlapped those in the normal subjects. There was a rather large overlap (63.2%) in post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and the normal subjects; it was less than the overlap in plasma 17-OHP (74%) and more than the overlap in plasma 21-DOF values (5.2%) in these same 2 groups. There was moderate overlap (21%) in the post-ACTH plasma 21-DB levels between the LOCAH heterozygotes and LOCAH patients, but no overlap between these 2 groups for either 21-DOF or 17-OHP. The abnormally elevated post-ACTH plasma 21-DB levels found in all the LOCAH patients as well as in some LOCAH heterozygotes suggest the existence of minor 21-hydroxylase deficiency in the mineralocorticoid synthetic pathway in these patients in addition to the well known impairment in the glucocorticoid pathway demonstrated by the elevated post-ACTH 21-DOF and 17-OHP levels.

Comparison of basal and adrenocorticotropin-stimulated plasma 21-deoxycortisol and 17-hydroxyprogesterone values as biological markers of late-onset adrenal hyperplasia.

Plasma 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) concentrations were assayed before (basal) and 1 h after ACTH stimulation in 4 groups of normal subjects (35 follicular phase women, 22 luteal phase women, 33 adult men, and 15 prepubertal children) and in a group of 31 patients with the late-onset form of congenital adrenal hyperplasia (LOCAH) due to 21-hydroxylase deficiency as well as in 31 LOCAH) heterozygotes. The mean basal plasma 21-DOF concentrations in each of the 4 groups of normal subjects were between 8 ng/dL (0.23 nmol/L) and 11 ng/dL (0.31 nmol/L), and they increased significantly after ACTH stimulation to between 36 ng/dL (1.04 nmol/L) and 44 ng/dL (1.27 nmol/L). There were no differences in basal or ACTH-stimulated plasma 21-DOF levels in these 4 groups, whereas their basal and post-ACTH plasma 17-OHP levels did vary. Among the LOCAH patients, 83.8% had basal plasma 21-DOF levels and 61.2% had basal plasma 17-OHP levels higher than the highest basal 21-DOF [30 ng/dL (0.86 nmol/L)] and 17-OHP [450 ng/dL (13.61 nmol/L)] concentrations in the normal subjects, and all individual 21-DOF and 17-OHP levels after ACTH stimulation [greater than or equal to 404 ng/dL (11.67 nmol/L) and greater than or equal to 1040 ng/dL (31.47 nmol/L), respectively] were markedly higher than the highest 21-DOF [76 ng/dL (2.19 nmol/L)] and 17-OHP [580 ng/dL (17.55 nmol/L)] levels in the normal subjects. The mean post-ACTH/basal plasma level ratios among the LOCAH patients were 19.75 for 21-DOF and 8.03 for 17-OHP. In LOCAH heterozygotes, basal 21-DOF values were higher than normal in 48.3%, and post-ACTH values were higher than normal in 93.5% of the cases. In contrast, basal plasma 17-OHP levels were similar in LOCAH heterozygotes and normal subjects, and only 16.1% of the LOCAH heterozygotes had post-ACTH plasma 17-OHP levels higher than the highest normal value. If sex and phase of the menstrual cycle are taken into account, along with the incremental responses (post-ACTH minus baseline value) of plasma 21-DOF and 17-OHP, to compare LOCAH heterozygotes and normal subjects, the discriminating power for detection of heterozygocity was somewhat increased for 21-DOF (to 100%) and appreciably increased for 17-OHP (to 30%).(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for decreased androgen 5 alpha-reduction in skin and liver of men with severe acne after 13-cis-retinoic acid treatment.

