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Increased mortality from cardiovascular diseases has been reported in acromegaly. Our objective was to evaluate the impact of glucose tolerance abnormalities and/or systemic hypertension in further worsening the acromegalic cardiomyopathy. The study design was open transversal. The subjects studied were 130 consecutive naive acromegalic patients (74 women and 56 men; age, 17-80 yr). Interventricular septum (IST) and left ventricular (LV) posterior wall thickness (PWT), LV mass index (LVMi), maximal early to late diastolic flow velocity ratio (E/A), isovolumic relaxation time (IRT), and LV ejection fraction (EF) were measured by echocardiography. The results were analyzed in line with the presence of glucose tolerance abnormalities (normal in 60, impaired in 38, diabetes mellitus in 32) and the presence (in 46) or absence (in 84) of hypertension. Patients with impaired glucose tolerance and diabetes mellitus had significantly higher age (P = 0.01), and systolic (P = 0.01) and diastolic (P = 0.01) blood pressures and lower E/A (P = 0.01) and EF (P = 0.01) than those with normal glucose tolerance. Disease duration, circulating GH and insulin-like growth factor I (IGF-I) levels, IST, LVPWT, LVMi, and IRT were similar in the 3 groups. Normotensive patients had significantly lower age (P

Summary Objective Lanreotide Autogel® 120 mg (ATG120; Ipsen S.p.A, Milan, Italy) is a high-dose, sustained-release aqueous gel formulation, supplied in a prefilled syringe and given by deep subcutaneous injection. The aim of this study was to compare efficacy and tolerability of ATG120 given every 4–8 weeks with those of octreotide LAR (o-LAR) given every 4 weeks. Design patients and intervention A phase III multicentre Italian open clinical study of 23 acromegalic patients (15 female, 8 male). All patients had received o-LAR for 6–18 months and, after 3 months wash out, ATG120 was given every 6 weeks for a total of four injections (Period 1). Then the interval between ATG120 injections was adjusted according to three different schemes: every 4, 6 or 8 weeks depending on GH levels (GH > 2·5 µg/l; 1

Alternative splicing of the 36-base pair exon 11 of the human insulin receptor (IR) gene and of the corresponding domain of the rat IR gene results in the synthesis of two IR isoforms with distinct functional characteristics. Altered expression of these IR isoforms has been previously demonstrated in the skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM); however, this observation was not confirmed by other studies and is still a matter of debate. To assess whether the reported altered isoform expression is due to the secondary metabolic derangement of diabetes, we examined alternative splicing of IR mRNAs (IR36+ and IR36-, corresponding to human Ex11+ and Ex11-) in the skeletal muscle and liver of 6-hour fasting 90% pancreatectomized insulin-resistant diabetic and control Sprague-Dawley rats, using the reverse transcriptase-polymerase chain reaction (PCR) technique. Both diabetic and control rats showed the same pattern of IR mRNA expression: the liver exclusively expressed IR36+ mRNA, whereas only IR36- mRNA was detected in muscle. In conclusion, diabetes mellitus per se does not alter the expression of IR isoforms in the liver and skeletal muscle, and therefore, at least in this animal model of NIDDM, impaired insulin action develops independently from a relative increase in IR36+ mRNA expression in skeletal muscle.

Objective: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4–8 weeks in somatostatin analogue-na"ive patients with acromegaly. Design: Open, non-comparative, phase III, multicenter clinical study. Methods: Fifty-one patients (28 women, aged 19–78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if ≤2.5 μg/l every 8 weeks (group A, 17 patients); if 2.5–5 μg/l every 6 weeks (group B, 15 patients); and if >5 μg/l every 4 weeks (group C, 19 patients). Treatment duration was 48–52 weeks. The primary objective was to control GH and IGF-I levels (GH≤2.5 μg/l and IGF-I normalized for age/gender). Secondary objectives were to assess GH, IGF-I, and acid-labile subunit (ALS) decrease, improvement of clinical symptoms and quality of life (QoL). Results: GH levels normalized in 32 patients (63%), similarly in de novo and post-op patients (72% vs 50%, p=0.48); in 100% of group A, in 73% of group B and in 21 % of group C (p

