Overexpression of the c-MET/HGF receptor in human thyroid carcinomas derived from the follicular epithelium.
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Adenocarcinoma, Follicular↗
Biomedical subjects
R Vigneri
Publications and source records attributed to R Vigneri.
Early occurrence of a thyroid carcinoma in a patient who developed Graves' disease after treatment for Hodgkin's disease.
We report the case of a patient who developed Graves' disease and a papillary thyroid cancer only 5 years after irradiation and adjuvant chemotherapy for Hodgkin's disease. This case is peculiar for the very short latency time between Hodgkin's disease treatment and thyroid cancer development, an event possibly related to Graves' disease with elevated serum levels of TSAb. We conclude that, in patients treated for Hodgkin's disease, continued follow-up by clinical examination and sonography of the thyroid is needed, especially if they develop Graves' disease.
Adult↗
Interleukin-1 beta inhibition of insulin release in rat pancreatic islets: possible involvement of G-proteins in the signal transduction pathway.
In vitro exposure of rat pancreatic beta cells to interleukin-1 beta (IL-1 beta) inhibits glucose-stimulated insulin release (2140 +/- 239 and 323 +/- 80 pg.islet-1.h-1 at glucose levels of 16.7 mmol/l in control and IL-1 beta-exposed islets, respectively, n = 7, p < 0.001). Cholera toxin (2 micrograms/ml) or pertussis toxin (0.5 microgram/ml) potentiated, as expected, glucose-induced insulin release in control islets, but, in addition, when added together with IL-1 beta, were able to prevent the IL-1 beta mediated inhibition of glucose-stimulated insulin secretion (2087 +/- 301 and 1662 +/- 173 pg.islet-1.h-1, respectively, p < 0.05 vs islets exposed to IL-1 beta alone). To investigate the mechanism by which the toxins prevent the IL-1 beta effect, we then measured nitrite levels, glucose oxidation and Ca2+ uptake. Nitrite levels in the culture medium were 4.2 +/- 1.4 and 24.0 +/- 5 pmol.islet-1.24 h-1 in control islets and in IL-1 beta-exposed islets, respectively (n = 6, p = 0.05). In islets exposed to IL-1 beta and cholera or pertussis toxins, nitrite levels were 9.1 +/- 3 and 12.4 +/- 6 pmol.islet-1.24 h-1, respectively (n = 6, NS vs control islets). Glucose oxidation at 16.7 mmol/l glucose was 31.1 +/- 2.9 pmol.islet-1.120 min-1 in control islets and 16.8 +/- 2.7 pmol.islet-1.120 min-1 in IL-1 beta-treated islets (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Glucose transport, phosphorylation, and utilization in isolated porcine pancreatic islets.
Porcine islets have been proposed as a donor source for human transplantation, mainly because of both structural and biological similarities of porcine and human insulin. However, the in vitro function of these islets is poorly characterized. In the present study, we first examined insulin release in response to glucose in static incubation experiments. Increasing glucose concentrations up to 8.3 mmol/L stimulated insulin release; however, this elevation was only twofold, and a paradoxical decline was observed at glucose concentrations higher than 8.3 mmol/L. In cultured porcine islets, a greater insulin secretion may be elicited by agents that increase intracellular cyclic adenosine monophosphate (cAMP) levels. To investigate the possible reasons for the porcine islet low response to glucose in vitro, we then evaluated in parallel experiments glucose transport, phosphorylation, and utilization. Glucose transport studies (using 3-O-methyl glucose uptake at 15 degrees C for 15 seconds) indicated the presence of both a high-affinity (Km, 1.2 +/- 0.6 mmol/L) and a low-affinity (Km, 11.8 +/- 1.9 nmol/L, n = 5) component. Glucose phosphorylation, evaluated by measuring the rate of glucose-6-phosphate formation in a fluorimetric assay, indicated that glucokinase activity had a maximum (Vmax) of 7.97 +/- 0.94 nmol/microgram DNA/h and a Km of 8.3 +/- 0.9 mmol/L (mean +/- SE, n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Childhood IQ measurements in infants with transient congenital hypothyroidism.
