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Biomedical subjects

R Vigneri

Publications and source records attributed to R Vigneri.

At least 109 records · Page 6Linked to original sources
PubMed1991

Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addition of either metformin or bed-time NPH insulin to glyburide.

In this study we compared, in 12 NIDDM patients with secondary failure to glyburide, the effect of adding either a single, low-dose bed time NPH insulin injection (0.2 U/Kg) or an oral metformin administration (500 mg x 3) to the previously ineffective sulfonylurea treatment. The addition of both insulin and metformin treatment significantly improved fasting plasma glucose, post-prandial plasma glucose and %HbA1. The effect of both combined therapies was already evident and maximal after 2 weeks of treatment. The addition of bed-time NPH insulin caused a greater decrease of fasting plasma glucose, although the difference with the addition of metformin was not significant. In contrast, the average post-prandial plasma glucose decrease was significantly greater after metformin addition. The addition of bed-time NPH insulin caused a significant increase in average body weight, while after metformin addition, average body weight was unchanged; no change in the average cholesterol and triglyceride level was observed after either combined therapies.

Adult↗
PubMed1990

Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells.

The effects of progesterone on the growth of breast carcinoma cells are undefined. In the present study we investigated the effect of progestins on insulin receptor gene expression and insulin action in human breast cancer cells. Treatment of T47D cells with the synthetic progestin R5020 induced a time- and dose-dependent increase in insulin receptor content as measured by both ligand-binding studies and radioimmunoassay. Binding was half-maximally stimulated at 300 pM R5020 and maximal levels were reached after 4 days of treatment. Progesterone was 10-fold less potent than R5020. Cortisol had no effect on insulin receptor levels, while 17 beta-estradiol and dihydrotestosterone had minimal effects. Progestin treatment both increased insulin receptor mRNA levels and altered the relative distribution of the multiple insulin receptor mRNA transcripts. In order to study the functional significance of the increased insulin receptor levels, we incubated T47D cells with progesterone and then treated them with insulin. Insulin alone had a small effect on cell growth; however, the effect of insulin was markedly potentiated by progesterone treatment. These studies in breast cancer cells demonstrate, therefore, that insulin receptor gene expression is under the regulation of progestins and raise the possibility that progestin-insulin interactions may regulate breast cancer cell growth in vivo.

Antibodies, Monoclonal↗
PubMed1990

Elevated insulin receptor content in human breast cancer.

The growth of breast cancer cells is under the regulation of hormones, growth factors, and their receptors. In the present study, we have employed a new, sensitive, and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0.95 + 0.68, P less than 0.001) and in six normal specimens obtained from reduction mammoplasty (0.84 +/- 0.78, P less than 0.001). The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino, V., V. Papa, V. Trischitta, A. Brunetti, P.A. Goodman, M.K. Treutelaar, J.A. Williams, B.A. Maddux, R. Vigneri, and I.D. Goldfine, 1989. Am. J. Physiol. 257:E451-457). The insulin receptor in breast cancer retained its ability to both bind insulin and undergo insulin-induced tyrosine kinase activation. Immunostaining of the specimens revealed that the insulin receptor was present in malignant epithelial cells, but was not detected in stromal and inflammatory cells. Univariant analysis revealed that the insulin receptor content of the tumors correlated positively with tumor size (P = 0.014), histological grading (P = 0.030), and the estrogen receptor content (P = 0.035). There were no significant correlations between insulin receptor content and the age, body weight, menopausal status, and nodal involvement of the patients. These studies indicate, therefore, that the insulin receptor content is increased in breast cancers and raise the possibility that the insulin receptor may have a role in the biology of these tumors.

Binding, Competitive↗
PubMed1990

Increased aggressiveness of thyroid cancer in patients with Graves' disease.