Particular problems in MEN 1 syndrome come from the morphological identification of pancreatic tumors because of their are often small [1 cm] and multiple [89% of the cases]. However intraoperatively it could be difficult to identify with palpation the tumors described by preoperative investigations and to decide the most suitable surgical treatment. The authors describe one case recently observed to underline and update the correct management.A 34 year old woman was admitted for the surgical treatment of an insulinoma. Polimenorrea, hypercalcemia and familiarity for MEN 1 syndrome were also present. A CT scan showed the tumors in the body and tail of the pancreas [diameter 0.5-1 cm]. MRI described only a small mass in pancreatic head. A calcium angiography was positive for insulin secretion after calcium infusion in hepatic and gastroduodenal artery, and for glucagon secretion after infusion in splenic artery. An intraoperative ultrasonography discovered three nodules that were enucleated. They were one insulinoma and two glucagonomas respectively. After enucleation glycemia became immediately normal.To avoid wide surgical resections [es. left pancreatectomy] we suggest a conservative treatment [multiple enucletion with or without a pancreatic-jejunum side-to-side anastomosis] with a meticulous preoperative and intraoperative evaluation of all pancreatic nodules.

Growth hormone segretagogues (GHS) are artificial molecules able to stimulate growth hormone (GH) secretion. They were discovered before the hypothalamic growth hormone-releasing hormone (GHRH). These molecules had a structure devoid of opiate activity, and GHRP-6 is the most representative compound. These compounds identified a new physiological system involved in GH regulation, and their action is independent of GHRH or somatostatin. Recently an endogenous ligand for the GHS receptor, ghrelin, was discovered, suggesting that this may be the third factor in the control of GH secretion. This peptide was isolated from the stomach and is characterized by the presence of an acylated group representing a new type of molecular hormonal structure; it is able to stimulate GH secretion in vitro and in vivo in the rat. As observed for the majority of GHS, ghrelin's action is not fully specific for GH release; the acute administration of ghrelin stimulates the release of significant amounts of PRL, ACTH and cortisol. Moreover, the presence of ghrelin in rat and human placenta has been reported, suggesting a possible role of this peptide in the local modulation of GH release and in maternal and fetal pituitary secretion. Ghrelin stimulates gastric acid secretion, is able to induce adiposity by activating a central mechanism for increasing food intake and decreasing fat utilization, and ghrelin mRNA and peptide are expressed in normal and adenomatous human pituitary tissue. Possible therapeutic applications of ghrelin remain to be assessed.

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

Gastrointestinal endocrine neoplasms are rare tumours that have been classified by the peptides they secrete and the resulting clinical syndromes. The incidence of these tumours is estimated to be less than 1-1.5 cases/100,000 of the general population. These gastrointestinal endocrine cells are characterized by similar cytochemical and ultrastructural characteristics, contain amines and they are capable of uptake of amine precursors to amines or peptides. The function of these cells is the neuroendocrine regulation of normal homeostatic mechanisms including vasomotor tone as well as carbohydrate, calcium and electrolyte metabolism. Each amine precursor uptake and decarboxylation cell normally synthesizes, stores and secretes its single amine or polypeptide and is responsive to its environment for stimulation or suppression in the related clinical syndrome.

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30-100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.

