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Hanne L Gulseth, Ingrid M F Gjelstad, Audrey C Tiereny, Danielle McCarthy, Julie A Lovegrove, Catherine Defoort, Ellen E Blaak, Jose Lopez-Miranda, Aldona Dembinska-Kiec, Ulf Risérus, Helen M Roche, Christian A Drevon and Kåre I Birkeland

Objective

Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome.

Design

In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test.

Results

There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the high-fat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010).

Conclusions

The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

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Mirjam Christ-Crain

Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences.

Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia.

The direct test including Vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay.

Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a “revival” of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy, and is superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite.

Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.

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Andreas Stomby, Alireza Salami, Per Dahlqvist, Johan Arild Evang, Mats Ryberg, Jens Bollerslev, Tommy Olsson, Gudmundur Johannsson and Oskar Ragnarsson

Objective

Cushing’s syndrome is associated with long-term cognitive deficits and affective symptoms such as depression and anxiety. The alterations in brain function underlying these deficits after Cushing’s syndrome are unclear and therefore we aimed to explore alterations in resting-state functional connectivity in patients with Cushing’s syndrome in remission.

Design

Cross-sectional case–control study.

Methods

Nineteen women with Cushing’s syndrome in remission for a median time of 7 years (IQR: 6–10) and a mean age of 45 years were included at three university clinics. These patients and 38 age-matched female controls underwent brain imaging at a single center. The main outcome measure was functional connectivity at rest, measured with functional magnetic resonance imaging.

Results

The medial temporal lobe (MTL) and prefrontal cortex networks, exhibited elevated functional connectivity among patients compared to controls. The degree of elevated functional connectivity in the MTL was negatively associated with time in remission.

Conclusions

Resting-state functional connectivity within glucocorticoid receptor-rich regions, particularly the MTL and medial prefrontal cortex, was increased in patients. These differences in connectivity may provide a neural basis for the cognitive deficits and affective symptoms commonly experienced by patients with Cushing’s syndrome in remission.

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Peter Wolf, Johanna Mayr, Hannes Beiglböck, Paul Fellinger, Yvonne Winhofer, Marko Poglitsch, Alois Gessl, Alexandra Kautzky-Willer, Anton Luger and Michael Krebs

Background: In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors we performed in depth characterization of the RAAS activity.

Methods: 8 patients with primary AI (female=5;age:56±21years;BMI:22.8±2kg/m2;mean blood pressure:140/83mmHg; hydrocortisone dose:21.9±5mg/day; fludrocortisone dose:0.061±0.03mg/day) and 8 matched healthy volunteers (female=5;age:52±21years;BMI:25.2±4kg/m2;mean blood pressure:135/84mmHg) were included in a cross-sectional case control study. Angiotensin metabolite profiles (RAS-Fingerprints) were performed by liquid chromatography mass spectrometry.

Results: In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (p=0.027), Angiotensin (Ang) I (p=0.022), AngII (p=0.032), Ang1-7 and Ang1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed Aldosterone-to-AngII ratio (AA2-Ratio, p=0.003) compared to controls. PRA-S, the angiotensin based marker for plasma-renin-activity, correlated with plasma renin activity (r=0.983;p< 0.01) and plasma renin concentration (r=0.985;p<0.001) and was significantly increased in AI patients.

Conclusions: AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyper-activated. The contribution of AngII in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

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Athanasia Ziagaki, Daniela Blaschke, Wilhelm Haverkamp and Ursula Plöckinger

Objective

Growth hormone (GH)-deficiency is related to increased cardiovascular mortality. We studied clinical status, concentration of amino-terminal-pro B-type natriuretic-peptide (NT-proBNP) and echocardiographic parameters during long-term GH-replacement (GH-R).

Methods

51 patients [29 females], 45.9±11.3 yrs. (mean±SD), median follow-up 36.2 months, echocardiography and laboratory determinations initially and at 12 months-intervals.