To evaluate whether coexistence of Graves' disease affects the prognosis of thyroid cancer we examined the clinical and pathological characteristics of 22 differentiated thyroid carcinomas concomitant with hyperthyroidism; 13 were associated with Graves' disease, and 9 with autonomous thyroid nodules. Carcinomas were identified in a consecutive series of 359 hyperthyroid patients (132 with Graves' disease and 227 with autonomous thyroid nodules) who underwent surgery during a 6-yr period. One hundred and thirty-seven thyroid carcinomas were found in the 582 euthyroid patients operated on in the same period. In Graves' patients, carcinomas were more often multifocal (46.1% vs. 0%), locally invasive (61.5% vs. 11.1%), and metastatic to lymph nodes (61.5% vs. 11.1%) or to distant sites (23.0% vs. 0%) than in patients with autonomous thyroid nodules. In addition, carcinomas concomitant with Graves' disease were larger (3.3 +/- 1.8 vs. 1.0 +/- 0.7 cm) than the ones associated with autonomous thyroid nodules and showed a high recurrence rate. In euthyroid patients, aggressiveness of thyroid cancer was intermediate. Serum TSH levels were suppressed in all hyperthyroid patients with thyroid cancer. However, circulating thyroid-stimulating antibodies were present in 12 of 13 cancer patients with Graves' disease, but were absent in patients with autonomous thyroid nodules. Our study suggests, therefore, that TSAb may play a role in determining the high aggressiveness of thyroid cancer in Graves' disease patients and indicates that a vigorous treatment should be pursued in this subgroup of patients.

Graves Disease↗
PubMed1990

Chronic exposure to high glucose and impairment of K(+)-channel function in perifused rat pancreatic islets.

Prolonged exposure to high glucose levels impairs the ability of pancreatic islets to secrete insulin as a response to that stimulus. Because glucose, like other insulin secretagogues, elicits insulin secretion by inhibiting the ATP-sensitive K+ channels, in this study, we investigated the effect of prolonged (24-h) exposure of rat pancreatic islets to high (16.7 mM) glucose concentration on 86Rb efflux (used as a tracer for K+). The data obtained indicate that islets exposed to high glucose concentration have impaired function of the glucose-sensitive K+ channel, this phenomenon is temporarily related to a defective response of glucose-induced insulin release, and these alterations are reversible.

Adenosine Triphosphate↗
PubMed1990

Improvement with metformin in insulin internalization and processing in monocytes from NIDDM patients.

This study investigated the relative effect of obesity alone and in combination with non-insulin-dependent diabetes mellitus (NIDDM) on the intracellular processing of insulin and evaluated the effect of metformin therapy on this process. Monocytes from 11 obese hyperinsulinemic subjects, 13 obese hyperinsulinemic NIDDM patients, and 7 nondiabetic control subjects were incubated with A14-125I-labeled insulin for 60 min at 37 degrees C, and intracellular insulin degradation was characterized by high-performance liquid chromatography. Total cell-associated insulin (insulin binding) and internalized and degraded insulin were decreased in obese subjects and significantly decreased in obese NIDDM patients compared with nondiabetic control subjects. In NIDDM patients, intracellular insulin degradation was inversely correlated with fasting plasma glucose (P less than 0.01). Eight obese subjects and 9 obese NIDDM patients were restudied after 4 wk of therapy with metformin (850 mg twice a day). Plasma levels of the drug were superimposable in the two groups. Metformin therapy did not change glucose and insulin levels in obese subjects but caused a decrease in blood glucose in obese NIDDM patients. Total cell-associated radioactivity (insulin binding) significantly increased in both groups (P less than 0.01). On the contrary, internalized radioactivity increased (0.83 +/- 0.3 vs. 1.31 +/- 0.35%, P less than 0.01), and similarly, insulin degradation was enhanced (54.6 +/- 8.9 vs. 74.22 +/- 9.15%, P less than 0.01) only in monocytes from obese NIDDM patients. However, the levels of these parameters were still lower than in control subjects (internalization, 2.94 +/- 0.68%; degradation, 93.03 +/- 3.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1989

Endocytosis, recycling, and degradation of the insulin receptor. Studies with monoclonal antireceptor antibodies that do not activate receptor kinase.

