Guglielmo Beccuti

Consuming more of daily caloric intake at dinner predisposes to obesity. A 6-year population-based prospective cohort study

Background/Objectives It has been hypothesized that assuming most of the caloric intake later in the day leads to metabolic disadvantages, but few studies are available on this topic. Aim of our study was to prospectively examine whether eating more of the daily caloric intake at dinner leads to an increased risk of obesity, hyperglycemia, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). Subjects/Methods 1245 non-obese, non-diabetic middle-aged adults from a population-based cohort underwent a 3-day food record questionnaire at enrollment. Anthropometric values, blood pressure, blood metabolic variables, and estimated liver fat were measured at baseline and at 6-year follow-up. Design Prospective cohort study. Results Subjects were divided according to tertiles of percent daily caloric intake at dinner. A significant increase in the incidence rate of obesity (from 4.7 to 11.4%), metabolic syndrome (from 11.1 to 16.1%), and estimated NAFLD (from 16.5 to 23.8%) was observed from the lower to higher tertile. In a multiple logistic regression model adjusted for multiple covariates, subjects in the highest tertile showed an increased risk of developing obesity (OR = 2.33; 95% CI 1.17–4.65; p = 0.02), metabolic syndrome (OR = 1.52; 95% CI 1.01–2.30; p = 0.04), and NAFLD (OR = 1.56; 95% CI 1.10–2.22; p = 0.01). Conclusions Consuming more of the daily energy intake at dinner is associated with an increased risk of obesity, metabolic syndrome, and NAFLD.

Hypopituitarism following brain injury: when does it occur and how best to test?

Aim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induce hypopituitarism, an under-diagnosed clinical problem. Moreover, this review aims to clarify, on the basis of the recent evidences, how these patients have to be tested for pituitary-function. Both retrospective and prospective studies recommended that patients with more severe form of Brain Injuries (BI) and in particular, those with fractures of the base of the skull or early diabetes insipidus, have to be closely monitored for signs and symptoms of endocrine dysfunction. Further studies will be crucial to raise awareness and remind physicians on the prevalence of hypopituitarism in patients with BI and to elucidate any incremental benefits these patients may receive from hormone replacement.

Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults

OBJECTIVE Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. METHODS We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. RESULTS The best GH cut-off to ghrelin test was 7.3 μg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 μg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 μg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. CONCLUSIONS Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.

Endocrine and Metabolic Actions of Ghrelin

The acylated form of ghrelin (GRLN) has been discovered as the natural ligand of the GH secretagogue (GHS) receptor-1a (GHS-R1a). This peptide, whose acylation is performed by a specific octanoyl-transferase, is predominantly produced by the stomach, although expressed by many other endocrine and nonendocrine, peripheral and central tissues. Also GHS-R1a shows wide distribution, being distributed in several central and peripheral tissues. GRLN displays strong GH-releasing activity but its action is not specific for GH exhibiting other neuroendocrine activities such as stimulation of PRL and ACTH and inhibition of LH. GRLN is now mostly recognized as a potent orexigenic factor stimulating food intake and modulating energy expenditure. At the peripheral level, GRLN modulates gastrointestinal motility and secretion and also exerts cardiovascular actions. Mostly, at the peripheral level, GRLN exerts probably its major physiological action regulating glucose and lipid metabolism. In fact, GRLN in its acylated form has a diabetogenic action while in its non-acylated form it has a favorable influence on glucose, lipid metabolism and insulin sensitivity as well as the inhibition of lipolysis. GRLN receptors have been well demonstrated either in the endocrine pancreas or the adipose tissue; at these levels there are receptors that bind GRLN independently of its acylation (therefore a non-GHS-R1a, still undefined receptor). In all, the products of the GRLN gene, i.e. acylated and nonacylated GRLN, as well as obestatin, play a major role in regulating peripheral metabolism and it is not by chance that their secretion is mostly under metabolic regulation.

