A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).

Thyroid Related Quality of Life in Elderly with Subclinical Hypothyroidism and Improvement on Levothyroxine is Distinct from that in Young Patients (TSAGE).

The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013-2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8-10 mU/l.

Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype.

To date, germline or somatic genetic events can be detected for at least 60% of paragangliomas. Strong genotype-phenotype associations have been recognized and become increasingly refined. Characteristics closely linked with genotype include syndromic presentation, age of onset, risk of metastatic disease and predominant anatomic site. In contrast, profiles of catecholamine secretion appear to be largely determined by anatomic location or cell type of origin. This review summarizes current knowledge of genotype-phenotype correlations for paragangliomas in different locations and scrutinizes previous publications on the respective tissues of origin to find potential explanations for site-related differences. We hypothesize that differential sensitivities of distinct chromaffin cell populations to hypoxia are major determinants of these differences, with increased sensitivity to hypoxia likely exacerbating vulnerability to mutation-derived disruption of hypoxic signaling pathways. Potential involvement of endothelin-1, tumor necrosis factor type 1 receptor-associated protein and the hypoxia-inducible miR-210 in the development of abdomino-thoracic or head and neck paragangliomas are discussed. Recognition of factors that predispose to chromosomal losses, or amplify sub-threshold molecular alterations towards tumorigenic events in different (chromaffin) cell types, may facilitate the leap from developing targeted therapies towards establishment of tumor preventative measures.

Melatonin secretion following brain midline irradiation is diminished, but not correlated with subjective sleep disturbances.

OBJECTIVE: Cranial irradiation for brain tumours or leukaemias has been related to cognitive, endocrine and psychosocial late effects as well as sleep disturbances and increased daytime sleepiness. Studies suggest that cranial irradiation might impact on pineal melatonin secretion. Melatonin is an important regulator in human circadian rhythms and the sleep-wake cycle. The objective of this study was to investigate melatonin secretion, subjective sleep parameters and their interplay in a cohort of cranially irradiated head and brain tumour and leukaemia survivors at least 3 years after radiotherapy. DESIGN: Cross-sectional study. PATIENTS: Thirty-eight adults. MEASUREMENTS: Melatonin secretion was evaluated by measuring its metabolite 6-sulphatoxymelatonin in collected overnight urine. Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. The Beck Depression Inventory II was used to screen for depressive symptoms because of their impact on sleep. RESULTS: Patients irradiated in the brain midline had significantly lower melatonin secretion (P = 0.008). Subjects exhibited a high prevalence of sleeping difficulties, daytime sleepiness and depression, with females and overweight subjects particularly affected. Melatonin values and subjective sleep parameters did not correlate with each other or with treatment and most patient variables. CONCLUSIONS: Our data suggest that radiation exposure to the pineal gland negatively affects melatonin secretion. This lack of pineal melatonin does not influence subjective sleep quality. As melatonin has important antioxidant and cancer-protective effects, further research is necessary to elucidate whether these patients have an increased risk of developing secondary neoplasms and other radiation late effects.

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model.

BACKGROUND: Determinations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model. METHODS: A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure. RESULTS: Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels. CONCLUSION: Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.

CUP Syndrome in Neuroendocrine Neoplasia: Analysis of Risk Factors and Impact of Surgical Intervention.