OBJECTIVE: In view of the fact that, during the first period of life, thyroid hormones are critical for brain development, we investigated whether even transient congenital hypothyroidism could affect the long-term intellectual development of affected infants. DESIGN: A case-control study of intellectual development, auxometric parameters and thyroid function performed in late infancy in children with documented transient congenital hypothyroidism or hyperthyrotrophinaemia at birth. PATIENTS: Nine children born in an endemic goitre area who had short-term transient congenital hypothyroidism or hyperthyrotrophinaemia after birth (TCH) were studied and compared to nine matched children born in the same area at the same time but having normal thyroid function at birth (N). MEASUREMENTS: Global, verbal and performance IQs were evaluated on the Wechsler scale. Height, bone age, total and free thyroid hormones, thyroid volume, thyroglobulin, basal and TRH stimulated TSH were also measured. RESULTS: Height and bone age were similar in the two groups. Thyroid function tests were also similar in the two groups except for basal and TRH stimulated serum TSH and serum Tg which were higher in the TCH than in the control group. Global, verbal and performance IQs were systematically lower in the TCH than in the N group. (78.3 +/- 11.1 vs 90.9 +/- 14.2, P < 0.05; 84.4 +/- 15.4 vs 96.2 +/- 14.8, P NS; 75.0 +/- 8.5 vs 89.2 +/- 12.5, P < 0.01 respectively). CONCLUSION: Infants born and living in an academic goitre area, who had biochemical signs of thyroid hypo-function at birth, had a lower intelligence quotient at the age of 7-8 years than matched controls living in the same environmental conditions but with normal thyroid function at birth. The present findings strongly suggest that abnormalities in thyroid function at birth, even when transient, can adversely affect long-term intellectual development.
Case-Control Studies↗
Recommendations concerning iodine prophylaxis.
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Democratic Republic of the Congo↗
Measurement of iodine before 131I in thyroid cancer.
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Humans↗
Incidence of type I diabetes in the district of Catania, Sicily.
The incidence of type I (insulin-dependent) diabetes was determined in the district of Catania (eastern Sicily) in children under 15 years of age over a 3-year period (1 January 1989 to 31 December 1991). Two independent sources of information were used. The primary source was contact with all medical services in the province, and the secondary source was the personal identification cards issued to all diabetic patients by the National Health System necessary for obtaining free medical care. The information obtained was 99.6% complete. The overall incidence was 10.2/10(5) per year. This study provides the first standardized data on the incidence of type I diabetes in Sicily and is consistent with the possibility of regional deviations from the proposed north to south gradient.
Adolescent↗
Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer.
IGF-I receptor (IGFR) content and its prognostic significance were evaluated in human breast cancer specimens using a sensitive and specific radioimmunoassay (V. Pezzino et al., Metabolism, 40: 861, 1991). The prognostic significance of IGFR expression was investigated by two different approaches: (a) detectable IGFR content was measured in 82% of specimens in a consecutive series of 184 human breast cancers and in 32% of 19 normal breast tissues. The average IGFR content in breast cancer was nearly 10-fold higher than the value observed in normal breast tissue (7.6 +/- 0.8 versus 0.8 +/- 0.1 ng/0.1 mg protein, mean +/- SEM; P < 0.001). IGFR content was positively correlated with estrogen (ER) and insulin receptor content (r = 0.269 and 0.515, respectively, Pearson correlation) but not with progesterone receptors (PR). No significant correlation was observed between IGFR content and a variety of tumor parameters (tumor size, lymph node involvement, grade) and host characteristics (age, body mass index, menopausal status); (b) IGFR content was measured in a noncontinuous series of 265 primary breast cancer specimens subdivided into 136 high-risk and 129 low-risk specimens on the basis of being either negative (ER-/PR-/aneuploid/high S-phase) or positive (ER+/PR+/diploid/low S-phase) for four well-established prognostic factors. IGFR levels were significantly higher in the low-risk group (6.4 +/- 0.4 ng/0.1 mg protein, mean +/- SEM) than in the high-risk group (3.6 +/- 0.5; P < 0.0001, Wilcoxon sum rank test). In summary, our data indicate that there is an elevated IGFR content in most human breast cancers compared with normal breast tissue and that an elevated IGFR content is a favorable prognostic indicator.
Adult↗
Different effects of glucose and glyburide on insulin secretion in rat pancreatic islets pre-exposed to interleukin-1 beta. Possible involvement of K+ and Ca2+ channels.
