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Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly--such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities. [ABSTRACT FROM AUTHOR]

A small proportion of the patients with acromegaly present with apparently normal basal GH levels and suppressible GH levels despite increased IGF-1 levels, a pattern called micromegaly by some authors. Whether this pattern represents a distinct entity or is just an expression of acromegaly in its early stages is still a matter of debate. Nevertheless, these patients have some peculiar characteristics such as being more likely older and male, mostly harbour microadenomas or small macroadenomas, and have lower IGF-1 and postglucose GH levels. Even though, the frequency and severity of clinical signs and comorbidities are similar to those of patients with classic acromegaly. In conclusion, micromegaly seems to be a distinct clinical entity with a different biological behavior characterized by a low GH output., Competing Interests: Declaration of Competing Interest LV, MRAM and LAN have no disclosures to report. AROJr is a current full time employee of Ipsen Bioscience in the USA – Senior Medical Director- receiving restricted stock units from the company., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: PRESTO 3 evaluated nurses' preference for the Somatuline® Autogel® syringe versus the Lanreotide Pharmathen syringe after injection-pad testing., Methods: This international simulated-use study included oncology/endocrinology nurses with ≥ 1 years' experience in managing neuroendocrine tumours (NETs) and/or acromegaly. Each nurse tested both syringes twice in a randomised order before completing an electronic survey. The primary objective was to assess overall preference (%, 95% confidence interval [CI]) for the Somatuline Autogel syringe versus the Lanreotide Pharmathen syringe. Secondary objectives included rating syringe performance and ranking the importance of syringe attributes., Results: Ninety-four nurses were enrolled: mean age, 41.0 (SD, 11.5) years. The percentage of nurses stating a preference ("strong" or "slight") for the Somatuline Autogel syringe (86.2% [95% CI 77.5-92.4%]) was significantly higher than 50% (p < 0.0001). Performance rating was significantly higher for the Somatuline Autogel syringe versus Lanreotide Pharmathen syringe for 10 of the 11 attributes tested (p < 0.05). The syringe attributes considered most important when injecting patients in routine clinical practice were "easy to use from preparation to injection" (30.9%) and "comfortable to handle during use from preparation to injection" (16.0%). The attribute most commonly rated as least important was "fast administration from preparation to injection" (26.6%)., Conclusion: Nurses strongly preferred the user experience of the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. "Ease of use" and "comfortable to handle" were the most important syringe attributes, and performance rating was significantly higher with Somatuline Autogel versus Lanreotide Pharmathen syringe for all but one attribute., (© 2023. The Author(s).)