The interpretation of echocardiographic abnormalities in acromegalic patients is complicated by non-specific age-related diseases, many of which are commoner in acromegaly. We have therefore investigated the cause-effect relationship between GH/IGF-I hypersecretion and precocious cardiovascular abnormalities in a series of young acromegalic patients.An open prospective study.20 acromegalic patients aged under 30 years, with normal blood pressure and glucose tolerance, and 20 age-matched control subjects.Cardiac morphological parameters and indices of systolic and diastolic function at rest were studied by Doppler echocardiography.Left ventricular mass (LVM) and LVM index (LVMi) were higher in acromegalics than in control subjects (215.0 +/- 15.4 g vs 140.8 +/- 8.5 g, P = 0.0002 and 109.8 +/- 5.9 g/m2 vs 82.1 +/- 3.7 g/m2, P = 0.0008, respectively), reaching values of left ventricular hypertrophy in 4 patients (20%). Both ejection fraction and fractional shortening were normal (66.4 +/- 2.1% vs 62.2 +/- 1.9% and 37.5 +/- 1.5% vs 35.8 +/- 1.3%, respectively), indicating normal left ventricular systolic function. Abnormalities of left and right diastolic ventricular filling were found, which consisted of an increased isovolumic relaxation time (99.2 +/- 2.7 ms vs 89.0 +/- 2.7 ms, P = 0.01) and impaired mitral and tricuspidal flow velocity curves.An increase in cardiac mass and subclinical biventricular diastolic dysfunction were observed in young acromegalic patients. These findings argue for a direct cause-effect relationship between GH/IGF-I hypersecretion and myocardial abnormalities, and indicate that careful cardiological evaluation is mandatory in all acromegalics, whatever their age.

Several studies have suggested that, in non-insulin-dependent diabetes mellitus, augmented gluconeogenesis is responsible for increased endogenous glucose production (EGP) and in the end determines fasting hyperglycaemia. However, human and animal studies have been conducted by comparing euglycaemic control subjects to hyperglycaemic diabetic probands. We measured EGP and hepatic gluconeogenesis comparing control and diabetic rats in the fasting state (with diabetic animals in hyperglycaemia), re-examining them in the presence of identical euglycaemia (with diabetic rats made acutely euglycaemic through i. v. phloridzin) or during a hyperinsulinaemic clamp. All rats were infused with [3-3H]-glucose and [U-14C]-lactate; the ratio between 14C-uridine-diphosphoglucose (reflecting 14C-glucose 6-phosphate) and 2 14C-phosphoenolpyruvate specific activities (both purified by high performance liquid chromatography from liver) measured hepatic gluconeogenesis. In diabetic animals, although overall EGP ( approximately 19.5 mg x kg[-1] x min[-1]) remained unaffected by experimental euglycaemia, the contribution of glycogenolysis largely increased (from 5.4 to 11.7 mg x kg(-1) min(-1), hyper- vs euglycaemia) while gluconeogenesis decreased (from 14.0 to 8.1 mg x kg(-1) x min[-1]); both were responsible for the augmented EGP (control rats, EGP: 12.7 mg x kg(-1) x min(-1); gluconeogenesis: 5.9 mg x kg(-1) x min(-1); glycogenolysis: 6.7 mg x kg[-1] x min[-1]). Finally, during insulin clamp, gluconeogenesis and glycogenolysis were similarly decreased, and both contributed to the hepatic insulin-resistance of diabetic animals. We conclude that, in this model of non-insulin-dependent diabetes, augmented gluconeogenesis is not primarily responsible for fasting hyperglycaemia and hepatic insulin resistance. Finally, failure to accurately match the experimental conditions in which diabetic and control humans or animals are compared affects gluconeogenesis, overestimating its role in determining hyperglycaemia.

Hyperuricaemia is known to be related to hyperlipidaemia. Evidence for an uricosuric effect of fenofibrate and for a lipid lowering effect of benzbromarone has been reported.1 Furthermore, after dietary intervention, 15 hyperuricaemic-hyperlipidaemic subjects showed considerably decreased triglyceride and cholesterol concentrations and increased renal excretion of uric acid.2 These observations suggest a relation between serum lipid levels and renal excretion of uric acid. This relation has been the objective of the present study. Some of the possible underlying mechanisms are discussed.

