Endocrinology and art. Dwarf with hypergonadism.
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Dwarfism↗
Biomedical subjects
G Tamburrano
Publications and source records attributed to G Tamburrano.
Relationship between blood pressure and glucose tolerance in acromegaly.
BACKGROUND: Hypertension represents a well-known risk factor for cardiovascular diseases. The pathogenesis of hypertension in acromegaly is commonly viewed as multifactorial, but the possible influence of metabolic disorders on blood pressure (BP) in affected patients is largely unknown. OBJECTIVE: The aim of the present study was to evaluate the impact of glucose metabolism abnormalities on BP values in a series of patients with active acromegaly. DESIGN: An open multicentre prospective study. PATIENTS: Sixty-eight patients with active disease, aged 47.5 +/- 11.7 years, have been studied. Thirty-nine had normal glucose tolerance (NGT), 16 impaired glucose tolerance (IGT) and 13 suffered from diabetes mellitus (DM). MEASUREMENTS: Mean clinical BP values were calculated as the mean of BP values obtained by sphygmomanometric measurement in three separate occasions and mean 24-h, diurnal and nocturnal systolic (SBP) and diastolic (DBP) values were obtained by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: Patient's age and the degree of glucose tolerance abnormalities were found to significantly and independently influence BP values. All clinical and ABPM SBP and DBP values significantly increased with age by linear regression (P < 0.02 for all BP values, 0.30 < or = R < or = 0.43), and the independent influence of this parameter on BP values was confirmed by mutivariate analysis. Similarly, the independent influence of glucose tolerance abnormalities on BP values was confirmed when introducing age as a covariable in a multivariate analysis, and patients with DM presented significantly higher clinical SBP and 24-h, diurnal and nocturnal SBP and DBP than patients with NGT (P < 0.02 for clinical SBP, P < 0.015 for all ABPM values, respectively). In addition, patients with DM showed significantly higher 24-h, diurnal and nocturnal DBP than those with IGT (P < 0.05 in all cases). In contrast, no significant difference was found between NGT and IGT patients. No significant influence of disease duration, BMI, GH, IGF-I, or fasting and 2-h post glucose load insulinaemia on BP values was observed. CONCLUSIONS: Abnormalities of glucose metabolism significantly contribute to increase systolic blood pressure and especially diastolic blood pressure in acromegalic patients. Careful control of blood pressure and of risk factors for developing systemic hypertension, with special reference to glucose tolerance, is mandatory to decrease cardiovascular morbidity and mortality in such patients.
Acromegaly↗
Marked improvement in cardiovascular function after successful transsphenoidal surgery in acromegalic patients.
OBJECTIVE: Transsphenoidal surgery results in biochemical remission of acromegaly in 45-80% of patients; however, few studies have addressed the impact of transsphenoidal surgery on cardiovascular function in acromegalic patients. The aim of this prospective study was to investigate the effects of postoperative GH/IGF-I normalization on echocardiographic parameters and blood pressure (BP) in a series of patients with active acromegaly. DESIGN: An open prospective study. PATIENTS: Thirty newly diagnosed acromegalic patients undergoing transsphenoidal surgery. MEASUREMENTS: Doppler echocardiography and 24-h ambulatory blood pressure monitoring were performed before and 6 months after transsphenoidal surgery. RESULTS: Fifteen patients were considered to be well controlled postoperatively (group A), as defined by normal age-corrected IGF-I levels and glucose-suppressed GH levels less than 2 mU/l, the remaining 15 patients being considered as poorly controlled (group B). In group A, a postoperative decrease of left ventricular mass index was observed (104.4 +/- 6.6 vs. 127.1 +/- 7.7 g/m2; P < 0.001), associated with an improvement of some indices of diastolic function, such as an increase of the early/late transmitral peak flow velocity (P < 0.05) and a decrease of isovolumic relaxation time (P < 0.01). No significant change was observed in group B. A significant decrease of 24-h systolic BP was also observed in group A (P < 0.05) and five of six patients normalized their BP circadian rythm. In contrast, a nonsignificant increase in BP values, with a persistent blunted BP profile where present, was observed in group B. CONCLUSIONS: We conclude that successful transsphenoidal surgery is able to induce a significant improvement in some cardiac parameters and a slight reduction in systolic blood pressure in acromegalic patients.
Acromegaly↗
Images in Cardiology: Asymptomatic right atrial myxoma in acromegalic man: a case of Carney complex.
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Acromegaly↗
Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features.
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.
Adenoma↗
Adrenomedullin, a new peptide, in patients with insulinoma.
