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Biomedical subjects

B L Wajchenberg

Publications and source records attributed to B L Wajchenberg.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effect of metformin on insulin-stimulated tyrosine kinase activity of erythrocytes from obese women with normal glucose tolerance.

The purpose of this study was to document the possible effect of solubilised erythrocytes on insulin-receptor binding and tyrosine kinase activity after 12 weeks of metformin administration to 13 healthy obese women with no history of diabetes and normal glucose as evaluated by conventional criteria. Subjects were given metformin 850 mg twice a day for 12 weeks. The results showed that plasma glucose response to an oral glucose challenge did not change following metformin, but that insulin response was significantly lower (p < 0.0001). In addition, both the number of insulin receptors and the tyrosine kinase activity per receptor of solubilised erythrocytes were significantly greater following metformin administration. Since both body weight and plasma glucose concentrations were similar before and after treatment, the effect of metformin on insulin-receptor binding and tyrosine kinase activity appeared to be independent of either of these variables. In summary, oral administration of metformin led to an increase in tyrosine kinase activity or erythrocyte insulin receptors, suggesting that such action occurs in the absence of any significant change in plasma glucose concentration.

Adult↗
PubMed1996

Growth hormone axis in cushing's syndrome.

All levels of the growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor (IGF) and IGF binding protein (IGFBP) axis are influenced by chronic hypercortisolism. Thus, there is a blunted response to GHRH alone or together with other stimuli associated with a marked suppression of endogenous GH secretion but accompanied by normal GHBP, normal to low IGF-1 and GHBPs 1 and 3 with the correspondent 41.5 and 38.5-kD molecular forms of the latter presenting values similar to normal. These findings may suggest enhanced GH sensitivity with normal or increased IGF-1 bioavailability to the correspondent tissue receptors. In conclusion, the glucocorticoid (GC)-induced target tissue resistance can neither be attributed to the suppression of the GH axis nor to changes in circulating GHBPs 1 and 3. However, it may be related either to the described 12-to-20-kD inhibitor(s) which antagonizes postbinding IGF-1 bioactivity (gene expression) and/or by the downmodulation of activator protein-1 (Fos/Jun) activity by the GC-GC receptor complex.

Carrier Proteins↗
PubMed1996

Pulsatile release and circadian rhythms of thyrotropin and prolactin in children with growth hormone deficiency.

We have measured mean concentrations and have appraised the pulsatile nature of thyrotropin (TSH) and prolactin (PRL) release in children with classical GH deficiency (GHD; n = 4) and neurosecretory GH dysfunction (NSD; n = 4) and have compared the results with those obtained in children with constitutional delay (control; n = 4). Blood samples were obtained at 20-min intervals for 24 h. Pulse analysis of TSH and PRL was undertaken using the Cluster pulse detection algorithm. Circadian rhythmicity of TSH and PRL was assessed using cosinor analysis. The mean 24-h concentration of GH in the control subjects was significantly higher than that obtained in the GHD and NSD groups. With regard to TSH, the mean serum concentration in the GHD and NSD group were higher than that of the control subjects. This augmentation reflects TSH pulses of large amplitude and area, and a higher interpulse valley mean rather than a difference in peak number or peak duration. No differences in mean PRL concentration or characteristics of PRL pulses were found between the control and GHD and NSD subjects. When the 24 h data sets were divided into day (0800-2000 h) and night (2000-0800 h), the mean nighttime TSH concentration was higher than the daytime concentration in the control, GHD, and NSD groups. Although there were no day versus night differences in TSH pulse frequency in either group, peak amplitude, area, and interpulse valley means were increased during the night in the control group, and peak area, duration, and amplitude mean in the NSD group. The nighttime mean PRL concentrations in the control, GHD, and NSD subjects were higher than those found during the day. This increase was accounted for by increases in PRL peak amplitude, area in the control group, and peak area, amplitude, and interpulse valley mean in the GHD and NSD groups. Cosinor analysis of the 24-h TSH and PRL data revealed clear circadian rhythmicity in all groups of subjects. These data suggest that GHD and NSD are associated with an increase in pulsatile TSH secretion due to an increase in pulse amplitude and interpulse valley mean.

Adolescent↗
PubMed1996

Metabolic effects of dietary sucrose and fructose in type II diabetic subjects.

OBJECTIVE: To investigate the metabolic effects of dietary fructose and sucrose in type II diabetic patients. RESEARCH DESIGN AND METHODS: Sixteen well-controlled type II diabetic subjects were fed three isocaloric diets for 28 days each. The three diets provided 50-55, 15, and 30-35% of total energy from carbohydrate, protein, and fat, respectively. In one diet, 20% of total calories were derived from fructose; in another, 19% of total calories were derived from sucrose; and in the control diet, only 5% of daily calories were derived from sugars, all other carbohydrates being supplied as polysaccharides. RESULTS: No significant differences were observed between either the fructose or the sucrose diet and the control polysaccharide diet in any of the measures of glycemic control, serum lipid levels, or insulin and C-peptide secretion. CONCLUSIONS: Our data suggest that in the short and middle terms, high fructose and sucrose diets do not adversely affect glycemia, lipemia, or insulin and C-peptide secretion in well-controlled type II diabetic subjects.

Adult↗
PubMed1995

The effects of spironolactone on testosterone fractions and sex-hormone binding globulin binding capacity in hirsute women.