Context: Treatment of acromegaly is multimodal for many patients, and medical treatments include somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and growth hormone receptor antagonists (GHRAs). However, recent real-world evidence on treatment patterns for patients with acromegaly is limited., Objective: This study evaluated medication usage, treatment changes, adherence, persistence, comorbidities, and health care resource utilization using deidentified data from MarketScan, a US claims database., Methods: Eligible patients (n = 882) were those receiving monotherapy or combination therapy for ≥90 days without treatment gaps., Results: Mean age at diagnosis was 48.6 years; 50.1% of patients were female. Over half (59.4%) had 1 line of treatment (LOT); 23.1% had 2 LOTs; 17.5% had at least 3 LOTs. Most patients (94.6%) initiated treatment with monotherapies. The most common first-line monotherapy treatments were cabergoline (DA, 36.8%), octreotide long-acting release (first-generation SRL, 29.5%), and lanreotide depot (first-generation SRL, 22.5%). Adherence for first-line treatments (proportion of days covered) was higher for first-generation SRLs (lanreotide depot: 0.8) compared with DAs (0.7). Treatment persistence (time between the first treatment record and a change in LOT/censoring) in LOT 1 was higher for GHRAs (24.8 months) and first-generation SRLs (20.0 months) compared with DAs (14.4 months). Female patients and those diagnosed at a younger age were more likely to have shorter treatment persistence. The most prevalent comorbidities were hyperlipidemia, essential hypertension, and sleep apnea., Conclusion: Patients with more comorbidities had more health care visits during the first year after diagnosis, suggesting increased disease burden. Real-world evidence on treatment patterns provides insights into recommendations for individualized therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: A systematic literature review was conducted to assess the use of home injections (self/partner/healthcare provider [HCP]-administered) of somatostatin analogs (SSAs) as an alternative to healthcare-setting injections in patients with acromegaly and neuroendocrine tumors (NETs)., Methods: MEDLINE/Embase/the Cochrane Library (2001-September 2021), key congresses (2019-2021), and bibliographies of relevant systematic reviews were searched. Eligible studies reported on efficacy/effectiveness, safety, adherence, patient-reported outcomes (PROs), and economic outcomes in populations receiving home injections of SSAs., Results: Overall, 12 studies were included, all reporting on SSAs (lanreotide Autogel/Depot or octreotide long-acting release) in acromegaly or NETs. Across four studies, home injection was associated with similar disease control in patients with acromegaly/NETs compared with healthcare-setting administration. High rates of treatment adherence were shown in two studies of patients with acromegaly receiving lanreotide injections at home. Two studies reported non-serious adverse events; incidence of adverse reactions was similar in both the home and healthcare administration settings. Preference for injection setting varied between studies and indications; nonetheless, higher satisfaction/convenience (>75% patients) was reported for home injections. Self- or partner-injection was associated with economic savings compared with administration in the healthcare setting across five studies., Conclusion: Efficacy/effectiveness, adherence, and safety outcomes of SSAs in the home injection setting were similar to those in the healthcare setting, with high reported satisfaction and convenience. Self/partner injection also resulted in cost savings. These findings provide a basis to understand outcomes related to home injection and encourage healthcare providers to discuss optimal treatment choices with their patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Real-world data evaluating patients' injection experiences using the latest devices/formulations of the long-acting (LA) somatostatin analogs (SSAs) lanreotide Autogel/Depot (LAN; Somatuline®) and octreotide LA release (OCT; Sandostatin®) are limited., Methods: PRESTO 2 was a 2020/2021 e-survey comparing injection experience of adults with neuroendocrine tumors (NETs) or acromegaly treated with LAN prefilled syringe versus OCT syringe for > 3 months in Canada, Ireland, the UK and the USA (planned sample size, 304)., Primary Endpoint: the proportion of patients with injection-site pain lasting > 2 days after their most recent injection, analyzed using a multivariate logistic regression model. Secondary endpoints included interference with daily life due to injection-site pain and technical injection problems in patients with current SSA use for ≥ 6 months., Results: There were 304 respondents (acromegaly, n = 85; NETs, n = 219; LAN, n = 168; OCT, n = 136; 69.2% female; mean age, 59.6 years). Fewer patients had injection-site pain lasting > 2 days after the most recent injection with LAN (6.0%) than OCT (22.8%); the odds of pain lasting > 2 days were significantly lower for LAN than OCT, adjusted for disease subgroup and occurrence of injection-site reactions (odds ratio [95% confidence interval]: 0.13 [0.06-0.30]; p < 0.0001). Injection-site pain interfered with daily life "a little bit" or "quite a bit" in 37.2% and 3.8% (LAN) versus 52.5% and 7.5% (OCT) of patients, respectively. Among patients with ≥ 6 months' experience with current SSA (92.4% of patients), technical injection problems never occurred in 76.8% (LAN) and 42.9% (OCT) of patients., Conclusions: Compared with OCT, significantly fewer patients using LAN had injection-site pain lasting > 2 days after their most recent injection. Also, fewer LAN-treated patients experienced technical problems during injection. These findings demonstrate the importance of injection modality for overall LA SSA injection experience for patients with acromegaly or NETs., (© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Purpose: This systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness., Methods: MEDLINE/Embase/the Cochrane Library (2001-June 2021) and key congresses (2018-2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required., Results: In total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens., Conclusions: Clinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control., (© 2022. The Author(s).)

Purpose: Patients receiving treatment for acromegaly often experience significant associated comorbidities for which they are prescribed additional medications. We aimed to determine the real-world prevalence of comorbidities and concomitant medications in patients with acromegaly, and to investigate the association between frequency of comorbidities and number of concomitantly prescribed medications., Methods: Administrative claims data were obtained from the IBM® MarketScan® database for a cohort of patients with acromegaly, identified by relevant diagnosis codes and acromegaly treatments, and a matched control cohort of patients without acromegaly from January 2010 through April 2020. Comorbidities were identified based on relevant claims and assessed for both cohorts., Results: Overall, 1175 patients with acromegaly and 5875 matched patients without acromegaly were included. Patients with acromegaly had significantly more comorbidities and were prescribed concomitant medications more so than patients without acromegaly. In the acromegaly and control cohorts, respectively, 67.6% and 48.4% of patients had cardiovascular disorders, the most prevalent comorbidities, and 89.0% and 68.3% were prescribed > 3 concomitant medications (p < 0.0001). Hypopituitarism and hypothalamic disorders, sleep apnea, malignant neoplasms and cancer, and arthritis and musculoskeletal disorders were also highly prevalent in the acromegaly cohort. A moderate, positive correlation (Spearman correlation coefficient 0.60) was found between number of comorbidities and number of concomitant medications in the acromegaly cohort., Conclusion: Compared with patients without acromegaly, patients with acromegaly have significantly more comorbidities and are prescribed significantly more concomitant medications. Physicians should consider the number and type of ongoing medications for individual patients before prescribing additional acromegaly treatments., (© 2021. The Author(s).)

