Christof Schöfl

23Na Magnetic Resonance Imaging of Tissue Sodium

Hypertension is linked to disturbed total-body sodium (Na+) regulation; however, measuring Na+ disposition in the body is difficult. We implemented 23Na magnetic resonance spectroscopy (23Na-MR) and imaging technique (23Na-MRI) at 9.4T for animals and 3T for humans to quantify Na+ content in skeletal muscle and skin. We compared 23Na-MRI data with actual tissue Na+ content measured by chemical analysis in animal and human tissue. We then quantified tissue Na+ content in normal humans and in patients with primary aldosteronism. We found a 29% increase in muscle Na+ content in patients with aldosteronism compared with normal women and men. This tissue Na+ was mobilized after successful treatment without accompanying weight loss. We suggest that, after further refinements, this tool could facilitate understanding the relationships between Na+ accumulation and hypertension. Furthermore, with additional technical advances, a future clinical use may be possible.

Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain.

The molecular mechanism of the action of lithium salts in the treatment of bipolar disorder is not well understood. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. The molecular basis of this are changes in gene expression regulated by transcription factors such as CREB (cAMP-response-element-binding protein). CREB contains a transactivation domain, in which Ser119 is phosphorylated upon activation, and a bZip (basic leucine zipper domain). The bZip is involved in CREB dimerization and DNA-binding, but also contributes to CREB transactivation by recruiting the coactivator TORC (transducer of regulated CREB). In the present study, the effect of lithium on CRE (cAMP response element)/CREB-directed gene transcription was investigated. Electrically excitable cells were transfected with CRE/CREB-driven luciferase reporter genes. LiCl (6 mM or higher) induced an up to 4.7-fold increase in 8-bromo-cAMP-stimulated CRE/CREB-directed transcription. This increase was not due to enhanced Ser119 phosphorylation or DNA-binding of CREB. Also, the known targets inositol monophosphatase and GSK3beta (glycogen-synthase-kinase 3beta) were not involved as specific GSK3beta inhibitors and inositol replenishment did not mimic and abolish respectively the effect of lithium. However, lithium no longer enhanced CREB activity when the CREB-bZip was deleted or the TORC-binding site inside the CREB-bZip was specifically mutated (CREB-R300A). Otherwise, TORC overexpression conferred lithium responsiveness on CREB-bZip or the CRE-containing truncated rat somatostatin promoter. This indicates that lithium enhances cAMP-induced CRE/CREB-directed transcription, conferred by TORC on the CREB-bZip. We thus support the hypothesis that lithium salts modulate CRE/CREB-dependent gene transcription and suggest the CREB coactivator TORC as a new molecular target of lithium.

Cystic fibrosis-related diabetes compared with type 1 and type 2 diabetes in adults

With increasing life expectancy of patients with cystic fibrosis (CF), secondary diabetes becomes more prevalent. It appears to be the most common co‐morbidity in persons with cystic fibrosis. Therefore, the objective of our study was to describe characteristics of cystic fibrosis‐related diabetes compared with type 1 and 2 diabetes (T1DM/T2DM) in adults.

Seeing the sodium in a patient with hypernatremia

A 34-year-old patient with diabetes insipidus after removal of a hypothalamic tumor, developed difficulties with his treatment and presented with hypernatremia. On admission his blood pressure was normal, he was confused, had polyuria and secondary hyperaldosteronism, and his serum [Na+] was 162 mmol/l. We lowered the serum [Na+] with free water and desmopressin so that after 13 days his serum [Na+] was 141 mmol/l and his symptoms were improved. We reviewed the patients charts and discovered that his body weight was 79.0 kg with hypernatremia, and 78.5 kg after correction of his serum [Na+] and aldosterone.