BACKGROUND: Neuroendocrine neoplasia (NEN) with unknown primary site (NEN-CUP tumors) may have a poor prognosis. We evaluated the clinical presentation, therapy, outcome, and risk factors for adverse outcomes in patients who had these tumors. METHODS: In 243 patients who had NEN, a retrospective review was performed in 38 patients who had NEN-CUP tumors. The 38 patients who had NEN-CUP tumors were evaluated in three groups: group 1 (surgery; primary tumor detected; ten patients); group 2 (surgery; no primary tumor detected; ten patients); and group 3 (no surgery; 18 patients). Risk factors were evaluated with univariate and multivariate analyses. RESULTS: Most patients who had NEN-CUP tumors [32 patients (84%)] had World Health Organization (WHO) performance score of 0 or 1, and most tumors [24 patients (63%)] were well differentiated (WHO grade, G1 or G2; Ki-67 index, ≤20%). Univariate analysis showed that greater survival was significantly associated with lower patient age, lower WHO performance score, lower WHO grade, lower number of metastatic sites, treatment with surgery, and no treatment with chemotherapy. Multivariate analysis showed that low WHO performance score (hazard ratio 7.63, 95% confidence interval (CI) 2.63-22.19) and treatment with surgery (hazard ratio 0.10, CI 0.028-0.381) were significant independent predictors of improved survival. CONCLUSIONS: In patients with NEN-CUP tumors, surgical treatment is an independent predictor of better survival. Therefore, surgical treatment may be indicated in patients with good general health status and well-differentiated NEN-CUP tumors.

A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Wnt signaling in estrogen-induced lactotroph proliferation.

Prolactinomas are the most common type of functioning pituitary adenoma in humans, but the control of lactotroph proliferation remains unclear. Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue. Dual immunofluorescence analysis revealed that Wnt4 expression was not confined to lactotrophs, but that it was expressed in all anterior pituitary cell types. Estradiol induced proliferation in the somatolactotroph GH3 cell line, in parallel with Wnt4 mRNA and protein induction. A reporter gene assay for TCF- and LEF-dependent transcription revealed that there was no activation of the canonical Wnt pathway in GH3 cells upon stimulation with Wnt-conditioned culture medium or coexpression of constitutively active mutant ß-catenin. Expression of ß-catenin in both GH3 cells and normal rat anterior pituitary cells was restricted to the cell membrane and was unaltered by treatment with estradiol, with no nuclear ß-catenin being detected under any of the conditions tested. We show for the first time that Wnt4 affects non-canonical signaling in the pituitary by inhibiting Ca(2+) oscillations in GH3 cells, although the downstream effects are as yet unknown. In summary, Wnt4 is expressed in the adult pituitary gland, and its expression is increased by estrogen exposure, suggesting that its involvement in adult tissue plasticity is likely to involve ß-catenin-independent signaling pathways.

Cross-sectional and longitudinal associations between insulin-like growth factor I and metabolic syndrome: a general population study in German adults.

BACKGROUND: A previous study showed an inverse association between the insulin-like growth factor I (IGF-I) and the risk of impaired glucose tolerance or diabetes mellitus. Moreover, myocardial infarction patients with high baseline IGF-I levels had a lower risk of diabetes mellitus. These data suggested a protective effect of IGF-I against the development of metabolic syndrome. However, there are no longitudinal data regarding IGF-I and metabolic syndrome. The aim of the present study was to investigate the longitudinal association between IGF-I and metabolic syndrome. METHODS: Data from the population-based Study of Health in Pomerania, Germany, were used for cross-sectional (n = 3903) and longitudinal (n = 2143) analyses (5-year follow-up). Metabolic syndrome was defined by three or more of the following five components: abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure and elevated nonfasting glucose. Serum IGF-I and IGF binding protein 3 (IGFBP-3) were determined by chemiluminescence immunoassays. Logistic and Poisson regression analyses were performed to determine associations. RESULTS: In cross-sectional analyses high IGFBP-3 as well as high and low IGF-I/IGFBP-3 ratio levels were associated with prevalent metabolic syndrome. In longitudinal analyses, the direction of the relation changed: men but not women with high IGF-I or IGF-I/IGFBP-3 ratio levels had an increased, whereas men with low levels had a decreased risk of incident metabolic syndrome. CONCLUSION: In concordance with previous studies, our cross-sectional analyses showed a relation between low IGF-I/IGFBP-3 ratio and the prevalence of metabolic syndrome. In contrast, the longitudinal analyses indicated that a high IGF-I level was a risk marker for incident metabolic syndrome.

Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations.

BACKGROUND: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. METHODS: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. CONCLUSION: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined.

Hypothyroidism following childhood cancer therapy-an under diagnosed complication.