Purpose: To evaluate factors that could potentially affect the hypothalamic-pituitary adrenal (HPA) axis response to insulin-induced hypoglycemia in children without history or symptoms of adrenal insufficiency and to propose a cut-off value to define a normal response in this population., Methods: Exploratory single-center study involving 78 children that prospectively underwent insulin tolerance test (ITT) for suspected growth hormone (GH) deficiency., Methods: Glucose, cortisol, GH, adrenocorticotrophic hormone (ACTH), epinephrine and norepinephrine levels were measured at baseline and after insulin-induced hypoglycemia. Serum cortisol was measured using Access automated immunoassay., Results: Mean (range) basal morning serum cortisol of 8 (2.2-19.5) µg/dL/222 (61-542) nmol/L increased after hypoglycemia to 20.5 (14.6-29.5) µg/dL/570 nmol/L (405-819) nmol/L. Peak serum cortisol levels of 14.6 µg/dL (405 nmol/L) and 15.4 µg/dL (428 nmol/L) corresponded to the 2.5th and 5th percentiles, respectively. Peak serum cortisol correlated with peak plasma epinephrine (r = 0.367; P = 0.0014) but did not correlate with age, BMI-SD or peak serum GH. Children with intact and abnormal GH responses presented similar mean peak serum cortisol levels (20.0 vs. 20.6 µg/dL/555 vs. 572 nmol/L; P = 0.21)., Conclusion: Our data indicate that the current cut-off to define normal HPA axis response in children after insulin-induced hypoglycemia warrants reevaluation to avoid over-diagnosis of adrenal insufficiency. Our results suggest that peak serum cortisol levels ≥ 15.4 µg/dL (428 nmol/L) in children undergoing ITT might represent a normal cortisol response to stress, regardless of age, BMI or GH secretory capacity.

A preferred treatment for residual/recurrent pituitary adenomas has not been established. The existence of higher complication rates for revision surgeries remains under debate. This study aimed to compare complication rates of primary and revision transsphenoidal endoscopic surgeries and to identify risk factors for complications. Data from 144 primary and 39 revision surgeries were analysed. The surgical complications evaluated were intraoperative and postoperative cerebrospinal fluid (CSF) leaks; meningitis; permanent diabetes insipidus (DI) and hypopituitarism; worsening visual acuity; ophthalmoplegias; visual field defects; otorhinolaryngological, systemic and vascular complications; and death. The variables that were potentially associated with surgical complications were gender, age, comorbidities, lumbar drain use, duration of lumbar drain use, invasion of the sphenoid and cavernous sinuses, presence and degree of suprasellar expansion, preoperative identification of the pituitary, CSF leaks and intraoperative pituitary identification. Intraoperative CSF leaks, visual field losses and worsening visual acuity were more common for revision surgeries. There were no between-group differences in the occurrence of postoperative CSF leaks; systemic, vascular and otorhinolaryngological complications; meningitis; DI and hypopituitarism; ophthalmoplegias; or death. Intraoperative identification of the pituitary was associated with lower rates of permanent DI and hypopituitarism, systemic complications, intraoperative CSF leaks and worsening visual acuity. Suprasellar expansion increased the risk of intraoperative CSF leaks but not endocrinological deficits or visual impairment. Intraoperative CSF leaks were associated with postoperative CSF leaks, meningitis, anterior hypopituitarism, DI and worsening visual acuity. Intraoperative CSF leaks, worsening visual acuity and visual field losses were more common in reoperated patients.