Results

At the last follow-up (last observation carried-forward) [LFU (LOCF)] insulin-like growth-factor-1 standard deviation score (IGF-1 SDS) was ±1 in 92% of the patients. The median NT-proBNP declined significantly and stabilized ( 40.5%) at LFU (LOCF) due to patients with a basal NT-proBNP >125 ng/L (indicative of heart-failure). The basal NT-proBNP and the final IGF-1 SDS were significant predictors of the NT-proBNP at LFU (LOCF). Initially left ventricular enddiastolic-diameter (LVEDD), left ventricular posterior wall-diameter (LVPWD) and ejection-fraction (EF) were normal, while interventricular septum diameter (IVSD) and left ventricular mass index (LVMi) were slightly increased. LVPWD and IVSD had significantly declined by year three. The LVMi was moderately to severely abnormal in 37.3% and 52.0% of patients initially and at LFU (LOCF). At LFU (LOCF) LVMi and IGF-1 were significantly correlated in the 14 male patients of this subgroup.

Conclusion

Long-term GH-R of GHD positively affected ISVD and LVPWD. In a subgroup of patients with severe GHD, LVMi increased concomitantly to the decline in NT-proBNP and this was positively correlated to the final IGF-1 concentration. Whether this observation indicates a positive development in a structurally altered heart muscle (reversal of adverse remodeling) or poses a future risk for heart failure needs further follow-up.

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Gherardo Mazziotti, Andrea Lania and Ernesto Canalis

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert physiological actions on the skeleton throughout life, by stimulating longitudinal bone growth in children, the acquisition of bone mass during adolescence and the maintenance of skeletal architecture in adults. When GH and IGF-I are secreted in excess, bone remodeling is enhanced leading to deterioration of bone microstructrure and impairment of bone strength. Indeed, acromegaly causes skeletal fragility, and vertebral fractures are reported in a remarkable number of patients exposed to GH and IGF-I excess. The management of skeletal fragility in acromegaly is a challenge, since the awareness of this complication is low, the prediction of fracture risk is difficult to ascertain, the risk of fractures remains after the control of acromegaly and the effectiveness of bone-active drugs is uknown. This review is an update on bone disorders associated with acromegaly and provides a perspective of possible therapeutic approaches based on emerging pathophysiological and clinical information.

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Jens Bollerslev, Ansgar Heck and Nicoleta Cristina Olarescu

Acromegaly is a rare and challenging disease calling for management in highly specialized multidisciplinary teams (MDTs). Untreated disease has severe morbidity and a clearly increased mortality. Major attainments have been gained over the latest decades, and therefore the aim of this review is to discuss recent achievements in modern multimodal therapy of acromegaly performed by MDTs, with an emphasis on an individualized, proactive management from the time of diagnosis to long term outcome.

Treatment by surgery is the only potential curative treatment, however even with modern techniques still with modest cure rates, leaving the patients to often long-term medical treatment. Treatment strategies have changed dramatically in the Western world over recent years, implying a more proactive treatment algorithm often with a shorter or longer pre-surgical treatment period with Somatostatin Receptor Ligands (SRLs). Not all patients will however respond to primary treatment with conventional SRLs and there has recently been a development of potential biomarkers for response that has been implemented in the clinical routine.

By today, multimodal treatment can bring every patient in remission, but still almost a third of all patients are undertreated according to large, international registries. On the other hand, it might be a challenge not to over-treat thereby bringing the patient into a state of relative or absolute growth hormone deficiency. Clinical series published during the last decade on treatment of patients with acromegaly have indicated a normalization of mortality, most probably reflecting the proactive and individualized modern treatment.

In conclusion, modern, multimodal treatment seems to have normalized mortality, but still the patients suffer from a high multi-organ morbidity and often multi-pharmacy. Every patient should receive an individualized, pro-active treatment in order to improve long-term outcome and to reduce costs for the society.

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Germano Gaudenzi, Alessandra Dicitore, Silvia Carra, Davide Saronni, Carlotta Pozza, Elisa Giannetta, Luca Persani and Giovanni Vitale

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors.

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Nicholas Russell and Mathis Grossmann

Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may in fact be dependent on its aromatisation to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT), and from observational studies in community dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic-pituitary-testicular axis regulation, reproductive function, growth hormone-insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism, and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators, and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT or as sole mode of ADT could be a useful strategy for men with prostate cancer.