In vitro islet exposure to interleukin 1 beta inhibits the beta-cell response to glucose. We have studied whether a similar inhibition also occurs in response to the sulphonylurea glyburide. Rat pancreatic islets were cultured for 24 h in the presence or absence of 50 U/ml interleukin 1 beta and then stimulated with either glucose or glyburide for 1 h at 37 degrees C. In control islets basal insulin secretion was 117 +/- 32 pg.islet-1.h-1 (mean +/- SEM, n = 7) and greatly increased in response to 16.7 mmol/l glucose (2140 +/- 293) or 10 mumol/l glyburide (1464 +/- 234). When islets were pre-exposed to interleukin 1 beta, insulin release was significantly reduced in response to glucose (323 +/- 80, p < 0.001) but not in response to glyburide (1316 +/- 185). Since both glucose and glyburide influence beta-cell K+ and Ca2+ efflux, to further investigate this different response in islets exposed to interleukin 1 beta we measured both Rb+ efflux (as index of the ATP-sensitive K+ channel activity) and Ca2+ uptake. In control islets, the increased insulin secretion in response to 16.7 mmol/l glucose or 10 mumol/l glyburide was associated with a reduction of 86Rb efflux (decrement of -50 +/- 1.2% and -49 +/- 2.3%, respectively, mean +/- SEM, n = 5). In contrast, in interleukin 1 beta pre-exposed islets both glucose and glyburide stimulation only slightly modified 86Rb efflux (decrement of -19 +/- 1.9% and -5.3 +/- 3.1%, respectively, n = 5, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Insulin receptor tyrosine kinase activity is reduced in monocytes from non-obese normoglycaemic insulin-resistant subjects.
Insulin sensitivity has been quantified by i.v. insulin tolerance test (0.1 U/kg of body weight) in 18 (11 male/7 female) non-obese (body mass index range 19-25 kg/m2) normoglycaemic subjects. We then compared the tyrosine kinase activity and internalization of insulin receptor in monocytes from the six most insulin-sensitive (group 1) and the six most insulin-resistant (group 3) subjects. Tyrosine kinase activity was measured on immunopurified receptors using 32P-ATP and poly-glutamic acid 4: tyrosine 1, sodium salt (poly-glu-tyr 4:1). Insulin internalization was studied by incubating cells with 1 nmol/l 125I-insulin and measuring total cell-bound and intracellular 125I-insulin by an acid dissociation procedure. Basal (in the absence of insulin) receptor kinase activity was similar in both groups. Maximal (in the presence of 100 nmol/l insulin) kinase activity was 41% lower in group 3 (13.8 +/- 3.6 fmoles 32P-ATP incorporated vs 23.3 +/- 4.0, p = 0.1). Delta increment of receptor kinase activity after insulin stimulation (calculated by subtracting basal from maximal activity) was significantly (p < 0.05) reduced in group 3 (21.3 +/- 3.8 vs 11.1 +/- 2.1) and significantly (p < 0.05) correlated to the in vivo insulin sensitivity. Both total cell-bound (0.70 +/- 0.09% of total radioactivity added vs 0.83 +/- 0.15) and intracellular (0.39 +/- 0.05 vs 0.44 +/- 0.09) 125I-insulin were similar in the two groups. These data suggest that in non-obese, normoglycaemic subjects a defective insulin receptor tyrosine kinase activity may contribute to the development of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Inhibition of the high-affinity glucose transporter GLUT 1 affects the sensitivity to glucose in a hamster-derived pancreatic beta cell line (HIT).
HIT is a hamster-derived beta-cell line which in contrast to normal beta cells that only express the high Km GLUT-2 glucose transporter, also expresses the low Km glucose transporter GLUT 1. In HIT cells the abnormal glucose transport mechanism is associated with a marked shift to the left of the glucose-induced insulin release dose-response curve. We have used this cell model to investigate whether changes in glucose transport affect the glucose-induced insulin release. HIT cells were first incubated with a concentration of cytochalasin B (0.4 mumol/l) that selectively inhibits the GLUT-1 but not the GLUT-2 transporter. The consequences of blocking glucose phosphorylation and insulin release were studied. Exposure to 0.4 mumol/l cytochalasin B for 1 h caused a selective loss of the low Km transport: the calculated Vmax of GLUT 1 was reduced from 1726 +/- 98 to 184 +/- 14 pmol.mg protein-1 5 min-1 (mean +/- SEM, n = 6, p < 0.005), while no major difference in the high Km (GLUT-2) transport was observed. In cytochalasin B exposed HIT cells the glucose phosphorylating activity (due to hexokinase and glucokinase) was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
3-O-Methylglucose↗
Structural and functional studies of insulin receptors in human breast cancer.