Background: Limited information is available on the utilization and healthcare costs among patients with acromegaly. The purpose of this study was to assess the impact of acromegaly on healthcare utilization and costs by locations of care (LoC)., Methods: Patients with acromegaly and controls were identified from an analysis of drug and medical claims filed from January 2010 to April 2019 from a US employer database. Each patient with acromegaly was matched with 20 random controls (without acromegaly) selected from the database. Claims were tracked for 12 months postdiagnosis (or matched date for controls). Outcomes by LoC, including costs, services, and likelihood of use, were compared using two-stage regression models or logistic regression models, controlling for demographic and job-related variables, and Charlson comorbidity index scores., Results: Claims from 60 patients with acromegaly and 1,200 controls were analyzed. Compared with the control group, patients with acromegaly had significantly higher likelihoods of receiving care in a physician's office [odds ratio > 1,000], inpatient [OR = 8.010], outpatient [OR = 12.656], laboratory [OR = 3.681], and 'other' locations [OR = 4.033] (all p  < .001), except in an emergency department (ED). Significantly more services were performed at each LoC for those with acromegaly ( p  < .01) but not in an ED. Total costs were more than 5-fold higher for the acromegaly cohort compared with controls ( p  < .05). Costs by LoC were consistently higher ( p  < .001) for patients with acromegaly vs. controls, with mean annual cost differences greatest in outpatient hospital/clinic ($9,611 vs $1,355), inpatient ($8,646 vs $739), physicians' office ($4,762 vs $1,301), other ($2,001 vs $367), and laboratory ($508 vs $66). ED-related treatment costs were not significantly different between cohorts., Conclusions: Compared with matched controls, patients with acromegaly were more likely to utilize healthcare services in nearly all LoCs and accrue higher expenditures at each LoC, with the exception of ED services.

Background: The Nottingham Health Profile (NHP) is a generic measure of perceived distress that has been used widely as an outcome measure in clinical practice and trials. The availability of two Brazilian datasets provided the opportunity to assess the psychometric performance of the NHP in different populations - adult growth hormone deficiency (GHD) and pulmonary hypertension (PH). The purpose of the study was to see how valuable the NHP could be in assessing outcomes in diseases where no disease-specific measures are available. Methods: Secondary analyses were performed with NHP data. Patients diagnosed with adult GHD or PH were administered the NHP during clinic visits on two occasions, two weeks apart. A disease-specific measure of quality of life (QoL) was also administered to the relevant sample of patients on each occasion. Results: The psychometric properties of the NHP were good for both disease groups. As expected, both samples reported high scores on energy level, the PH sample scored high on physical functioning and the GHD sample on emotional reactions. For both samples, most of the NHP sections were able to distinguish between groups of respondents with different ratings of perceived general health. While most sections of the NHP were relatively highly correlated with the QoL measures, pain and sleep did not seem to be important predictors of QoL in either of the samples. Conclusions: The use of the NHP in adult GHD and PH populations in Brazil is not recommended as there are high-quality disease-specific measures available for each disease. However, where no disease-specific measures are available, the NHP can provide good descriptive information of the impact of disease on different patient populations., Competing Interests: Competing interests: AH and SPM are employees of Galen Research Ltd., which is the copyright holder of the NHP, QoL-AGHDA and CAMPHOR. ARO Jr is an employee of Ipsen Bioscience in Cambridge/MA, US., (Copyright: © 2021 Heaney A et al.)

Purpose: The physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents., Methods: We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia., Results: Basal plasma levels of copeptin (median: 5.2 pmol/L) increased significantly after hypoglycemia (median 9.7 pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3 pmol/L) compared with individuals with intact pituitary response (median: 5.2 pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (r s  = 0.30; P = 0.010), cortisol (r s  = 0.33; P = 0.003), prolactin (r s  = 0.25; P = 0.03), IL-6 (r s  = 0.35; P = 0.008) and with BMI-SDS (r s  = - 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004)., Conclusion: Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.

Background: Pulmonary Hypertension (PH) impacts negatively on patients' health-related quality of life (HRQoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was the first PH-specific and validated instrument for use in different languages worldwide. This report describes the adaptation and psychometric validation of the CAMPHOR into Brazilian Portuguese language., Methods: The translation and validation process included a bilingual and lay panel translation; cognitive debriefing interviews; psychometric testing in two repeated times assessing internal consistency, reproducibility and validity of the questionnaire. The Nottingham Health Profile (NHP) questionnaire was used as a comparator to test for convergent validity., Results: The translation captured the same concepts as the English questionnaire and produced a comprehensive instrument in a Brazilian-Portuguese version expressing common, natural language. The psychometric evaluation involved 102 patients (48.8 ± 14.5 years, 80,4% female]. Cronbach's alpha coefficients were above 0.9 on all three CAMPHOR scales. There was excellent test-retest reliability (coefficients above 0.85 on all scales). CAMPHOR Symptoms scale and Activities scale correlated highly with Physical Mobility section and CAMPHOR QoL scale was strongly associated with the Emotional Reactions and Social Isolation sections of NHP. There was a significant association between gender and perceived general health (p < 0.05). There were significant differences in CAMPHOR scale scores between patients who differed according to their perceived disease severity and general health., Conclusions: The present CAMPHOR version demonstrated good psychometric properties and provides a reliable instrument for assessing HRQL and QoL in Brazilian PH patients, addressing patients' perspective of their illness in a comprehensive way.