About 3-5% of pituitary tumors occur in pediatric patients, often showing a considerable severity during childhood and puberty and major difficulties in their therapeutic management. As far as macroprolactinomas are concerned, surgery is often not resolutive, so that the need for postoperative treatment, consisting of either radiotherapy or bromocriptine, is the rule for tumors with extrasellar extension. In the present manuscript we report two cases of macroprolactinomas in adolescent patients suffering from delayed puberty, short stature and ocular symptoms together with hormonal levels indicating the presence of hypopituitarism. In both patients bromocriptine therapy showed a particular efficacy both in controlling tumor size and growth and in reducing clinical signs and symptoms. We conclude proposing DA-therapy as a first line of management in adolescents affected by macroprolactinomas, even in the presence of neurological symptoms.

We tested the hypothesis that glucosamine, a putative activator of glucose toxicity in vitro through acceleration of the hexosamine pathway, may determine in vivo the two key features of glucose toxicity in diabetes, namely, peripheral insulin resistance and decreased insulin secretion. Two groups of awake rats were studied either with intraarterial administration of glucosamine (5 mumol.kg-1.min-1) or saline. Insulin secretion was determined after arginine, glucose (hyperglycaemic clamp), and arginine/glucose infusions, while insulin-mediated glucose metabolism was assessed by the euglycaemic hyperinsulinaemic clamp in combination with [3-3H]-glucose infusion. Glucosamine had no effects on arginine-induced insulin secretion both at euglycaemia and hyperglycaemia, but significantly (40-50%) impaired glucose-induced insulin secretion (both first and second phases). During euglycaemic hyperinsulinaemic clamp studies, glucosamine decreased glucose uptake by approximately 30%, affecting glycolysis (estimated from 3H2O rate of appearance) and muscle glycogen synthesis (calculated from accumulation of [3H]-glucosyl units in muscle glycogen) to a similar extent. Muscle glucose 6-phosphate concentration was markedly reduced in the glucosamine-infused rats, suggesting an impairment in glucose transport/phosphorylation. Therefore, an increase in hexosamine metabolism in vivo: 1) inhibits glucose-induced insulin secretion, and 2) reduces insulin stimulation of both glycolysis and glycogen synthesis, thereby mimicking in normal rats the major alterations due to glucose toxicity in diabetes.

Ten consecutive patients with surgically proven beta-islet cell tumors, strongly suspected clinically because of positive laboratory findings, were studied by MRI at 0.5 T. Results were correlated with CT and angiography. MRI detected all 10 insulinomas, with the location confirmed at surgery. Lesion size was < 1 cm in three cases, between 1 and 2 cm in five cases, and between 2 and 3 cm in two cases. A false-negative diagnosis was obtained with CT in 6 of 10 and with angiography in 3 of 10 cases. Our results suggest that if motion artifact can be controlled or reduced, MRI can be employed to localize insulinomas in patients with positive clinical and laboratory findings.

Two brothers and a sister with acromegaly--one of them with acromegalogigantism--are described. They all presented pituitary adenomas, and the diagnosis was made between the ages of 17 and 29. There was no feature of multiple endocrine neoplasia. The familial investigation consisted of detailed interrogation, basal hormonal evaluation and HLA determination (haplotypes A and B) in 14 members, including the patients themselves. Despite basal plasma GH levels ranging from 8.00 to 10.00 ng/ml in 3 other family members, the normality of both GH response to induced-hyperglycemia and CT-imaging of the pituitary gland excluded the diagnosis of acromegaly in these subjects. No correlation with the HLA haplotypes was observed. Differential diagnosis with familial multiple endocrine neoplasia (MEN type 1) is discussed. Previous reports of familial acromegaly are reviewed and analysed. It appears that familial acromegaly may be considered as a specific entity for two main reasons: 1) owing to the low incidence of acromegaly in the general population, familial cases are unlikely to be fortuitous. 2) most of the reported cases share some common clinical features, such as a male predominance, a high incidence of acromegalogigantism, and the presence of a pituitary macroadenoma. However, the primitive disorder and the genetic transmission of the disease are still unknown.