The endocytosis, recycling, and degradation of the insulin receptor were studied in IM-9 cells and U-937 cells by employing two monoclonal antibodies directed at the alpha subunit of the human insulin receptor, antibodies MA-5 and MA-10. Antibody MA-5 is an insulin agonist and MA-10 is an insulin antagonist (Forsayeth, J., Caro, J.F., Sinha, M.K., Maddux, B.A., and Goldfine, I.D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3448-3451). Both monoclonal antibodies, like insulin, induced the endocytosis of the insulin receptor within 15 min. Upon removal of extracellular ligand the internalized receptor recycled to the cell surface. At this time there was no degradation of the receptor as measured by a sensitive insulin receptor radioimmunoassay. After 20 h of incubation, insulin and MA-5, but not MA-10, induced significant receptor degradation as measured by both insulin receptor radioimmunoassay and metabolic labeling studies. These studies demonstrated, therefore, that: 1) internalization and recycling of the receptor can be induced by antireceptor monoclonal antibodies that are either insulin agonists or insulin antagonists; 2) enhanced receptor degradation can be induced by monoclonal antibodies that are insulin agonists; and 3) the process of receptor internalization does not necessarily lead to enhanced receptor degradation. Since prior studies have indicated that neither MA-5 nor MA-10 enhance insulin receptor kinase activity, the present studies also suggest that insulin receptor endocytosis and degradation induced by ligands different than insulin can occur without activation of this process.

Antibodies, Monoclonal↗
PubMed1989

Human insulin receptor radioimmunoassay: applicability to insulin-resistant states.

A radioimmunoassay of the human insulin receptor was developed employing a potent rabbit polyclonal antibody to the human insulin receptor and a highly purified human placental insulin receptor preparation. The receptor, obtained by sequential affinity chromatography with insulin receptor monoclonal antibody-agarose and wheat germ agglutinin-agarose, was radiolabeled with 125I-Bolton-Hunter reagent at specific activities of 2,100-3,300 Ci/mmol. Over 75% of this ligand was immunoprecipitable with the polyclonal antireceptor antibody and remained immunoprecipitable for greater than 45 days. The assay was sensitive to unlabeled receptor concentrations as low as 0.2 ng/0.5 ml; unlabeled insulin did not cross-react and unlabeled insulin-like growth factor (IGF)-I receptor cross-reacted weakly. The radioimmunoassay was applicable to the measurement of insulin receptors in tissues and cells that were extracted by solubilization in 1% Triton X-100; no purification of the extracted receptor was necessary. Of the three major target tissues for insulin action studied, liver had the highest concentration of receptors (47.6 ng/mg protein); fat and muscle had lower levels. Other studies with the radioimmunoassay indicated that insulin receptors were decreased both in monocytes from obese hyperinsulinemic subjects and in fibroblasts from patients with leprechaunism.

Female↗
PubMed1989

High frequency of cancer in cold thyroid nodules occurring at young age.

In order to evaluate the risk of malignancy of cold thyroid nodules occurring in young as compared with adult patients, we studied a consecutive series of 2327 patients with a solitary cold thyroid nodule over a 6-year period. None of these patients had been previously irradiated in the neck or head. Fine needle aspiration of the nodule and cytologic examination were carried out in all patients and, on the basis of this evaluation and clinical examination 391 patients were selected for surgery; 109 patients were 4-20 years old and 2218 patients were older than 20 years. Malignancy was found in 11 (10.1%) and in 112 (5.0%) of cold thyroid nodules occurring in young and adult patients, respectively. The annual incidence of cold thyroid nodules in the population of the area studied was 5.2 vs 55.9 (per 10(5) inhabitants) in the young and in the adult group, respectively, and the annual incidence of thyroid cancer was 0.53 vs 2.82 (per 10(5) inhabitants) in the young and in the adult patients, respectively. The present study indicates, therefore, that in the absence of head or neck irradiation, cold thyroid nodules are much less frequent in young age, but that the malignancy rate of cold nodules occurring in young patients is 2-fold higher than in adults patients.

Adolescent↗
PubMed1989

Effects of high glucose on insulin secretion by isolated rat islets and purified beta-cells and possible role of glycosylation.