To investigate the effect of 13-cis-retinoic acid (13-cis-RA) treatment on androgen metabolism in men with severe nodulocystic acne, eight men with severe acne received an oral daily dose of 0.7 mg/kg 13-cis-RA over 3 months. Exploration of androgen metabolism in serum samples, 24-h urine collections, and skin biopsies obtained before and at the end of the treatment revealed no significant alterations in serum levels of either adrenal or gonadal androgens. However, the treatment did induce significant decreases in serum levels of the 5 alpha-reduced androgens: 5 alpha-dihydrotestosterone (P < 0.02), androsterone glucosiduronate (P < 0.04), and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate (P < 0.004). Unlike serum, the urinary 5 alpha-reduced metabolites 5 alpha-androstan-3 alpha, 17 beta-diol and androsterone did not vary significantly despite a decrease in the excretion of the latter. Moreover, a marginally significant increase in urinary excretion of etiocholanolone, very similar to the decrease in androsterone excretion, was observed. The ratio of androsterone to etiocholanolone decreased significantly (P < 0.004) after 13-cis-RA therapy and suggested a metabolic deviation from the androgen 5 alpha- to 5 beta-reduction pathway in the liver. The most pronounced effect was observed in skin biopsies, which lost 80% of their ability to form 5 alpha-dihydrotestosterone (P < 0.001). It is concluded that 13-cis-RA therapy in men with severe nodulocystic acne did not alter gonadal or adrenal functions, but it did induce 1) a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies; 2) significant decreases in serum 5 alpha-dihydrotestosterone, androsterone glucosiduronate, and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate; and, finally, 3) deviation of the liver androgen 5 alpha- to 5 beta-reduction pathway. The effect of 13-cis-RA treatment on severe acne is consistent with the dramatic decrease in androgen 5 alpha-reduction observed mainly in the skin.

Detection of islet cell antibodies by a microcytotoxicity method.

A microcytotoxicity test for antibodies against islet cells (ICA) is described. Sera from patients with insulin-dependent diabetes, their healthy first degree relatives, and normal controls, genotyped for HLA-A, -B and -DR, were tested by 4 different methods. Cytoplasmic ICA and complement fixing ICA were detected by indirect immunofluorescence with human pancreas sections, and cytotoxic complement dependent ICA and surface ICA were tested against murine beta cell suspensions. Strong correlation was found between cytotoxic and surface antibodies (P less than 10(-7). The technique described is appropriate for use in the screening of large numbers of sera.

Islet-cell antibodies (ICA-CFICA) and HLA genotypes in 107 IDD patients and their first-degree relatives.

The prevalence of ICA and CFICA in relation to HLA-DR genotypes was analyzed in 107 insulin-dependent diabetic (IDD) patients with a duration of IDD ranging from onset to 30 years, and 247 nondiabetic first-degree relatives. In 46 patients tested at onset of IDD, the prevalence of ICA and of CFICA was 61 and 50%, respectively; with the longer duration of IDD, the prevalence of CFICA decreased more rapidly than that of ICA. No significant association was observed between ICA and any HLA allele in patients tested from onset till 2 years after onset. However, a higher prevalence of ICA was found in DR3 positive patients with a duration of IDD of more than 2 years (p less than 0.02). Among the healthy relatives, the prevalence of ICA was 7% in parents and 13% in siblings; one out of 101 siblings had CFICA. No association was found between ICA and any HLA marker. The presence of ICA in sibs was independent of the number of haplotypes they shared with the IDD proband: among the 13 ICA-positive healthy sibs, one shared 2 haplotypes, nine shared 1 haplotype and three shared no haplotype with the proband, which is not different from the random distribution.

Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men.

OBJECTIVE: We investigated the effect of an intensive training program on fasting leptin and adiponectin levels. METHODS: Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle. RESULTS: Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations. CONCLUSIONS: An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.

Highly sensitive and specific time-resolved fluoroimmunoassay (TR-FIA) of cyproterone acetate and free cyproterone.

We have developed a non-isotopic TR-FIA for Cyproterone acetate and Cyproterone in plasma. Synthesis of the biotinylated tracers, biotinylated Cyproterone acetate, and Cyproterone, as well as the preparation of anti-Cyproterone acetate and anti-Cyproterone antisera are reported. The specificity of anti-Cyproterone acetate antiserum resulting from the coupling of link bridge (link bridge between steroid and BSA), on the 3-position on the steroid skeleton, allowed to carry out the Cyproterone acetate assay directly on extracted plasma (without chromatography). On the other hand Cyproterone assays require a purification step, including extraction plus chromatography, because the plasma Cyproterone acetate concentrations in Cyproterone acetate-treated women are 200 times higher than for Cyproterone. Theses plasma TR-FIA of Cyproterone acetate and Cyproterone presented the advantage of needing only small doses of radioactivity for recovery controls, and better practicability related to the only existing RIA described to date.

17 beta-Estradiol: oral or parenteral administration in hyperandrogenic women? Metabolic tolerance in association with cyproterone acetate.

OBJECTIVE: To compare the metabolic effects of two different administration routes of estrogen associated with cyproterone acetate (CPA) in young women. DESIGN: Randomized and prospective study. SETTING: University medical and research center. PATIENTS: Sixty-five premenopausal young women with clinical hyperandrogenism. INTERVENTIONS: A high dose of CPA was administered, associated with either transdermal (group T) or oral (group O) 17 beta-E2. MAIN OUTCOME MEASURES: Glucose tolerance, plasma lipid level, coagulation and fibrinolysis parameters, and angiotensinogen, before and at 6 and 12 months during treatment. RESULTS: At 12 months, fasting blood glucose and basal insulin levels were significantly lower in group O than in group T. The increase in angiotensinogen was greater in group O, however, without modification in arterial blood pressure. No significant difference between the two groups was observed in lipids, coagulation, and fibrinolysis. CONCLUSION: Natural estrogens associated with CPA have no patent deleterious metabolic effect. However, the choice of oral estrogen administration seems to be better among patients with disorders such as hyperandrogenism or obesity with potential hyperinsulinism.

Marital status and family size of type 1 diabetic patients in a French cohort.

OBJECTIVE: To compare the marital status, the number of offspring and the cumulative incidence of type 1 diabetes in offspring of type 1 diabetic men and women. METHODS: From the database of patients attending our department, we reviewed the files of all the 352 subjects aged >=40 years with type 1 diabetes and compared male and female patients for whom age, age at diagnosis of diabetes, marital status, socio-economic status, number and age of offspring, diagnosed type 1 diabetes in the offspring could be obtained from patient's record and/or direct interview (86 males and 78 females). RESULTS: In this population, 73% of women and 81% of men were married or living a marital life (NS), and 35% of women versus 8% of men had no offspring (P<0.0001). The proportion of parents with 2 offspring or more was 43% in females and 61% in males (p=0.03) and was not related to the socio-economic status. The number of offspring with diagnosed type 1 diabetes was small (8/229) and did not show significant association with gender of the parent, with a cumulative incidence of 3.2 and 3.7% in offspring of type 1 diabetic mothers and fathers respectively. CONCLUSION: Type 1 diabetic women born before 1960 had fewer children than men. In this cohort, there was no difference in the cumulative incidence of type 1 diabetes in offspring of type 1 diabetic men and women despite reduced family size in women.

Effects of a single bout of exercise and exercise training on steroid levels in middle-aged type 2 diabetic men: relationship to abdominal adipose tissue distribution and metabolic status.

Lower androgen levels have been suggested to be associated with type 2 diabetes and central obesity and are probably involved into the development of atherosclerosis. The present study investigates the effect of acute and chronic exercise on Dehydroepiandrosterone (DHEA) levels in relation to abdominal fat distribution and metabolic status in type 2 diabetes. Twenty weight-stable, middle-aged males with type 2 diabetes were enrolled in the study and participated in a submaximal (VO(2) peak) and moderate (50% VO(2) peak) exercise bout. The subjects were randomly assigned either to a trained or a control group, respectively. Physical training consisted of an 8 week program of aerobic exercise (75% VO(2) peak, 45 min), twice a week and intermittent exercise, once a week, on a bicycle ergometer. Acute exercise significantly increased DHEA and Testosterone (T) levels. Physical training increased VO(2) peak (42%, p <0.001), insulin sensitivity index (K(ITT) ) (57.5%, p <0.02), and basal DHEA levels (36%, p <0.05), and decreased HbA1c (29%, p <0.001), visceral adipose tissue (VAT) (44%, p <0.01) and subcutaneous adipose tissue (SAT) levels (18%, p <0.01). Body weight, BMI and insulin, T levels were not modified. Changes in DHEA levels were not correlated with changes in insulin sensitivity and abdominal fat distribution. In conclusion, exercise training favourably affects DHEA levels independently of improvements of metabolic status and abdominal fat distribution in patients with type 2 diabetes.