BACKGROUND: It has been demonstrated that adrenomedullin, a newly discovered peptide, affects the release of insulin from pancreatic islets cells, suggesting a role in the insulin-regulating system. OBJECTIVE: To investigate whether adrenomedullin secretion is modified in patients with insulin-secreting islet cell tumours. DESIGN: The study was performed in nine patients with surgically treated insulinoma. Circulating adrenomedullin was assayed using a specific radioimmunoassay and its localization and distribution in the tumour were determined by means of immunohistochemistry. RESULTS: Adrenomedullin concentrations were significantly greater in patients with insulinoma (6.6 +/- 3.2 fmol/ml) than in controls (2.1 +/- 1.1 fmol/ml). In six patients monitored before and after surgery, plasma adrenomedullin decreased from 6.3 +/- 2.9 fmol/ml to 3.0 +/- 1.6 fmol/ml. Immunoreactive adrenomedullin was localized exclusively in the tumours cells, whereas stroma, surrounding pancreas parenchyma and major ducts were negative for the peptide. CONCLUSIONS: Our findings indicate that circulating adrenomedullin is increased in insulinoma and that this increase is related to the neoplastic phenotype.
Adenoma, Islet Cell↗
Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy.
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<0.001), LVPWT (P<0.001), IST (P = 0.003), LVMi (P<0.001), and IRT (P = 0.02) and significantly higher E/A (P<0.001) and EF (P<0.001) than hypertensive subjects. Disease duration, circulating GH, and IGF-I levels were similar in the 2 groups. Multiple regression analysis showed that systolic blood pressure was the strongest predictor of LVMi (P = 0.0004), followed by GH levels (P = 0.02), whereas diastolic blood pressure was the strongest predictor of LVEF reduction (P<0.0001), followed by glucose tolerance status (P = 0.02). Age was the strongest predictor of both E/A impairment (P<0.0001) and IRT (P = 0.01), followed by IGF-I levels (P = 0.02). Compared to patients with uncomplicated acromegaly, those with hypertension but without abnormalities of glucose tolerance had an increased prevalence of LV hypertrophy (75% vs. 37.2%) as well as of impaired diastolic (50% vs. 7.8%) and systolic function (18.7% vs. 3.9%), whereas patients with glucose tolerance abnormalities but without hypertension had only an increased prevalence of impaired diastolic (39.7%) and systolic function (31.7%). The subgroup of acromegalic patients suffering from hypertension and diabetes mellitus had the highest prevalence of LV hypertrophy (84.6%), diastolic filling abnormalities (69.2%), and impaired systolic function at rest (53.9%). A careful cardiac investigation should thus be performed in all acromegalic patients showing these complications.
Acromegaly↗
Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg).
Pharmacotherapy of acromegaly has been improved in recent years as new long-acting somatostatin analogs have became available; they have been suggested as an alternative treatment to pituitary surgery and radiotherapy. To avoid the inconvenience of multiple daily injections during long-term therapy, a slow release formulation of lanreotide (LAN), to be administered im at a dose of 30 mg every 7-14 days, has been introduced in the therapeutic management. The suppressive effects of a short-term LAN treatment on GH and insulin-like growth factor I (IGF-I) hypersecretion were shown to be similar to those obtained with sc octreotide. However, scant data have been reported concerning a long-term treatment with this drug. In the present study the efficacy and tolerability of a 24-month LAN treatment were evaluated in 118 active acromegalic patients; 71 had been previously operated on and treated with s.c. octreotide (operated patients), 24 previously operated on had been irradiated and treated with s.c. octreotide (irradiated patients), and the remaining 23 were newly diagnosed (de novo patients). The efficacy was considered on the basis of controlled GH (fasting, <7.5 mU/L; glucose-suppressed, <3.0 mU/L) and IGF-I (age-adjusted normal values) secretion. In the 118 patients as a whole, circulating GH and IGF-I levels were significantly decreased during the 24-month LAN treatment (P < 0.0005 at all time points vs. basal value). After 24 months of therapy, controlled GH and IGF-I levels were achieved in 64%, 37%, and 78% and in 51%, 37%, and 70% of operated, irradiated, and de novo patients, respectively. A reduction in tumor size was documented in 5 of 23 de novo patients (22%). Among the 84 operated/irradiated with evident tumor remnant, significant shrinkage was documented in 5 patients (5.9%). Treatment was well tolerated by the majority of patients. Only 2 patients (1.7%) withdrew from LAN treatment due to severe side effects. In conclusion, a 24-month treatment with slow release lanreotide (30 mg) is effective in reducing GH and IGF-I levels; furthermore, in de novo patients it induces disease control in 70% of patients and causes tumor shrinkage in 22% of them, with excellent compliance. These data suggest that LAN can be used in long-term treatment of acromegalic patients.