We investigated the effect of 24 h of exposure to various glucose concentrations on insulin secretion by isolated rat pancreatic islets and purified rat beta-cells. Compared with islets cultured with standard medium (5.5 mM glucose), islets cultured with 16.7 mM glucose showed a higher basal insulin release (means +/- SE, 3.0 +/- 0.5 vs. 0.7 +/- 0.2%, n = 8, P less than .005) and reduced glucose-stimulated insulin secretion (2.4 +/- 0.3 vs. 5.8 +/- 0.4%, n = 8, P less than .005). Similar results were also obtained with purified beta-cells. The effect of high glucose was time dependent (present after 12 h, maximal after 24 h) and reversible: when islets cultured with high glucose were transferred to standard medium, normal responsiveness to glucose was restored within 8 h and normal basal release within 24 h. Mannitol, 3-O-methylglucose, and 2-deoxyglucose were not able to mimic the effects of glucose. Islets or purified beta-cells cultured in the presence of high glucose had a normal response when stimulated with glyburide, dibutyryl cyclic AMP, and isobutylmethylxanthine. Tunicamycin, an inhibitor of N-terminal glycosylation, prevented glucose-induced desensitization when added during 24 h of islet culture with 16.7 mM glucose. Swainsonine, another agent that influences glycosylation, had a similar effect. Our study indicates 1) that 24 h of exposure to high glucose induces a specific and reversible impairment of insulin secretion in response to glucose, 2) that this is a direct effect of glucose on beta-cells, and 3) that islet glucose metabolism and glycosylation processes may play a critical role in determining glucose desensitization.

Animals↗
PubMed1989

Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients.

We investigated intracellular processing of the insulin-receptor complex in monocytes from 12 healthy control subjects, 11 obese nondiabetic subjects, and 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM) by measuring receptor internalization, recovery of cell-surface insulin binding after receptor internalization, and the release of intracellular intact insulin (insulin retroendocytosis). When monocytes from the three groups of subjects were exposed to 100 nM unlabeled insulin for 30 min at 37 degrees C, the subsequent cell-surface 125I-labeled insulin binding was reduced, but the total number of insulin receptors, measured by radioimmunoassay, was not changed. These findings indicate a redistribution of insulin receptors from the surface to the cell interior. Insulin-receptor internalization was significantly lower in monocytes of obese NIDDM patients (mean +/- SE 17.8 +/- 4.7%) than in obese subjects and healthy control subjects (33.5 +/- 4.5%, P less than .05, and 34.4 +/- 3.7%, P less than .02, respectively). Moreover, in downregulated cells, a complete recovery of the initial insulin binding was observed in control subjects but not in obese NIDDM patients or obese nondiabetic subjects. The release of internalized insulin was also reduced in obese NIDDM patients and obese subjects (t 1/2 = 49.0 +/- 2.4 min, P less than .02; 47.4 +/- 5.7 min, P less than .05; and 32.9 +/- 3.8 in NIDDM patients, obese subjects, and control subjects, respectively). In the radioactivity released from monocytes of obese subjects and obese NIDDM patients, the percentage of intact insulin was higher (P less than .05) than in control subjects, suggesting reduced intracellular insulin degradation in obese subjects and obese NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus↗
PubMed1989

Low-dose bedtime NPH insulin in treatment of secondary failure to glyburide.

Secondary failure to oral hypoglycemic agents (OHAs) is a possible outcome for non-insulin-dependent diabetes mellitus (NIDDM) patients and poses a serious therapeutic problem. In this study, we evaluated the effect of adding a single bedtime low-dose NPH insulin injection to the previous ineffective sulfonylurea therapy in 23 NIDDM patients with true secondary failure to OHAs. This treatment schedule was conducted for 3 mo by 18 patients (78%) who completed the study. In these patients, the addition of NPH insulin (0.2 +/- 0.01 IU/kg body wt) greatly decreased fasting and postprandial plasma glucose (P less than .001) and glycosylated hemoglobin (P less than .005). No weight gain was observed in any of the patients studied. Five patients dropped out: 2 patients (9%) due to insufficient compliance, 2 patients (9%) due to the multiple insulin injections required to achieve good metabolic control, and 1 patient (4%) due to recurrent hypoglycemic episodes. No correlation was observed between glucagon-stimulated C-peptide values and amelioration of metabolic control. In conclusion, most NIDDM patients with secondary failure to OHAs may be successfully treated with the addition of a single low-dose bedtime NPH insulin injection, and residual beta-cell function evaluation is not able to predict the effectiveness of the combined treatment.

C-Peptide↗
PubMed1989

Evaluation of albumin excretion rate in overnight versus 24-h urine.