As it's well known from the clinic, human syndromes depending on pituitary GH, ACTH and PRL secreting tumors are associated with alteration of glucose homeostasis. There is an hypothetical but convincing explanation for this, based on a number of concrete observations and experiments. The main mechanism for glucose intolerance or overt diabetes is related to insulin-resistance. The increased concentration of the three hormones would alter the action of insulin on its target cells at binding and (mainly) post-binding level. Besides recent researches indicate that the hypothalamus may play an important role in the pathogenesis of at least some cases of pituitary adenomas and, directly or indirectly, of the glucose homeostasis derangement.

Early diagnosis of total or partial GH (GHD) deficiency permits immediate treatment with biosynthetic GH and the achievement of a final stature close to the target one. However we frequently observe a progressive reduction in rate of growth ("vaning") during this therapy which delays attainment of adult stature compared to normal subjects. Subacute administration of GH on alternating days results in fair comparability of GH and Sm-C levels with physiological levels and it is therefore preferable to the i.m. route. Treatment should be interrupted when the growth rate is L2 cm/year or upon attainment of puberal stage P4 (female)-P5 (male). Rare side effects are the appearance of hypothyroidism, anti-GH antibodies (treatment with Met-Gh) and Creutzfeldt-Jakob disease (extractive GH).

Previous studies have shown that in patients with primary adult myxoedema (PAM) the rise in blood glucose (BG) and plasma insulin (IRI) after various stimuli is higher and more sustained than in normals, so that in this condition insulin resistance may be hypothesized. In the search for factors involved glucose (BG), insulin (IRI), glucagon (IRG), (assayed with an antiserum which is not specific for pancreatic glucagon) and growth hormone (GH), have been determined in blood during the oral glucose tolerance test, OGTT, (100 g), arginine intravenous infusion, ATT (30 g/30 min), and insulin-induced hypoglycemia, ITT (0.1 kg), in patients with PAM, without clinical diabetes, and in normal control subjects. During OGTT, glucose and IRI levels were higher than normal; on the other hand, IRG (probably gut glucagon, or enteroglucagon) levels were lower than in normals. During ATT blood glucose in PAM was slightly higher than normal at 30′ and lower at 90′ and 120′; insulin levels were higher than normal at any time; GH and IRG (very likely pancreatic glucagon, or nesidioglucagon) responses were lower than normal. During ITT, blood glucose levels dropped slowly but progressively and GH levels were lower than normal. It is concluded that in primary adult myxoedema glucagon, both enteric and pancreatic, and growth hormone secretions are impaired. The resistance to insulin action observed in PAM does not seem to be due to an excess of growth hormone or (nesidioglucagon).

Type 1 (insulin-dependent) diabetes is a disease characterized by a prodromal period with beta-cell destruction mediated by mononuclear white blood cells and their products. Several markers have been identifyed to characterize the prodromal phase of the disease. During this phase alterations involving lymphocyte activation are present; an increased percentage of circulating activated lymphocytes is detectable and these cells show a decreased interlukin (IL2) production (1) together with an increased release of IL2 receptors (IL2R) which can be detected in serum (2).

Changes in hormonal (insulin, glucagon, cortisol and growth hormone), glucose and FFA levels in blood were studied in four young, normal subjects during, and following, alcohol infusion after 12 hours' fasting. Similar studies were made during and after saline infusions in the same subjects after a comparable period of fasting. At the end of the infusions of alcohol or saline an arginine test was performed in order to compare insular and pituitary responses. The same investigations were performed in another three young, healthy subjects after 36 hours' fasting. A chronic alcoholic suffering from hypoglycemia was studied after a 12 hours' fast when he was first seen and again nine months after alcohol withdrawal. The results are in keeping with the hypothesis that alcohol has a priming effect on islet alpha and beta cells when there is no substrate defect. When glycogen stores are exhausted hypoglycemia ensues. An adrenergic reaction supervenes and consequently FFA, cortisol and glucagon rise to high levels. The growth-hormone response to an arginine stimulus was lower after alcohol than after saline in all subjects. In the chronic alcoholic patient the plasma growth-hormone response was initially very poor to all of the stimuli, but after nine months' alcohol withdrawal pituitary activity had returned to normal.