Acromegaly↗
p16 (INK4a, MTS-1) gene polymorphism and methylation status in human pituitary tumours.
OBJECTIVE: The p16 gene, which encodes a physiological inhibitor of the cyclin D-CDK4 complex, is now considered as an important tumour-suppressor gene in a variety of tumours. A marked reduction of its expression has been reported to occur without significant genetic alterations in human pituitary adenomas, although rare point mutations of uncertain functional significance have been described. On the other hand, p16 gene silencing due to hypermethylation has been reported in several human primary tumours. The aim of this study was to further investigate the pathogenetic events leading to p16 gene inactivation in pituitary tumours. DESIGN: To screen a european series of human pituitary tumours for p16 gene alterations and possible gene hypermethylation. PATIENTS: A representative series of 31 human pituitary tumours-30 macroadenomas, including a MEN-1 non-secreting pituitary adenoma and a non-MEN-1 familial giant GH-secreting adenoma, and one FSH-secreting pituitary carcinoma-was studied. METHODS: Polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) analysis was used to screen for p16 gene alterations in all cases. Direct sequencing of PCR-products was obtained by the di-deoxynucleotide method where suspected abnormalities of the PCR-SSCP analysis were observed. In 24 samples, a methylation-specific PCR assay (MSP-PCR) was used to determine p16 gene methylation status. RESULTS: Two sporadic cases of pituitary adenomas had a similar single A to G base substitution leading to an heterozygous Ala140Thr p16 polymorphism, which has not previously been described in such tumours, but is known to be functionally silent. No other p16 abnormality could be suspected from PCR-SSCP analysis in this series. In contrast, the presence of methylated-specific PCR products was observed in 20/24 cases (83.3%). CONCLUSIONS: This study confirms that p16 gene mutations are not involved in the pathogenesis of human pituitary tumours, although polymorphisms can be demonstrated, depending on the population considered. In contrast, the high incidence of hypermethylation of the p16 gene suggests that such an alteration occurs early in pituitary tumours, and may play a role in pituitary tumorigenesis.
Adenoma↗
Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: a retrospective study.
OBJECTIVE: We analysed the effects of 6-months' treatment with octreotide s.c. and lanreotide-SR on circulating GH and IGF-I levels in acromegaly. DESIGN: Open retrospective study. PATIENTS: Thirty-eight patients with active acromegaly (plasma IGF-I levels greater than 2 standard deviations for age-matched controls and increased serum GH levels not suppressible by oral glucose load) were studied. All patients received s.c. octreotide at a dose of 150-600 microg/day for six months as first therapy and subsequently, lanreotide i.m., 30-60 mg either at 14 or 10 day intervals, for 6 months. A 3 months' washout was applied before starting lanreotide treatment. MEASUREMENTS: Mean serum GH levels (from three samples), IGF-I, and clinical examination were performed before and 30, 60, 90 and 180 days after octreotide and lanreotide treatments. Safety tests, HbA1c and, thyroid function were evaluated every three months. RESULTS: Circulating GH and IGF-I levels were significantly reduced (P < 0.001) after one, three and six months of both octreotide and lanreotide treatment. The absolute values were lower and the percent decrease in serum GH levels obtained after octreotide treatment was significantly greater, at all scheduled assessments, than after lanreotide (P < 0.01). Serum IGF-I levels during octreotide were significantly lower only after the first month of therapy (P < 0.01). CONCLUSIONS: Our study shows that octreotide s.c. is able to induce an earlier reduction in IGF-I levels and a more marked reduction in GH levels than lanreotide. However, after six months of therapy the number of patients with safe GH levels and normal IGF-I age-matched levels, was similar with both drugs. Therefore we suggest that octreotide treatment be preferentially used in the short-term presurgical treatment, while lanreotide can be used in chronic therapy when better compliance is necessary.
Acromegaly↗
Cardiac effects of slow-release lanreotide, a slow-release somatostatin analog, in acromegalic patients.
