Vincenzo Cappiello

Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly

OBJECTIVE Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF‐I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP‐3 and acid‐labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking.

Ghrelin secretion in severely obese subjects before and after a 3-week integrated body mass reduction program

Ghrelin, the endogenous ligand of GH-secretagogue receptors, has been implicated in the regulation of feeding behavior and energy balance. Aim of the study was to investigate ghrelin levels in fasting conditions and after a standard meal test in obese subjects before and after a 3-week integrated body weight reduction (BWR) program (consisting of energyrestricted diet, exercise training, psychological counselling and nutritional education). Weight, height, fat mass, fat free mass (by impedentiometry), circulating ghrelin, insulin and leptin levels were evaluated in 10 obese subjects (3 male, 7 female; mean age: 35±9.3 yr; body mass index BMI: 45.2±10.6 kg/m2) before and after weight reduction. At baseline, obese subjects showed significantly lower ghrelin levels than controls, which were negatively correlated with BMI, weight, insulin and leptin levels. Fasting ghrelin levels were not modified by standard meal test in obese subjects (from 110.8±69.7 to 91.8±70.2 pmol/l p=ns), while a significant reduction was observed in controls (from 352.4±176.7 to 199.0±105.2 pmol/l; p<0.01). After a 3-week integrated BWR program obese subjects significantly reduced weight, BMI and leptin levels, while no significant changes were found both in fasting ghrelin and in ghrelin response after the meal. In conclusion, 5% weight loss obtained after a short-term period of integrated BWR program is not sufficient to normalize fasting ghrelin levels nor to restore the normal ghrelin suppression after a meal in severely obese subjects.

Effects of two different somatostatin analogs on glucose tolerance in acromegaly.

Impaired glucose tolerance is present in many acromegalic patients and treatment with somatostatin analogs has variable effects on glycemic control. The aim of this study was to compare the effects of 2 somatostatin analogs on glucose metabolism, lanreotide slow release (L-SR) and octreotide long acting release (O-LAR), in 10 patients with acromegaly (2 of whom with overt Type 2 diabetes mellitus). Glucose and insulin levels in fasting conditions and in response to OGTT, evaluated as AUC, insulin resistance (IR) evaluated by homeostatic model assessment (HOMA-IR), glycosylated hemoglobin (HbA1c), GH, IGF-I, were assessed during L-SR and O-LAR treatment. Mean fasting glucose, glucose response to OGTT and HbA1c levels in 8 non-diabetic patients did not significantly change after L-SR therapy while they all increased after O-LAR treatment (p<0.05 vs baseline and L-SR). Mean HOMA-IR values calculated in acromegalic patients before medical therapy were higher than in normal subjects (p<0.005) and showed a significant decrease during both treatments (p<0.05). In the 2 diabetic acromegalic patients a worsening in glucose metabolism was observed during O-LAR treatment but not during L-SR. GH and IGF-I levels significantly decreased with both drugs and normalized respectively in 38% and 12% with L-SR, 50% and 25% with O-LAR. In conclusion, both drugs decreased IR in acromegalic patients; O-LAR seems to be more detrimental to glucose metabolism than L-SR, despite being more effective in reducing GH and IGF-I levels.

Ghrelin and adiponectin in patients with Cushing's disease before and after successful transsphenoidal surgery

background  Ghrelin, an endogenous ligand of the GH secretagogue receptor that exerts orexigenic activity, is negatively correlated with body mass index (BMI) and insulin resistance. Conversely, low levels of adiponectin (ApN), a circulating adipocytokine with antidiabetic, antiatherogenic and anti‐inflammatory properties, have been found in several insulin‐resistant conditions. Although Cushings syndrome causes several metabolic and hormonal changes leading to insulin resistance and central obesity, few data concerning the impact of glucocorticoid excess on ghrelin and ApN levels are so far available.

Circulating ghrelin levels in celiac patients

OBJECTIVE:Ghrelin, the gut–brain peptide, recently identified as the natural endogenous ligand for growth hormone secretagogue receptors, exerts various endocrine and nonendocrine effects, including the control of energy homeostasis and food intake, but its possible relevance in malabsorption syndromes is unknown. Therefore, the aim of this study was to evaluate circulating ghrelin levels in adults with untreated and treated celiac disease (CD) and, for comparison, in healthy subjects.METHODS:Fasting serum ghrelin levels were measured in 30 consecutive patients with newly diagnosed CD, 13 celiac patients successfully treated with a gluten-free diet (GFD), and 30 healthy controls.RESULTS:Ghrelin levels were abnormally high in patients with active CD compared with controls (297 ± 17.6 vs 218 ± 15.2 pmol/L, p < 0.01) and correlated positively with intestinal mucosal lesion severity (rs= 0.444, p < 0.02). In the successfully GFD-treated patients, ghrelin values were normal compared with controls (233 ± 22.0 vs 218 ± 15.2 pmol/L, ns) and, moreover, correlated negatively with body mass index (r=−0.632, p = 0.02), unlike in the untreated patient group (r=−0.263, ns).CONCLUSION:High ghrelin levels characterized our series of adult patients with newly diagnosed CD and correlated significantly with the degree of severity of intestinal mucosal lesions. This is the first evidence of a relationship between ghrelin and inflammatory processes, but the mechanisms involved are still unclear. Furthermore, our findings suggest that an interplay of hormonal, metabolic, and nutritional factors could influence ghrelin secretion under pathophysiological circumstances.

Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults.

objective  To evaluate circulating levels of ghrelin and adiponectin (ApN) in GH‐deficient (GHD) adults before and after short‐ and long‐term recombinant human GH (rhGH) administration.

Recombinant hGH replacement therapy and the hypothalamus–pituitary–thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?

objective  Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD.

Evaluation of insulin resistance in acromegalic patients before and after treatment with somatostatin analogues

Many studies have recently shown that simple computer-solved indices, based on fasting glucose and insulin levels, closely mirror the euglycemic clamp technique in studying insulin resistance or pancreatic insulin secretion. Few data are at present available on the evaluation of these novel indices in acromegalic patients, known to be GH-dependent insulin-resistant subjects, in particular during medical treatment with somatostatin analogues. Indeed, these drugs are able to inhibit not only GH and IGF-I levels, but also insulin and glucagon pancreatic secretion, with contrasting effects on glucose metabolism. In this study, insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR) and insulin sensitivity by quantitative insulin check index (QUICKI) in 27 normoglycemic acromegalic patients, before and after 6-month therapy with somatostatin analogues (lanreotide-SR 30–60 mg every 7–28 days in 15 and octreotide-LAR 20–30 mg every 28 days in 12). Thirty-five age- and sexmatched healthy subjects and 17 surgically treated acromegalic patients (5 cured and 12 not cured) were studied as control groups. Before medical treatment, HOMA-IR was higher in acromegalic patients than in healthy controls (4±3 vs 1.7±0.7, p<0.05), while QUICKI was lower (0.33±0.04 vs 0.36±0.03, p<0.05). During medical therapy, HOMA-IR decreased to 2.4±1.6 (p<0.05) and became similar to that recorded in both healthy subjects and surgically treated patients. However, fasting glucose was increased and fasting insulin was decreased. QUICKI did not significantly change from basal values. No differences were observed between patients who normalized or not hormonal levels. The effects of the 2 drugs, though higher glucose levels were seen in patients treated with octreotide-LAR. In conclusion, this study demonstrates that medical treatment is able to improve insulin resistance, even if only successful surgery is able to completely normalize both HOMA-IR and QUICKI.

Blood pressure-independent cardiac hypertrophy in acromegalic patients.

OBJECTIVE Acromegaly is frequently associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathological studies on acromegalic hearts have shown an extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy. The aim of this study was to assess left ventricular wall structure in acromegaly by ultrasonic tissue characterization. DESIGN AND METHODS We studied 10 untreated acromegalic patients and 10 age-matched healthy control subjects. The echo patterns of two-dimensional long-axis end-diastolic echocardiograms were assessed by colour-scale analysis of the interventricular septum, with estimates of the mean colour scale value, the broad band (Bb) and the derived collagen volume fraction (dCVF). We also measured electrocardiographic QT interval dispersion (QTd) as a marker of dyshomogeneous ventricular repolarization. RESULTS Seven patients had left ventricular hypertrophy according to the sex-independent criteria; of these, two had arterial hypertension. None of our patients had echocardiographic evidence of diastolic or systolic dysfunction. All patients showed significantly increased myocardial echoreflectivity (Bb = 106.4+/-12.1 versus 79.3+/-6.5; dCVF% = 2.78+/-0.53 versus 1.58+/-0.29; P < 0.0001) and QTd (66+/-13 ms versus 54+/-8 ms, P < 0.05). A significant correlation was found between dCVF and the duration of acromegaly (r = 0.80; P = 0.005). CONCLUSIONS Left ventricular remodelling observed in acromegaly is not related to the presence of arterial hypertension; we hypothesize that the increased echoreflectivity and QTd are long-term consequences of cardiac hypertrophy and prolonged exposure to high levels of growth hormone and insulin-like growth factor-I.

Ghrelin in human medullary thyroid carcinomas

Objective  Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. It has been identified previously in several normal and tumoral neuroendocrine tissues, including human medullary thyroid carcinomas (MTCs). The aim of the study was to evaluate ghrelin levels in patients with MTC and nontoxic goitre (NTG) with elevated calcitonin (CT) levels, as an additional marker of the disease.