Objective: To evaluate the maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort., Methods: The prevalence of tumor growth, miscarriage, preterm, low birth weight, congenital malformations and impairment in neuropsychological development in children among women treated with CAB were assessed in a Brazilian multicentre retrospective observational study, RESULTS: We included 194 women with a mean age of 31 (17-45) years, 43.6% presenting microadenomas and 56.4% macroadenomas, at prolactinoma diagnosis. In 233 pregnancies, CAB was withdrawn in 89%, after pregnancy confirmation. Symptoms related to tumor growth occurred in 25 cases, more frequently in macroadenomas. The overall miscarriage rate was 11%, although higher in the subgroup of patients with CAB maintainance after pregnancy confirmation (38% vs. 7.5%). Amongst the live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 4.3%. Neuropsychological development impairment was reported in 7% of cases., Conclusions: Our findings confirm previous results of safety in maternal and fetal outcomes in CAB-induced pregnancies; nevertheless, CAB maintenance after pregnancy confirmation was associated with higher miscarriage rate; result that must be further confirmed.

Human phosphodiesterases (PDEs) comprise a complex superfamily of enzymes derived from 24 genes separated into 11 PDE gene families (PDEs 1-11), expressed in different tissues and cells, including heart and brain. The isoforms PDE4, PDE7, and PDE8 are specific for the second messenger cAMP, which is responsible for mediating diverse physiological actions involving different hormones and neurotransmitters. The cAMP pathway plays an important role in the development and function of endocrine tissues while phosphodiesterases are responsible for ensuring the appropriate intensity of the actions of this pathway by hydrolyzing cAMP to its inactive form 5'-AMP. PDE1, PDE2, PDE4, and PDE11A are highly expressed in the pituitary, and overexpression of some PDE4 isoforms have been demonstrated in different pituitary adenoma subtypes. This observed over-expression in pituitary adenomas, although of unknown etiology, has been considered a compensatory response to tumorigenesis. PDE4A4/5 has a unique interaction with the co-chaperone aryl hydrocarbon receptor-interacting protein (AIP), a protein implicated in somatotroph tumorigenesis via germline loss-of-function mutations. Based on the association of low PDE4A4 expression with germline AIP -mutation-positive samples, the available data suggest that lack of AIP hinders the upregulation of PDE4A4 protein seen in sporadic somatotrophinomas. This unique disturbance of the cAMP-PDE pathway observed in the majority of AIP -mutation positive adenomas could contribute to their well-described poor response to somatostatin analogs and may support a role in tumorigenesis.

Background/objective: Type 1 diabetes mellitus (DM1) presents important risk factors for cardiovascular events., Objective: To compare the components of the aortic pulse wave (APW) and the hemodynamic parameters among children and adolescents with DM1 and healthy individuals., Methods: This is a cross-sectional study, with 36 children and adolescents diagnosed with DM1 (11.9 ± 3.2 years) matched by sex and age with the control group (n = 36, 12.4 ± 2.9 years). The components of the APW and the hemodynamic parameters were evaluated non-invasively, using Mobil-O-Graph., Results: On the week of the evaluation, DM1 patients presented glycated hemoglobin (hemoglobin A1C [HbA1c]) of 9.48 ± 2.22% and fasting glycemia of 222.58 ± 93.22 mg/dL. Augmentation index (AIx@75), reflection coefficient, and augmentation pressure (AP) were significantly higher in the DM1 group (29.0 ± 9.7%, 63.0 ± 7.9, and 7.8 ± 2.7 mm Hg, respectively) compared with the control group (20.6 ± 7.9%, 53.4 ± 9.1 and 4.9 ± 2.1 mm Hg, respectively). The systolic volume (52.6 ± 11.9 and 60 ± 12.4 mL) and the cardiac output (4.3 ± 0.5 and 4.6 ± 0.5 L/min) decreased in the DM1 group in relation to the control group. The pulse pressure amplification (PPA) was significantly lower in the DM1 group (1.4 ± 0.15) compared with the control group (1.6 ± 0.17). PPA correlated negatively with total vascular resistance (TVR), AP and reflection coefficient, and positively with cardiac index in both groups. In the DMI group, the AIx@75 correlated negatively with age, height, systolic volume, and PPA, and correlated positively with the TVR and reflection coefficient., Conclusions: These results confirm the presence of arterial stiffness in this population and extend the knowledge, showing, for the first time, the reduction of PPA in the DM1 group., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The measurement of circulating concentrations of growth hormone (GH) is an indispensable tool in the diagnosis of both GH deficiency and GH excess. GH is a heterogeneous protein composed of several molecular isoforms, but the physiological role of these different isoforms has not yet been fully understood. The 22KD GH (22 K-GH) is the main isoform in circulation, followed by 20KD GH (20 K-GH) and other rare isoforms. Studies have been performed to better understand the biological actions of the different isoforms as well as their importance in pathological conditions. Generally, the non-22 K- and 20 K-GH isoforms are secreted in parallel to 22 K-GH, and only very moderate changes in the ratio between isoforms have been described in some pituitary tumors or during exercise. Therefore, in a diagnostic approach, concentrations of 22 K-GH accurately reflect total GH secretion. On the other hand, the differential recognition of GH isoforms by different GH immunoassays used in clinical routine contributes to the known discrepancy in results from different GH assays. This makes the application of uniform decision limits problematic. Therefore, the worldwide efforts to standardize GH assays include the recommendation to use 22 K-GH specific GH assays calibrated against the pure 22 K-GH reference preparation 98/574. Adoption of this recommendation might lead to improvement in diagnosis and follow-up of pathological conditions, and facilitate the comparison of results from different laboratories., Competing Interests: Non applicableNon applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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 .).