Nigella sativa (black seed) effects on plasma lipid concentrations in humans: A systematic review and meta-analysis of randomized placebo-controlled trials

The effects of Nigella sativa (NS) on plasma lipid concentrations are controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to obtain a conclusive result in humans. PubMed-Medline, SCOPUS, Web of Science, and Google Scholar databases were searched (up to August 2015) to identify RCTs investigating the impact of NS on total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides concentrations. A random-effects model and the generic inverse variance weighting method were used for quantitative data synthesis. Meta-regression, sensitivity analysis, and publication bias assessments were performed using standard methods. A total of 17 RCTs examining the effects of NS on plasma lipid concentrations were included. Meta-analysis suggested a significant association between NS supplementation and a reduction in total cholesterol (weighed-mean-difference [WMD]: -15.65mg/dL, 95% CI: -24.67, -6.63, p=0.001), LDL-C (WMD: -14.10mg/dL, 95% CI: -19.32, -8.88, p<0.001), and triglyceride levels (WMD: -20.64mg/dL, 95% CI: -30.29, -11.00, p<0.001). No significant effect on HDL-C concentrations (WMD: 0.28mg/dL, 95% CI: -1.96, 2.53, p=0.804) was found. A greater effect of NS seed oil versus seed powder was observed on serum total cholesterol and LDL-C levels, and an increase in HDL-C levels was found only after NS seed powder supplementation. NS has a significant impact on plasma lipid concentrations, leading to lower total cholesterol, LDL-C, and TG levels while increased HDL-C is associated with NS powder only. Further RCTs are needed to explore the NS benefits on cardiovascular outcomes.

Long-term outcomes of the treatment of central precocious puberty

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Timing of food intake: Sounding the alarm about metabolic impairments? A systematic review

&NA; Growing evidence points to an association between timing of food intake and obesity in humans, raising the question if when to eat matters as much as what and how much to eat. Based on the new definition of obesity as a chronobiological disease, an unusual or late meal timing represent a circadian chronodisruption, leading to metabolic impairments. Preliminary data from cross‐sectional and experimental studies suggest that changes in meal timing can influence obesity and success of weight loss therapy, independently from total energy intake, dietary composition and estimated energy expenditure. A systematic review of observational and experimental studies in humans was conducted to explore the link between time of food ingestion, obesity and metabolic alterations. Results confirm that eating time is relevant for obesity and metabolism: observational and experimental studies found an association between meal timing, weight gain, hyperglycemia and diabetes mellitus with benefits deriving from an early intake of food in the day in a wide range of individuals. Herein clinical, future perspectives of chronoprevention and chronotherapy of obesity and type 2 diabetes are also provided. In conclusion, meal timing appears as a new potential target in weight control strategies, and therapeutic strategies should consider this contributor in the prevention of obesity. Graphical abstract Figure. No caption available.

Progression of pituitary tumours: impact of GH secretory status and long-term GH replacement therapy

BackgroundMost patients treated for hypothalamic–pituitary tumours develop GH deficiency. Long-term GH replacement treatment in adults with a previous history of hypothalamic–pituitary tumour could represent a concern about increasing the risk of tumour enlargement or recurrence.PurposeTo assess the progression risk of hypothalamic–pituitary tumours according to the GH secretory status (normal GH secretion, non-treated and treated GH deficiency). and determine the predictors of neoplasm recurrence.MethodsWe retrospectively reviewed 309 patients with tumours of the hypothalamic–pituitary region (294 subjects underwent neurosurgery while 81 radiotherapy) who were followed for 9.9 ± 8.3 years.ResultsOut of 309 patients, 200 were affected by severe GH deficiency; 90 of these underwent GH therapy. The tumour progression rate did not differ among GH-sufficient, not-treated and treated GH-deficient patients (16.5%, 16.4%. and 10.0%, respectively). In a multivariate analysis, previous radiotherapy (HR 0.12, CI 0.03–0.52, p < 0.005) and residual tumour (HR 8.20, CI 2.38–28.29, p < 0.001) were independent predictors of recurrence. After controlling for multiple covariates, the tumour recurrence risk in GH-sufficient and GH-treated patients was similar to that observed in not-treated GH-deficient patients.ConclusionsWith limitations of retrospective analysis, GH therapy is not associated with an increased progression rate of tumours of the hypotalamic–pituitary region during long follow-up, thus supporting the long-term safety of GH treatment. The only predictors of tumour recurrence appear to be the presence of residual disease and the lack of radiotherapy.

MANAGEMENT OF ENDOCRINE DISEASE: Long term outcome of central precocious puberty

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.