CRH and SRIF Have Opposite Effects on the Wnt/β-Catenin Signalling Pathway Through PKA/GSK-3β in Corticotroph Pituitary Cells

ABSTRACT The Wnt/ß-catenin signalling pathway is involved in tumorigenesis including endocrine tumors. We investigated the Wnt/ß-catenin pathways modulation by corticotropin-releasing hormone (CRH) and somatostatin or somatotropin release-inhibiting factor (SRIF) in mouse pituitary AtT-20 corticotroph cells. The Wnt/β-catenin signalling pathway was activated by CRH and inhibited by SRIF. We provide evidence that cAMP/PKA signalling is involved affecting the GSK-3β phosphorylation status at phospho-GSK-3β (Ser9), thereby altering β-catenin degradation downstream. Furthermore, CRH and SRIF showed concordant effects on cell proliferation. Our data demonstrate an important role of the Wnt/β-catenin pathway in the proliferative control of pituitary corticotroph cells and describe a mechanism for its regulation by CRH and SRIF.

The Rational Use of Pituitary Stimulation Tests

BACKGROUND Diseases of the pituitary gland can lead to the dysfunction of individual hormonal axes and to the corresponding clinical manifestations. The diagnostic assessment of pituitary function has not yet been standardized. METHODS The members of the Neuroendocrinology Section and the Pituitary Study Group of the German Society for Endocrinology (Deutsche Gesellschaft für Endokrinologie) prepared outlines of diagnostic methods for the evaluation of each of the pituitary hormonal axes. These outlines were discussed in open session in recent annual meetings of the Section and the Study Group. RESULTS For the evaluation of the thyrotropic axis, basal TSH and free T4 usually suffice. For the evaluation of the gonadotropic axis in men, the testosterone level should be measured; if the overall testosterone level is near normal, then calculating the free testosterone level may be additionally useful. In women, an intact menstrual cycle is sufficient proof of normal function. In the absence of regular menstruation, measurement of the basal estradiol and gonadotropin levels aids in the diagnosis of the disturbance. For the evaluation of the adrenocorticotropic axis, the basal cortisol level may be helpful; provocative testing is in many cases necessary for precise characterization. The evaluation of the somato-tropic axis requires provocative testing. Aside from the insulin tolerance test, the GHRH-arginine test has become well established. Reference ranges normed to the body mass index (BMI) are available. CONCLUSION The diagnostic evaluation of pituitary insufficiency should proceed in stepwise fashion, depending on the patients clinical manifestations and underlying disease. For some pituitary axes, measurement of basal hormone levels suffices; for others, stimulation tests are required. In general, the performance of combined pituitary tests should be viewed with caution.

Seasonal Variation in Blood Pressure in 162,135 Patients With Type 1 or Type 2 Diabetes Mellitus

Seasonal variation in blood pressure (BP) has been observed in different populations. However, only few studies have focused on BP seasonality in diabetic patients. This study examined the seasonal patterns in BP in 62,589 patients with type 1 diabetes mellitus (T1DM) and in 99,546 patients with type 2 diabetes mellitus (T2DM) from the German/Austrian Diabetes Follow‐up Registry. Adjusted mean BP values revealed seasonal cycles of 12 months, with higher BP in colder months. Using harmonic regression models, the estimated systolic BP difference throughout the year was 2.28/2.48 mm Hg in T1DM/T2DM (both P<.001). Interestingly, seasonal variation in diastolic BP was larger in T1DM than in T2DM (1.24/0.64 mm Hg, P<.001). A sex difference was observed in T1DM only, while age differences occurred in both types of diabetes. Correlations between BP and potentially related factors such as outdoor temperature indicated that reasons underlying BP seasonality are likely to be complex and vary by subgroup.