To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis (n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD (p = 0.0001) or a CNS neoplasm (p < 0.00005) but not leukaemia (p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care (p = 0.004) and hospital follow-up (p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings.

The atrial natriuretic peptide does not serve osmoregulation but predicts outcome following brain injury.

Atrial natriuretic peptide (ANP) plays an important role in body fluid homeostasis. ANP has been established as a marker of cardiac dysfunction and may play a role in brain edema development after traumatic brain injury (TBI). In order to identify its specific assignment following TBI, we related clinical data and treatment variables in 63 patients to longitudinal midregional (MR) proatrail natriuretic peptide (ANP) measurements. ANP correlated significantly to age (p < 0.0001) and vasopressin release (p < 0.001). Following TBI, ANP was increased initially and on day 3 (cut-off 100 pg/L) in 22% of the patients, in 31% on day 7, and was normalized at follow-up examination. The group comparison revealed that ANP levels did not significantly differ with regard to injury severity, but that high ANP levels predicted a worse Glasgow Outcome Score at 6 months (p < 0.05). While the initially intact osmoregulation - a correlation of urine volume and high serum sodium (r = 0.536, p = 0.003) or low urine osmolality (r = -0.556, p = 0.009) - got lost post-injury, the ANP release was triggered by volume load (p < 0.005). High ANP levels correlated with the neuroendocrine stress response, i.e., high cortisol (p = 0.05) and prolactin (p < 0.001) levels. We conclude that MR-proANP measurements reveal a significant predictive function for the prognosis of TBI.

Not Simply a Structural Problem: Psychological Determinants of Headache in Patients with Tumors of the Sellar Region.

OBJECTIVE: Headache in patients with tumors of the sellar region (TSR) has previously been attributed entirely to biomechanical causes. This study aimed to investigate the influence of psychological determinants for the occurrence of and disability due to headaches in patients with TSR. METHODS: This was a cross-sectional single-center study with a logistic regression approach. Eighty-four patients (75%) with pituitary adenomas and 28 with other TSR prior to first-time neurosurgery were investigated. One-hundred and twelve patients received standardized questionnaires on personality, headache characteristics, and disability due to headache. Fifty-nine patients additionally filled in questionnaires about coping with stress and pain catastrophizing. Separate logistic regression models were used to predict the risk of headache occurrence and disability due to headache by personality, stress coping, and pain catastrophizing. RESULTS: Conscientiousness, neuroticism, and pain catastrophizing were significant predictors of headache occurrence. The amount of explained variance for both models predicting headache occurrence was comparable to that in primary headache. Neuroticism, pain catastrophizing, and humor as a coping strategy predicted disability due to headache with a high variance explanation of 20-40%. CONCLUSION: For the first time, we report data supporting a strong psychological influence on headache and headache-related disability in patients with TSR, which argue against purely mechanistic explanatory models. Physicians treating patients with TSR and headaches should adopt an integrative diagnostic and treatment approach, taking the biopsychosocial model of pain into account.

Reduced pituitary size in subjects with mutations in the THRB gene and thyroid hormone resistance.

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α, ß) with differential tissue distribution. Thyroid hormone receptor ß (TRß) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the ß form of the receptor (pituitary, liver). This study seeks to identify the effects of mutant TRß on pituitary size. Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHß in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist). Results: Patients with mutant TRß (resistance to thyroid hormone ß, RTHß) showed elevated free tri-iodothyronine/thyroxine levels with normal thyroid-stimulating hormone levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHß patients in comparison to healthy controls (F(1,35) = 7.05, P = 0.012, partial η2 = 0.17). Conclusion: RTHß subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.

A role for beta-melanocyte-stimulating hormone in human body-weight regulation.

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.

Central insulin action regulates peripheral glucose and fat metabolism in mice.

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.

The interface between thyroid and diabetes mellitus.

Thyroid disease and type 1 but also type 2 diabetes mellitus (DM) are strongly associated, and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with DM and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH.