Fourteen patients with pituitary lesions and 6 normal subjects underwent the following tests: a) LHRH (100 mcg) + TRH (200 mcg) + Human Insulin (0.1 UI/kg) i.v. (Politest "A"); b) LHRH (100 mcg) + TRH (200 mcg) + GHRH 1-29NH2 (100 mcg) i.v. (Politest "B"); c) GHRH 1-29NH2 (100 mcg) i.v. (GHRH-TEST). FSH, LH and PRL, as assayed in patients and controls in response to Politest "A" and "B", revealed no significant differences between the tests. Plasma TSH values were significantly higher after Politest "B" in both patients and normals. The GH response after Politest "A" and "B" was similar in magnitude and concordant in 88.8% of cases.

A case of carcinoma of the stomach associated with severe hypoglycemia is reported. Diagnosis of insulinoma was excluded on the basis of history as well as laboratory tests. Postmortem examination revealed widespread small metastases to various organs; no metastasis was found in the pancreas; the histology of this gland did not show any pathological finding. No impairment in pituitary, thyroid, adrenal and liver function was detected. Fasting blood sugar ranged from 18 to 56 mg/100 ml. An oral glucose tolerance test showed a diabetic pattern with low insulin. Tolbutamide, glucagon and glucose injected i.v. gave only a moderate rise in plasma insulin levels; plasma glucagon response to arginine was subnormal. The determination of NSILA-s and gastrin in the serum of this patient gave normal values. Diazoxide infusion induced an increase in blood glucose and subsequent treatment with diazoxide relieved hypoglycemia for some months. The occasional detection of an islet cell antibody by immunofluorescence in this case is not easily understandable, but it might partly account for the carbohydrate intolerance. An impairment in gluconeogenesis dependent upon some substrate deficiency might account for the hypoglycemia in this patient.

Glucose ingestion, food intake or acute exercise produced rapid variations in insulin binding on monocytes. Insulin seems to play a minor or any role in this phenomenon in contrast pancreatic glucagon might be involved since it usually rises when an increase in insulin receptor affinity has been observed. To investigate the role of pancreatic glucagon we have studied the effect of arginine infusion on monocyte insulin receptor in five normal subjects. Results indicate that the aminoacid employed does not induce any change in insulin receptor affinity and concentration suggesting that the simultaneous increase in plasma insulin and pancreatic glucagon levels does not exert any action.

The aim of this chronobiological study was to investigate temporal correlations in the circadian patterns of 6 hormones, namely somatotrophic hormone (STH), prolactin (PRL), cortisol (F), aldosterone (ALD), insulin (IRI) and C-peptide (CP), assayed in systemic blood serum drawn at 07:00, 10:00, 13:00, 16:00, 19:00 and 22:00 h from an antecubital vein in 19 young subjects (aged 20-29 yr, comprising 10 males and 9 females; and 20 elderly subjects (aged 70-81 yr, comprising 10 males and 10 females). All subjects were sampled on a normal dietary sodium intake (120-140 mEq/24h) while following a social routine of diurnal activity (07:00-23:00) and nocturnal rest (23:00-07:00). Time-qualified data were analyzed by lead-lag correlation and by cosinor analysis. According to the lead-lag correlation findings, it would appear that the correlation which exists between several time-qualified series in young subjects is no longer present in elderly subjects. The circadian rhythms which were found to have lost their temporal correlations with advancing age were those between STH and IRI, STH and ALD, PRL and IRI, PRL and CP, and ALD and CP. It should be noted that the correlation between hormonal rhythms breaks down mainly on account of a peculiar age-related change in the magnitude of the circadian fluctuation. This chronological decline in amplitude led to the conclusion that the senescence of endocrine rhythmic functions is a biological phenomenon characterized by altered circadian variability.