This study was performed to assess whether the albumin excretion rate (AER) measured in overnight urine (N-AER) and 24-h urine (24-h AER) gives comparable results. For this reason we evaluated N-AER and 24-h AER on the same day from 35 control subjects, 57 patients with insulin-dependent diabetes mellitus (IDDM), and 63 patients with non-insulin-dependent diabetes mellitus (NIDDM). AER values obtained from the two urine collection procedures were significantly different (P less than .01), with 24-h AER approximately 30% higher than N-AER. Moreover, when the same cutoff value (20 micrograms/min) was used to define the normal range, 21% of IDDM patients and 6.3% of NIDDM patients had on the same day normal N-AER and abnormal (greater than 20 micrograms/min) 24-h AER. Although N-AER values were significantly correlated to 24-h AER values (r = 0.67, P less than .001), it was not possible to assess an N-AER value able to predict a 24-h AER value greater than 20 micrograms/min. In conclusion, N-AER and 24-h AER cannot be used as an equivalent method to establish AER.

Albuminuria↗
PubMed1988

Comparison of solubilized and purified plasma membrane and nuclear insulin receptors.

Prior studies have detected biochemical and immunological differences between insulin receptors in plasma membranes and isolated nuclei. To further investigate these receptors, they were solubilized in Triton X-100 and partially purified by wheat germ agglutinin-agarose chromatography. In these preparations, the nuclear and plasma membrane receptors had very similar pH optima (pH 8.0) and reactivities to a group of polyclonal antireceptor antibodies. Further, both membrane preparations had identical binding activities when labeled insulin was competed for by unlabeled insulin (50% inhibition at 800 pM). Next, nuclear and plasma membranes were solubilized and purified to homogeneity by wheat germ agglutinin-agarose and insulin-agarose chromatography. In both receptors, labeled insulin was covalently cross-linked to a protein of 130 kilodaltons representing the insulin receptor alpha subunit. When preparations of both receptors were incubated with insulin and then adenosine 5'-[gamma-32P]triphosphate, a protein of 95 kilodaltons representing the insulin receptor beta subunit was phosphorylated in a dose-dependent manner. These studies indicate, therefore, that solubilized plasma membrane and nuclear insulin receptors have similar structures and biochemical properties, and they suggest that they are the same (or very similar) proteins.

Adenosine Triphosphate↗
PubMed1988

Metformin enhances certain insulin actions in cultured rat hepatoma cells.

The effect of the oral antidiabetic agent metformin on insulin regulation of glycogen metabolism, tyrosine-aminotransferase activity, and [1-14C]aminoisobutyric acid uptake was studied in H4IIE cultured rat hepatoma cells. Metformin enhanced both basal (from 0.213 +/- 0.016 to 0.262 +/- 0.024 nmol/mg protein, p less than 0.01) and insulin stimulated [3H] glucose incorporation into glycogen in a time-dependent and dose-dependent manner. A small effect of metformin was seen at 1 mumol/l, and its greatest effects were obtained at 10 mumol/l. At the same concentrations, metformin did not influence basal tyrosine-aminotransferase activity but it potentiated insulin stimulated tyrosine-aminotransferase activity (+29.2 +/- 1.4%, p less than 0.01) and prevented the loss of tyrosine-aminotransferase responsiveness to insulin in H4IIE cells desensitised by a previous exposure to insulin. In contrast, metformin had no effect on basal or insulin-stimulated [1-14C]aminoisobutyric acid uptake. Over the concentrations of metformin that enhanced insulin action in H4IIE cells, the drug had no significant effect on insulin binding to its receptor. These studies suggest, therefore, that metformin may influence cellular metabolism by potentiating certain insulin actions through mechanisms that may be beyond insulin receptor binding.

Aminoisobutyric Acids↗
PubMed1988

Personality traits and mental prognosis in patients with congenital hypothyroidism not treated from early life.

Congenital hypothyroidism, if not treated in very early life, severely impairs the neuropsychological development of affected subjects. We have carried out a detailed analysis of cognitive functioning and personality traits in 18 congenital hypothyroid patients treated late and/or unproperly. Significant cognitive defects were observed, the most important being a defective learning ability and an impaired capacity to judge socially significant events and to project complex actions in a temporal perspective. A mental retardation (IQ less than 70) was observed in 8/18 (44.4%) of these patients, a moderate intellective deficit in 5/18 (27.8%) and an IQ greater than 85 in the remaining 5 patients (27.8%). These data indicate that the mental defect of congenital hypothyroid patients may be overestimated. The patients personality was characterized by dependence on the mother, worrying about their body, maladjustment and socialization problems. Since the intellective prognosis of these patients may significantly improve when the environmental conditions are optimized, social and psychological help must always be suggested.

Adolescent↗