We characterized the structure and the function of insulin receptors isolated from 10 human breast cancer specimens. We observed that the insulin receptor content, as determined by a specific radioimmunoassay, was four fold increased in human breast cancer tissue when compared to normal breast tissues. In both cancer and normal breast tissues, insulin receptor mRNA consisted of two major species of approximately 11.0 and 8.5 kilobases. The size of the insulin receptor alpha subunit was determined by 125I-insulin cross-linking followed by immunoprecipitation and polyacrylamide gel electrophoresis; a value of 135kDa was observed for receptors from both breast cancer and normal breast tissues. The functional binding ability of insulin receptors from cancer tissues was slightly lower as compared to normal tissue derived insulin receptor (% B/T = 2.22 +/- 0.50 per ng of insulin receptor as determined by radioimmunoassay vs. 2.96 +/- 0.49, mean +/- S.E.M.). The concentration of insulin that caused half maximal inhibition of 125I-insulin binding was very similar for both cancer and normal breast receptors (80pM). The size of the insulin receptor beta subunit as determined by receptor autophosphorylation was 95kDa. Basal and maximal insulin (100nM) stimulated receptor tyrosine kinase activity, in terms of both receptor autophosphorylation and phosphorylation of an exogenous substrate, was similar in malignant and normal breast tissue derived insulin receptor. Also, a very similar insulin stimulated Km value for ATP was showed by the tyrosine kinase of insulin receptors from breast cancer and normal breast tissue (11.1 and 10.8 microM ATP, respectively). However, in insulin receptors from breast cancer tissue the average tyrosine kinase sensitivity to insulin, as calculated on the exogenous substrate, was higher, although not significantly, with respect to normal breast tissue (ED50 at 0.28 +/- 0.09 and 1.08 +/- 0.33 nM insulin, respectively). A similarly different sensitivity to insulin was observed also for receptor autophosphorylation. In conclusion, this study demonstrates that breast cancer tissues have an increased number of structurally and functionally normal insulin receptors. In some breast cancer tissues, however, the sensitivity of the receptor tyrosine kinase activity to insulin is greatly increased. These data suggest that, in vivo, the mitogenic effect of insulin may play a role in the biology of certain breast cancers.
Breast Neoplasms↗
Relationship between insulin receptor tyrosine kinase activity and internalization in monocytes of non-insulin-dependent diabetes mellitus patients.
Reduced insulin receptor tyrosine kinase activity and internalization have been reported in non-insulin-dependent diabetes mellitus (NIDDM) patients. To clarify whether in NIDDM the defective internalization is caused by the defective kinase activity, we studied receptor tyrosine kinase activity and internalization in monocytes from eight lean control and six obese subjects and 10 obese NIDDM patients. Receptor internalization was also stimulated by an anti-insulin receptor antibody (MA-10) that is unable to stimulate receptor kinase activity. Basal exogenous tyrosine kinase activity was not different in monocytes from the three groups of subjects. As compared with control subjects (2,690 +/- 637 fmol 32P incorporated), insulin (100 nmol/L)-stimulated tyrosine kinase activity was lower in NIDDM patients (1,262 +/- 318, P < .05), but not in obese subjects (2,640 +/- 731). Basal receptor autophosphorylation did not differ between the three groups, whereas insulin-stimulated autophosphorylation in comparison to that in control subjects was reduced in NIDDM patients (P < .05), but not in obese subjects. In NIDDM patients, receptor internalization induced by both insulin and MA-10, was lower (P < .05) than that in control and obese subjects. No correlation was found between receptor internalization and exogenous tyrosine kinase activity (r = .30, NS) or autophosphorylation (r = .08, NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
An intact and functional soluble form of the insulin receptor is secreted by cultured cells.
We have recently reported that the insulin receptor (IR), a tetrameric transmembrane protein located on the surface of target cells, is present as a soluble form in human plasma. In the present study we investigated whether human cells in culture release an intact and functional form of the IR. We found that IRs are secreted into the incubation medium by four cell lines (IM-9 human lymphoblasts, MCF-7 human breast cancer cells, HepG2 human hepatoma cells, and 3T3 mouse fibroblasts transfected with human IRs). IR secretion was further characterized in IM-9 cells. IR release was time, temperature, and energy dependent, and enhanced by incubation with insulin. The dilution slope of secreted IRs in a specific IR RIA was parallel to that produced by highly purified human placenta IRs. Ligand binding studies revealed that secreted receptors bound insulin with high affinity, and the Scatchard analysis revealed two orders of binding sites (the high affinity site had a dissociation constant of 0.32 +/- 0.08 nM). Analysis of secreted receptors by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a molecular size of 135 kilodaltons for the alpha-subunit and 95 kilodaltons for the beta-subunit. Other experiments indicated that the beta-subunit tyrosine kinase activity of the secreted receptor was stimulated by insulin. These studies indicate, therefore, that a soluble, intact, and functional IR is secreted by cultured cells, and that this soluble protein could be involved in certain insulin-mediated functions, such as receptor down-regulation.