Serum insulin-like growth factor I and its binding protein 3 in their relation to intima-media thickness: results of the study of health in Pomerania (SHIP).

OBJECTIVE: Previous studies detected associations between lower insulin-like growth factor I (IGF-I) levels and increased risk of congestive heart failure or ischaemic heart disease. The aim of the present study was to assess the association of IGF-I and its binding protein 3 (IGFBP-3) with the carotid intima-media thickness (IMT) as marker of asymptomatic cardiovascular disease. DESIGN AND POPULATION: From the population-based Study of Health in Pomerania (SHIP), a total of 2286 participants aged 45 years or older with readable ultrasound of the carotid arteries were available for the present analyses. METHODS AND MEASUREMENTS: Serum IGF-I and IGFBP-3 levels were categorized into three groups (low, moderate, high) according to the sex-specific 10th and 90th percentile. Analyses of variance (anova) and logistic regression analyses adjusted for age, waist circumference, diabetes, hypertension and creatinine clearance were performed. RESULTS: After adjusting for confounding factors, IGF-I and the IGF-I/IGFBP-3 ratio were positively related to IMT in anova. Logistic regression analyses confirmed these findings and showed that high IGF-I levels, a high IGF-I/IGFBP-3 ratio and low IGFBP-3 levels were associated to higher odds of increased IMT. CONCLUSION: In conclusion, high IGF-I or high IGF-I/IGFBP-3 ratio values and low IGFBP-3 levels are associated with increased IMT. Therefore, systemic levels of the IGF axis or alterations in the balance of its components are associated with subclinical atherosclerotic disease.

Proinsulin and the proinsulin/insulin ratio in overweight and obese children and adolescents: relation to clinical parameters, insulin resistance, and impaired glucose regulation.

BACKGROUND: In adults with impaired glucose regulation (IGR) or type 2 diabetes mellitus (T2DM), proinsulin (PI) and its ratio to insulin (ins; PI/I ratio) are frequently elevated. OBJECTIVE: Here we assessed the relationship among fasting PI, clinical parameters, and carbohydrate metabolism, a potential difference of the PI/I ratio between overweight and obese youth with or without IGR in an oral glucose tolerance test (OGTT) and the predictive power of PI levels for IGR. DESIGN AND PATIENTS: In a cross-sectional study, data of n = 259 children and adolescents attending our obesity clinic were studied. METHODS: Fasting PI levels were determined in all patients and matched to the standard assessment of obesity. In n = 154 subjects at risk for T2DM, an OGTT was performed sampling for glucose, ins, and PI. MAIN OUTCOME MEASURES: ins, glucose, PI, PI/I ratio, insulin resistance [homeostasis model assessment of insulin resistance index (HOMA-IR)]. RESULTS: Puberty (by Tanner) and relative body weight [body mass index (BMI)-standard deviation of BMI (SDS)] showed a linear relationship to fasting PI levels (p < 0.001 for Tanner I vs. II-V; p = 0.04 and p = 0.026 for BMI-SDS < 2 vs. 2-2.5 and 2-2.5 vs. > 2.5, respectively). Subjects with ins resistance (HOMA-IR > 95th percentile, n = 140) had higher fasting PI levels than those without (p < 0.001), with no significant difference in fasting PI/I ratio (p > 0.05). As compared to subjects with normal glucose regulation, subjects with IGR (n = 35) had higher fasting PI (p = 0.001) and an increased PI/I ratio, both during fasting and at 30 min during OGTT (p = 0.049 and p = 0.014, respectively). CONCLUSIONS: Children and adolescents with IGR have disproportionately elevated PI levels, both during fasting and after acute glucose stimulation indicating ß-cell dysfunction.

Clinical Experience of the Efficacy and Safety of Low-dose Tolvaptan Therapy in a UK Tertiary Oncology Setting.

CONTEXT: In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy. OBJECTIVE: To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy. METHODS: Retrospective evaluation in a tertiary cancer center. RESULTS: Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ±â€…4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ±â€…9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01). CONCLUSION: In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.