Pasireotide is a new-generation somatostatin analog that acts through binding to multiple somatostatin receptor subtypes. Studies have shown that pasireotide induces hyperglycemia, reduces glucocorticoid secretion, alters neurotransmission, and potentially affects stress responses typically manifested as hyperglycemia and increased corticosterone secretion. This study specifically aimed to evaluate whether pasireotide treatment modifies glucose and costicosterone secretion in response to acute restraint stress. Male Holtzman rats of 150-200 g were treated with pasireotide (10 µg/kg/day) twice-daily for two weeks or vehicle for the same period. Blood samples were collected at baseline and after 5, 10, 30, and 60 min of restraint stress. The three experimental groups comprised of vehicle + restraint (VEHR), pasireotide + restraint (PASR), and pasireotide + saline (PASNR). Following pasireotide treatment, no significant differences in baseline glucose and corticosterone levels were observed among the three groups. During restraint, hyperglycemia was observed at 10 min (p < .01 for both comparisons), peaked at 30 min (p < .01 for both comparisons) and showed higher 60 min areas under glucose curves in the VEHR and PASR stressed groups when compared to the non-stressed PASNR group (p < .05 for both comparisons). Restraint also increased corticosterone secretion in the VEHR and PASR stressed groups at 5 min (p < .01 for both comparisons), and peaked at 30 min (p < .01 for both comparisons) with corresponding higher 60 min areas under corticosterone curves when compared to the non-stressed PASNR group (p < .01 for both comparisons). In conclusion, pasireotide treatment does not modify hyperglycemic- and corticosterone-restraint stress responses, thus preserving acute stress regulation.

The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition.

Background: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months)., Methods: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal., Results: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found., Conclusion: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients., (© 2016 S. Karger AG, Basel.)

Objective: To study glucose profiles of gestational diabetes (GDM) patients with 72 h of continuous glucose monitoring (CGM) either before (GDM1) or after (GDM2) dietary counseling, comparing them with nondiabetic (NDM) controls., Design and Methods: We performed CGM on 22 GDM patients; 11 before and 11 after dietary counseling and compared them to 11 healthy controls. Several physiological and clinical characteristics of the glucose profiles were compared across the groups, including comparisons for pooled 24-h measures and hourly median values, summary measures representing glucose exposure (area under the median curves) and variability (amplitude, standard deviation, interquartile range), and time points related to meals., Results: Most women (81.8%) in the GDM groups had fasting glucose <95mg/dL, suggesting mild GDM. Variability, glucose levels 1 and 2h after breakfast and dinner, peak values after dinner and glucose levels between breakfast and lunch, were all significantly higher in GDM1 than NDM (P<0.05 for all comparisons). The GDM2 results were similar to NDM in all aforementioned comparisons (P>0.05). Both GDM groups spent more time with glucose levels above 140mg/dL when compared with the NDM group. No differences among the groups were found for: pooled measurements and hourly comparisons, exposure, nocturnal, fasting, between lunch and dinner and before meals, as well as after lunch (P>0.05 for all)., Conclusion: The main differences between the mild GDM1 group and healthy controls were related to glucose variability and excursions above 140mg/dL, while glucose exposure was similar. Glucose levels after breakfast and dinner also discerned the GDM1 group. Dietary counseling was able to keep glucose levels to those of healthy patients., (© 2016 European Society of Endocrinology.)