The sera of ten patients with unexplained hypoglycaemia were examined for antibodies to pancreatic islets. Antibodies to pancreatic A, B and D cells (ICAb) were detected in one patient with an associated gastrointestinal tumour.

Acromegaly is a severe slow-developing disease associated with a poor prognosis for cardiovascular disease. To evaluate the impact of age and gender on the severity of the disease, 151 de novo patients with acromegaly (79 women, 72 men, age range 19-77 yr) were included in this open retrospective multi-center cohort study. Basal GH and IGF-I levels, GH response after glucose load and maximal tumor diameter at MRI were measured in all patients at diagnosis. Fasting GH levels and maximal tumor diameter were similar in women and men, while serum IGF-I levels were lower (664.9+/-24.9 vs 755.9+/-32 microg/l; p=0.02) and GH nadir after glucose load was higher (27.5+/-3.7 vs 18.5+/-2.2 microg/l; p=0.04) in women than in men. In both sexes, patients' age was negatively correlated with basal and nadir GH, IGF-I levels and tumor size; fasting GH levels were positively correlated with IGF-I levels and nadir GH after glucose. No interaction between age and gender was found on biochemical and morphological parameters. At diagnosis, elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after glucose load and smaller adenomas than young patients. Women have lower IGF-I levels but higher GH nadir after glucose load than men. These age and gender differences should be considered to appropriately evaluate the activity of acromegaly throughout a life-span.

Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). Design: This was a multicenter, international, collaborative study. Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries. Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures. Intervention: There was no intervention. Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Lanreotide (LAN) 60 mg (LAN60), a new long-acting formulation of LAN alleged to suppress GH/IGF-I hypersecretion for 28 d in acromegalic patients, was administered in a prospective open multicenter study to 92 patients with active acromegaly (61 women and 31 men, aged 20-79 yr). LAN60 was given as adjuvant treatment (AT) in 62 patients; the other 30 patients [primary treatment (PT)] were de novo (n = 20) or previously treated only by pharmacotherapy (n = 10). After wash-out from previous treatments, LAN60 was started im every 28 d for 3 injections; the dose was then individually tailored, aiming at lowering GH to less than 2.5 micro g/liter and IGF-I to the normal range. After a median follow-up of 24 months (range, 6-48 months), IGF-I normalized in 65% of patients, decreasing from 199 +/- 8% (expressed as a percentage of the upper limit of normal range; mean +/- SE) to 87 +/- 4% (P < 0.0001). GH fell to less than 2.5 microg/liter in 63% of patients and to less than 1 microg/liter in 25%, decreasing from 20 +/- 3 to 3 +/- 0.4 microg/liter (P < 0.0001). A progressive increase in the rate of IGF-I normalization was observed (from 49% at 1 yr to 77% at 3 yr). The rate of GH/IGF-I normalization was 72% at 36 months by Kaplan-Meier analysis. No tachyphylaxis was observed throughout the study. Shortening the interval between injections to 21 d improved GH/IGF-I suppression. PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Tumor shrank in 39% of assessable patients and in 50% of PT. Plasma glucose levels did not change, and high density lipoprotein cholesterol increased (by 19.3 +/- 5.1%; P = 0.0215). Gallstones appeared or worsened in 13% of patients. LAN60 is a new, very effective and long-lasting formulation for the treatment of acromegaly. The persistence of a powerful suppression of GH/IGF-I levels, the progressive increase in the rate of IGF-I normalization, and the similarity in the efficacy achieved in PT and AT patients point to a role for LAN60 in the primary treatment of acromegaly.