3T3 Cells↗
Insulin-resistant MDA-MB231 human breast cancer cells contain a tyrosine kinase inhibiting activity.
In most human breast cancer cell lines, insulin, via its own receptor, stimulates cell growth. However, in MDA-MB231 breast cancer cells, insulin at concentration as high as 100 nM has no effect on cell growth, although insulin receptors (IRs) are overexpressed in these cells (29.1 ng IR/10(6) cells), and IR binding characteristics are similar to other breast cancer cell lines. IR tyrosine kinase activity is markedly reduced both in intact MDA-MB231 cells and in isolated IRs purified on a wheat germ agglutinin affinity column. MDA-MB231 cells contain a factor that inhibits both basal and insulin-stimulated IR tyrosine kinase activity in a concentration-dependent manner. This inhibitory activity copurifies with the IR on insulin-Sepharose affinity chromatography and is also effective against the tyrosine kinase activity of the IR-related insulin-like growth factor-I receptor and the oncoprotein v-abl but is ineffective against c-src tyrosine kinase activity. It is possible, therefore, that this tyrosine kinase inhibitor plays a role in regulating the mitogenic potential of the IR in some human breast cancers.
Breast Neoplasms↗
Glucose modulates glucose transporter affinity, glucokinase activity, and secretory response in rat pancreatic beta-cells.
Pancreatic islets were cultured for 24 h in medium containing either low (1.4), normal (5.5), or high (16.7 mM) glucose, and then insulin secretion was measured at the end of 1 h incubation at 37 degrees C. Insulin release in the absence of glucose was 64 +/- 20, 152 +/- 11, and 284 +/- 30 pg.islet-1.h-1 (mean +/- SE, n = 6, G1.4 and G16.7 vs. G.5.5, P < 0.05) and the response to 22 mM glucose stimulation was 640 +/- 136, 2460 +/- 276, and 1890 +/- 172 pg.islet-1.h-1, respectively (n = 6, G1.4 vs. G5.5, P < 0.01, G16.7 vs. G5.5, P = 0.065). The 50% maximal response of insulin secretion (increment over baseline) was reached at an average glucose concentration of 9.9 +/- 0.7 mM in islets preexposed to G5.5, and at glucose 13.3 +/- 0.9 and 4.8 +/- 0.4 mM (P < 0.05 in respect to G5.5) in islets preexposed to G1.4 and G16.7, respectively. To investigate the molecular mechanism responsible for this altered glucose sensitivity, we measured, in parallel experiments, the kinetic characteristics of glucose transport, glucokinase, and glucose utilization. Glucose transport was measured by evaluating 3-O-methylglucose uptake. The apparent Km of the low-affinity transporter (GLUT2) was 16.6 +/- 2.4 mM in isolated pancreatic cells cultured at 5.5 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
3-O-Methylglucose↗
[Physiopathology of the autonomous thyroid nodule].
"Autonomous" thyroid nodule is a localized nodular lesion of the thyroid gland characterized by growth, iodine uptake and function, all independent from TSH control. These nodules represent a heterogeneous anatomic and clinical entity. The clinical diagnosis is based upon a negative suppression of nodule iodine uptake and scan imaging by T3 administration. The nodule function is determined by high serum thyroid hormone levels and/or low TSH (measured by ultrasensitive assay). Etiology and pathogenesis of these nodules is not yet completely clarified. Both genetic and environmental factors determine nodule growth and function: thyroid cells, in fact, are genetically heterogeneous and may have intrinsic (congenital) characteristics that may promote the growth of cellular clones having mitotic and functional activity that is partially independent of TSH. In these particular cell clones, environmental factors like iodine deficiency or other goitrogens may favour the growth of autonomous nodules and also, by activating their function, may induce toxicity. The autonomous thyroid nodules need to be treated only when they become toxic: in this case both surgical excision or radioiodine may be used.
Humans↗