Cardiac involvement, mostly characterized by left ventricular hypertrophy associated with various degrees of cardiac dysfunction, greatly contributes to the increased mortality and morbidity observed in acromegaly. Lanreotide is a new SRIF analog characterized by a slow-release (SR) formulation with the peculiarity of a 30-mg im administration every 10-14 days. In this study, 13 patients with postoperative active acromegaly (9 females, 4 males, 45.9 +/- 16.3 yr old) underwent an echo-Doppler and hormonal study before and during a 12-month period of treatment with SR-lanreotide. GH and insulin-like growth factor I plasma levels (mean +/- SD) decreased significantly throughout the study period (from 10.1 +/- 2.2 to 3.9 +/- 0.9 ng/mL for GH, P < 0.005; and from 511.0 +/- 33.0 to 305.0 +/- 34.2 ng/mL for insulin-like growth factor I, P < 0.0001). Left ventricular mass index (mean +/- SD, 137.1 +/- 7.5 g/m2 at baseline) decreased after 3 months (120.0 +/- 5.4 g/m2), 6 months (111.7 +/- 5.7 g/m2), and 12 months (110.3 +/- 5.2 g/m2) of treatment (P < 0.005 at each time-point). This reduction in left ventricular mass index was accompanied by an improvement in some indexes of left ventricular diastolic function, especially the isovolumetric relaxation time (mean +/- SD, 109.1 +/- 4.6 m/sec at baseline), which decreased after 3 months (91.9 +/- 2.8 m/sec), 6 months (92.3 +/- 3.2 m/sec), and 12 months (92.2 +/- 3.0 m/sec) of treatment (P < 0.005 at each time-point). We conclude that SR-lanreotide is able to improve cardiac morphology and functional abnormalities in acromegaly; whether such beneficial effects on cardiac parameters will contribute to improve life expectancy in these patients should be further investigated.
Acromegaly↗
Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.
As there are few data on the evaluation of the adequacy of levothyroxine (L-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on L-T4 therapy. Samples were taken before the daily administration of L-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after L-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During L-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean L-T4 daily dose of 1.5 +/- 0.3 microg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The L-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients. In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of L-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.
Adult↗
Evidence for glucose/hexosamine in vivo regulation of insulin/IGF-I hybrid receptor assembly.
Hybrid receptors composed of an insulin alphabeta-hemireceptor and a type 1 IGF alphabeta-hemireceptor are formed in tissues expressing both molecules. We recently reported an increased hybrid receptor expression in skeletal muscle of type 2 diabetic patients that is inversely correlated with in vivo insulin sensitivity. It is unclear whether these changes were due to primary abnormalities or to secondary derangements acting in vivo, such as hyperglycemia. To address this, we determined abundance of hybrids in skeletal muscle from three groups of rats: controls, diabetic (90% pancreatectomy), and diabetic treated with phlorizin to normalize plasma glucose levels. We found that the abundance of hybrid receptors was higher in diabetic rats compared with control and phlorizin-treated diabetic rats (percentage of 125I-insulin bound versus total added radioactivity [B/T] = 1.8+/-0.11, 0.4+/-0.01, and 0.32+/-0.04, respectively; P < 0.0001). Fasting plasma glucose levels were positively correlated with hybrids abundance (r = 0.77, P < 0.002). Hybrid receptor protein content, assessed by immunoblotting, was 2.4-fold higher in diabetic rats as compared with control and phlorizin-treated diabetic rats. Because it has been shown that some of the regulatory effects of glucose may be mediated by the glucosamine pathway, we subsequently determined the effect of an in vivo glucosamine infusion on hybrid receptor formation. We found that abundance of hybrids was significantly higher in muscle from glucosamine-treated rats compared with control rats (B/T = 0.17+/-0.02 and 0.11+/-0.01, respectively; P < 0.009). Quantitation of hybrid content by immunoblotting revealed that their abundance was 1.9-fold higher in glucosamine-treated rats. The results demonstrate that 1) elevated glucose levels in diabetic rats are associated with increased expression of hybrid receptors in muscle, 2) correction of hyperglycemia with phlorizin completely reverses increased expression of hybrids, and 3) glucosamine infused into control rats mimics the effects of hyperglycemia on hybrid receptor formation. Thus, the results support the hypothesis that glucose acting, at least in part, through the glucosamine pathway may play an important role in regulating hybrid receptor assembly in vivo.
Animals↗
Pancreatic endocrine tumours.
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.
Adenoma↗
Inverse relationship between serum triglyceride levels and fractional urate excretion.
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Adult↗
Relative contribution of glycogenolysis and gluconeogenesis to hepatic glucose production in control and diabetic rats. A re-examination in the presence of euglycaemia.
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.
Animals↗
Functioning human insulinomas. An immunohistochemical analysis of intracellular insulin processing.
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.
Adolescent↗