Introduction: Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life., Methods: We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment., Findings and Conclusions: Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

Pancreas transplantation (PTX) has been demonstrated to restore long-term glucose homeostasis beyond what can be achieved by intensive insulin therapy or islet transplants. Moreover, PTX has been shown to decrease the progression of the chronic complications of diabetes. However, PTX patients require chronic use of immunosuppressive drugs with potential side effects. The long-term follow-up of PTX patients demands special care regarding metabolic deviations, infectious complications, and chronic rejection. Diabetes and other endocrine metabolic abnormalities following transplantation are common and can increase morbidity and mortality. Previous recipient-related and donor-related factors, as well as other aspects inherent to the transplant, act together in the pathogenesis of those abnormalities. Early recognition of these disturbances is the key to timely treatment; however, adequate tools to achieve this goal are often lacking. In a way, the type of PTX procedure, whether simultaneous pancreas kidney or not, seems to differentially influence the evolution of endocrine and metabolic abnormalities. Further studies are needed to define the best approach for PTX patients. This review will focus on the most common endocrine metabolic disorders seen in the long-term management of PTX: diabetes mellitus, hyperlipidemia, and bone loss. The authors here cover each one of these endocrine topics by showing the evaluation as well as proper management in the follow-up after PTX.

Although it is a rare condition, the accurate diagnosis and treatment of Cushing's disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing's syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing's disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.

PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis., (© 2016 Society for Endocrinology.)

Introduction: adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor, and it has recently been suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating the AMPK system. This study aimed to evaluate the effects of candesartan, an angiotensin II receptor blocker, on cardiac and hepatic AMPK activity basally as well as after surgical stress under general anesthesia., Materials and Methods: Male Wistar rats were treated with 5 mg/kg/day candesartan in their drinking water for two weeks. Levels of cardiac and hepatic AMPK activity were determined, using a kinase activity assay, basally and after surgical stress under general anesthesia., Results: Chronic administration of candesartan increased hepatic AMPK activity approximately 4 times (p<0.05) while no significant change was demonstrated in cardiac AMPK. Cardiac and hepatic AMPK activities were not significantly increased by surgical stress alone performed under anesthesia. However, chronic treatment with candesartan decreased AMPK activity in both liver and heart after surgical stress under anesthesia (p<0.01 for both comparisons)., Conclusions: While chronic candesartan treatment may stimulate AMPK activity in certain organs such as the liver, when combined with surgical stress under anesthesia it inhibits pathways regulating AMPK activity., (© The Author(s) 2013.)

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence., Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL., Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples., Setting: The study was conducted at university hospitals., Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study., Outcome: Outcomes included genetic screening and clinical characteristics., Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context., Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Aims: The current article provides a brief overview of the criteria for defining disease control in acromegaly., Methods: This was a retrospective, narrative review of previously published evidence chosen at the author's discretion along with an illustrative case study from Latin America., Findings and Conclusions: In the strictest sense, "cure" in acromegaly is defined as complete restoration of normal pulsatile growth hormone secretion, although this is rarely achieved. Rather than "cure", as such, it is more appropriate to refer to disease control and remission, which is defined mainly in terms of specific biochemical targets (for growth hormone and insulin-like growth factor-1) that predict or correlate with symptoms, comorbidities and mortality. However, optimal management of acromegaly goes beyond biochemical control to include control of tumour growth (which may be independent of biochemical control) and comprehensive management of the symptoms and comorbidities typically associated with the disease, as these may not be adequately managed with acromegaly-specific therapy alone.

Context: Traditionally, acromegaly is viewed as a disease resulting from GH hypersecretion from an autonomous pituitary somatotropinoma., Objective: To test the hypothesis that GH secretion in acromegaly is still subjected to normal hypothalamic control, we studied the daily rhythmicity of GH secretion in normal controls and patients with newly diagnosed, untreated acromegaly., Design and Setting: This was an observational inpatient study in the General Clinical Research Center at the University of Michigan., Patients or Other Participants: One hundred four normal controls and 67 acromegalic patients were included in the study., Intervention: The intervention consisted of frequent blood sampling over 24 hours., Main Outcome Measure(s): We hypothesized that acromegalic patients would show rhythmicity, sexual dimorphism, and age-related decline of GH secretion similar to normal controls., Results: Both normal controls and the patients exhibited 3 major GH waves with the highest values at 12:00 pm, 5:00 pm, and 1:00 am (P < .001 for all). Both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). The amplitude of the maximal (nocturnal) GH secretory wave (1:00 am) as compared with the nadir GH secretion (9:00 am) was clearly different between the 2 groups, with a significantly smaller magnitude in acromegaly (P < .001). A subsequent subanalysis of both groups was performed separately for both genders. Similar to the entire groups, both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). Patients with clearly elevated GH values have shown an age-related decline of GH secretion (r = -0.35, P < .001), similar to controls., Conclusions: The analysis of GH profiles in multiple patients with untreated acromegaly discloses the persistence of the hallmarks of the central control of GH regulation, ie, nictohemeral rhythmicity, sexual dimorphism, and an age-related decline of GH output.