Carbohydrate intake and insulin requirement in children, adolescents and young adults with cystic fibrosis-related diabetes: A multicenter comparison to type 1 diabetes☆

BACKGROUND & AIMS In cystic fibrosis-related diabetes (CFRD), energy needs differ from type 1 (T1D) or type 2 diabetes, and endogenous insulin secretion is not totally absent. We analyzed whether daily carbohydrate intake, its diurnal distribution and insulin requirement per 11 g of carbohydrate differ between CFRD and T1D. METHODS Anonymized data of 223 CFRD and 36,780 T1D patients aged from 10 to <30 years from the multicenter diabetes registry DPV were studied. Carbohydrate intake and insulin requirement were analyzed using multivariable regression modeling with adjustment for age and sex. Moreover, carbohydrate intake was compared to the respective recommendations (CFRD: energy intake 130% of general population with 45% carbohydrates; T1D: carbohydrate intake 50% of total energy). RESULTS After demographic adjustment, carbohydrate intake (238 ± 4 vs. 191 ± 1 g/d, p < 0.001) and meal-related insulin (0.52 ± 0.02 vs. 0.47 ± 0.004 IU/kg*d, p = 0.001) were higher in CFRD, whereas basal insulin (0.27 ± 0.01 vs. 0.38 ± 0.004 IU/kg*d, p < 0.001) and total insulin requirement per 11 g of carbohydrate (1.15 ± 0.06 vs. 1.70 ± 0.01 IU/d, p < 0.001) were lower compared to T1D. CFRD patients achieved 62% [Q1;Q3: 47; 77] of recommended carbohydrate intake and T1D patients 60% [51; 71] of age- and gender-specific recommended intake (p < 0.001). CFRD and T1D patients had a carbohydrate intake below healthy peers (79% [58; 100] and 62% [52; 74], p < 0.001). The circadian rhythm of insulin sensitivity persisted in CFRD and the diurnal distribution of carbohydrates was comparable between groups. CONCLUSIONS In pediatric and young adult patients, carbohydrate intake and insulin requirement differ clearly between CFRD and T1D. However, both CFRD and T1D patients seem to restrict carbohydrates.

IGF-I–IGFBP-3–acid-labile subunit (ALS) complex in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH)

UNLABELLED It has been shown that changes in IGF-I and IGFBP levels in children with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are correlated with different states of metabolic control. Our approach was to analyze the serum levels of IGF-I, IGFBP-3, their molar ratio IGF-I:IGFBP-3 (MR), and ALS in a cohort of CAH children and adolescents, and their associations with different clinical and biochemical parameters. DESIGN AND PATIENTS 56 patients, aged between 5.6 and 19.0 years were studied cross-sectionally. All patients had genetically proven CAH and received standard steroid substitution therapy. We measured serum levels of IGF-I, IGFBP-3, and ALS by commercial ELISA and calculated MR and assigned population-based SD scores (SDS). RESULTS (median, quartiles) Overall IGF-I was not significantly altered (0.05 SDS, -1.21, 0.92), whereas IGFBP-3 was significantly elevated (1.50 SDS; 0.58, 1.95, p<0.0001) compared to the reference population. Consecutively, MR was decreased (-0.64 SDS; -1.38, 0.32; p=0.0017). ALS was clearly decreased (-1.95 SDS; -3.075, -1.00; p<0.0001). ALS, IGF-I, MR, and IGFBP-3 SDS were lower in pubertal than in prepubertal patients (p<0.05). ALS SDS were lower in girls (p=0.0038). Correlation analyses (r(s), p) revealed correlations between MR/ALS and chronological age (-0.583, <0.0001/-0.428, 0.0010), MR/ALS and Tanner stages (-0.500, <0.0001/-0.334, 0.0118), MR/ALS and bone age (0.407, 0.0075/0.426, 0.0049), and between MR and ALS (0.405, 0.0020), respectively. For MR and ALS, we found no significant correlations for BMI, HOMA-IR, hydrocortisone and fludrocortisone dosage, or parameters of metabolic control. CONCLUSIONS Our data provide evidence that the components of the trimeric IGF-I-IGFBP-3-ALS complex are altered in CAH children with possible implications on pubertal growth and final height.

Hyperparathyroidism-jaw tumor syndrome.

Hyperparathyroidism-jaw tumor syndrome is a condition characterized by overactivity of the parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck and secrete a hormone that regulates the bodys use of calcium. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue.