Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size.Objective: Our objective was to establish the health status of adults with CAH.Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom.Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years.Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts.Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

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We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dualtracer dilution methodology. Six healthy lean male subjects (age 33 Ϯ 3 yr, body mass index 22.7 Ϯ 0.6 kg/m A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a onecompartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 Ϯ 3.8 vs. 10.4 Ϯ 3.9 vs. 11.1 Ϯ 2.7 ϫ 10 Ϫ2 ml⅐kg Ϫ1 ⅐min Ϫ1per mU/l; P ϭ nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective (P Ͻ 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52-82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/ transport was least responsive to insulin and was maximally activated by 62% (34-96%) above basal at 80 min compared with maximum 279% (116-565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP (P Ͻ 0.02) with half-times of 207 (84-510), 12 (7-22), and 29 (16-54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP (r ϭ 0.96, P Ͻ 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity (r ϭ 0.73, P ϭ 0.10) and disposal sensitivity (r ϭ 0.55, P ϭ 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.glucose kinetics; compartment modeling; D-[U-13 C]glucose; 3-O-methyl-D-glucose; insulin action; glucose transport; glucose disposal; endogenous glucose production; intravenous glucose tolerance test Glossary New Model EGP 0Endogenous glucose production extrapolated to zero insulin concentration (mmol/min) EGP b EGP at basal insulin concentration (mmol/min) F 01Total non-insulin-dependent glucose flux (mmol/min) g 1 (t), g 3 (t)Concentrations of D-[U-13 C]glucose and 3-O-methyl-D-glucose in the accessible compartment (mmol/l) G(t)Total glucose concentration in the accessible compartment (mmol/l) I(t), I b Plasma insulin and basal (preexperimental) plasma insulin (mU/l) k 03 Transfer rate constant of 3-O-methyl-D-glucose excretion (minTransfer rate constant from nonaccessible to accessible compart-Deactivation rate constants (minActivation rate constants (min Ϫ2per mU/l) q 1 (t), q 2 (t)Masses of D-[U-13 C]glucose in the two compartments (mmol) q 3 (t), q 4 (t)Masses of 3-O-methyl-D-glucose in ...

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The Mycobacterium tuberculosis fatty acid synthase type II (FAS-II) system has the unique property of producing unusually long-chain fatty acids involved in the biosynthesis of mycolic acids, key molecules of the tubercle bacillus. The enzyme(s) responsible for dehydration of (3R)-hydroxyacyl-ACP during the elongation cycles of the mycobacterial FAS-II remained unknown. This step is classically catalyzed by FabZ-and FabA-type enzymes in bacteria, but no such proteins are present in mycobacteria. Bioinformatic analyses and an essentiality study allowed the identification of a candidate protein cluster, Rv0635-Rv0636-Rv0637. Its expression in recombinant Escherichia coli strains leads to the formation of two heterodimers, Rv0635-Rv0636 (HadAB) and Rv0636-Rv0637 (HadBC), which also occurs in Mycobacterium smegmatis, as shown by split-Trp assays. Both heterodimers exhibit the enzymatic properties expected for mycobacterial FAS-II dehydratases: a marked specificity for both long-chain (>C 12) and ACP-linked substrates. Furthermore, they function as 3-hydroxyacyl dehydratases when coupled with MabA and InhA enzymes from the M. tuberculosis FAS-II system. HadAB and HadBC are the long-sought (3R)-hydroxyacyl-ACP dehydratases. The correlation between the substrate specificities of these enzymes, the organization of the orthologous gene cluster in different Corynebacterineae, and the structure of their mycolic acids suggests distinct roles for both heterodimers during the elongation process. This work describes bacterial monofunctional (3R)-hydroxyacyl-ACP dehydratases belonging to the hydratase 2 family. Their original structure and the fact that they are essential for M. tuberculosis survival make these enzymes very good candidates for the development of antimycobacterial drugs.(3R)-hydroxyacyl-ACP dehydratase ͉ hydratase 2 ͉ mycolic acid biosynthesis ͉ fatty acid elongation ͉ hot dog fold