Background: Endocrine complications after acute lymphoblastic leukemia (ALL) are common., Methods: Final height, GH/IGF-1 axis, and body mass index were analyzed after 13.7 (7.0-20.7) years from diagnosis in 34 boys aged <12 years at diagnosis and 41 girls <10 years at diagnosis. A modified German BFM-83 ALL protocol included (n = 42) or did not include (n = 33) prophylactic cranial irradiation. In 27 patients, GH after insulin tolerance test, IGF-1, cortisol, free T(4) and estradiol/testosterone were determined., Results: Final height was significantly reduced (mean Z-score for height between final height and diagnosis, ΔHAZ = -0.61, p = 0.0001). At that point, 3 patients were obese (4%) and 17 were overweight (22.7%). Patients aged ≤ 4 years at diagnosis and those irradiated had a greater loss in final height (p = 0.001 and p = 0.008, respectively). Abnormalities in GH/IGF-1 axis were observed in 4 patients: 3 had a GH peak <6 ng/ml and 1 had a serum IGF-1 concentration <25 ng/ml. Growth deficit was significantly higher in patients with hormonal deficiency (p = 0.006)., Conclusions: Treatment of ALL during childhood is associated with final height deficit. Young age at diagnosis and radiotherapy were the major risk factors. GH/IGF-1 deficiency was found particularly in irradiated patients, even though it was detected in 1 non-irradiated patient., (Copyright © 2013 S. Karger AG, Basel.)

There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint., (© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.)

5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats.

Background: Women with previous gestational diabetes mellitus (pGDM) face a higher risk of developing type 2 diabetes and, consequently, a higher cardiovascular risk. This study aimed to compare the carotid intima-media thickness (cIMT) from young women with pGDM to those with metabolic syndrome (MS) and to healthy controls (CG) to verify whether a past history of pGDM could be independently associated with increased cIMT., Methods: This is a cross-sectional study performed in two academic referral centers. Seventy-nine women with pGDM, 30 women with MS, and 60 CG aged between 18 and 47 years were enrolled. They all underwent physical examination and had blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), and triglycerides determined. The cIMT was measured by ultrasound in several carotid segments. The primary endpoint was cIMT and clinically relevant parameters included as predictors were: age, systolic blood pressure, waist, BMI, total cholesterol, LDLc, triglycerides, fasting glucose, previous history of GDM as a whole group, previous history of GDM without MS, presence of DM, presence of MS, and parity., Results: cIMT was significantly higher in pGDM when compared to CG in all sites of measurements (P < 0.05) except for the right common carotid. The pGDM women showed similar cIMT measurements to MS in all sites of measurements, except for the left carotid bifurcation, where it was significantly higher than MS (P < 0.001). In a multivariate analysis which included classical cardiovascular risk factors and was adjusted for confounders, pGDM was shown to be independently associated with increased composite cIMT (P < 0.01). The pGDM without risk factors further showed similar cIMT to MS (P > 0.05) and an increased cIMT when compared to controls (P < 0.05)., Conclusions: Previous GDM was independently associated with increased composite cIMT in this young population, similarly to those with MS and regardless the presence of established cardiovascular risk factors.

Neuroglucopenia induced by 2-deoxy-D-glucose (2DG) activates hypothalamic glucoreceptors leading to increased hepatic glucose production and insulin inhibition. This response is similar to what is observed with intravenous injection of angiotensin II (Ang II). However, the involvement of an angiotensin-converting enzyme inhibitor on neuroglucopenia has not been investigated. The aim of this study was to determine the effects of chronic enalapril treatment on plasma glucose, insulin and lipid levels in response to neuroglucopenia. Male Holtzman rats (120-170 g) were chronically treated with enalapril (10 mg/kg per day) in the drinking water for two weeks. On the day of experiment the animals received an i.v. enalapril final dose one hour before the neuroglucopenic stress by 2DG infusion (500 mg/kg), and blood samples were drawn before and 5, 10, 20, 30 and 60 minutes following infusion. The hyperglycaemic response to 2DG was not significantly changed by enalapril treatment. The enalapril-treated group exhibited a peak of plasma insulin higher than controls. Plasma triglyceride showed a significant increase only in the enalapril group after neuroglucopenic stress (p < 0.05).These data show that chronic enalapril treatment changes insulin and triglyceride responses to neuroglucopenia, suggesting an effect on glucose-induced insulin secretion and the storage of triglycerides.