This study explored the effect of the anti-androgen spironolactone on sex-hormone binding globulin (SHBG) and the distribution of circulating testosterone (T) into various free and bound fractions in seven women with hirsutism assessed before and then monthly for three months on a regimen of spironolactone, 100 mg bid as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgen parameters and serum T fractions studies. None of the women were judged obese based upon body mass index values. After three months of spironolactone therapy, there was little change in the hirsutism index, and measurement of serum T, androstenedione, DHEA-S and 17 beta-estradiol showed no significant changes, the same occurring with SHBG-binding capacity. However, there was a shift in the distribution of circulating T, with a decrease in SHBG-bound T and an increase in albumin-bound and free T (non-SHBG-bound fractions). As previous reports suggest that non-SHBG-bound fractions represent bioavailable fractions, the current data suggests that T fraction studies may not be clinically useful parameters of hyperandrogenism in women receiving antiandrogen therapy.

Adolescent↗
PubMed1995

Erythrocyte insulin-like growth factor-I receptor evaluation in normal subjects, acromegalics, and growth hormone-deficient and insulin-dependent diabetic children.

Insulin-like growth factor-I (IGF-I) receptors are characterized in several animal and human tissues. IGF-I receptor studies performed in erythrocytes to assess IGF-I receptor status at target-cell tissues are potentially useful for clinical studies, since tissue biopsies or cultures are not required. However, validation of results is challenged by some investigators on the basis of discrepancies described in comparative studies with other cell types, probably related to populations of different cell ages affecting binding to red blood cells (RBCs). By correcting cell age for creatine, we studied IGF-I receptor status in 24 normal subjects (11 adults and 13 children, eight prepubertal and five pubertal) and 33 patients with pathologic conditions (five adult acromegalics, six children with pituitary dwarfism, and 22 type I diabetic children, 15 prepubertal and seven pubertal). Acromegalic patients with higher plasma IGF-I and insulin levels presented lower IGF-I specific binding ([Bo] mean +/- SEM, 6.1% +/- 0.8%) and affinity ([ED50] 28.5 +/- 2.2 ng/mL) than normal adults (Bo, 10.9% +/- 0.7%; ED50, 16.4 +/- 0.9 ng/mL; P < .001), and growth hormone (GH)-deficient children showed higher IGF-I binding 24.6% +/- 1.7%, P < .001) without significant affinity alterations than normal prepubertal children (Bo, 14.7% +/- 1.0%). Both prepubertal and pubertal type I diabetic children with higher GH levels presented decreased IGF-I binding (11.4% +/- 0.9% for prepubertal, P < .05; 10.0% +/- 1.1% for pubertal, P < .05) to RBC receptors in comparison to the respective control group (14.7% +/- 10% and 14.9% +/- 1.3%, prepubertal and pubertal, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1995

Ectopic ACTH syndrome.

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

Adrenal Glands↗
PubMed1995

A 138-nucleotide deletion in the thyroglobulin ribonucleic acid messenger in a congenital goiter with defective thyroglobulin synthesis.

Two siblings (HSN and AcSN) with congenital goitrous hypothyroidism were investigated in terms of clinical, biochemical, and molecular biology. Diagnosis of defective thyroglobulin (Tg) was based on findings of low serum T4, low normal or normal serum T3, a negative percholate discharge test, and the virtual absence of the serum Tg response to challenge by bovine TSH. Only minute amounts of Tg-related antigens were detected by RIA in the goitrous tissue (HSN, 0.82 mg/g, compared to 70-90 mg/g in normal thyroid tissue), as confirmed by sodium dodecyl sulfate-agarose gel electrophoresis that indicated the virtual absence of Tg. The Tg messenger ribonucleic acids (mRNAs) from controls and HSN thyroid tissue were first reverse transcribed and then divided into several portions from positions 57-8448; the resulting complementary DNAs were, in turn, amplified by reverse polymerase chain reaction. The amplification of nucleotides 5165-6048 from control thyroid tissue Tg mRNA showed a fragment of 884 base pairs (bp). In contrast, the fragment present in the HSN was +/- 750 bp and lacked the normal fragment. The sequencing of the smaller fragment revealed that 138 bp were missing between positions 5590-5727 of the HSN Tg mRNA. This deletion does not affect the reading frame of the resulting mRNA and is potentially fully translatable into a Tg polypeptide chain that is shorter by 46 residues. A cysteine residue is maintained by the junction between the proximal T from leucine 1831 and the distal GT from cysteine 1877. DNA genomic polymerase chain reaction amplification excludes a deletion in the Tg gene and indicates that the deleted 138-nucleotide sequences lie in the same exon. The functional consequences of the deletion are not entirely clear, but it is conceivable that the excision of this segment of the Tg molecule could affect the protein structure, resulting in its premature degradation, very low colloid storage, and diminished thyroid hormone production rate.

Adult↗
PubMed1995

Growth hormone pulsatility in active and cured acromegalic subjects.

GH secretion in normal subjects is periodic, with pulses prevailing during sleep. During the day (basal secretion), GH levels are, in general, undetectable. We studied GH secretion by cluster analysis, collecting samples every 20 min for 24 h in 44 subjects: 11 patients with active acromegaly; 16 "cured" acromegalics, and 17 normal subjects. The purpose of this study was to compare GH secretion between patients with active acromegaly and "cured" patients and between "cured" acromegalic patients and normal controls. The number of pulses detected through the 24-h GH profile was not different between acromegalic patients regardless of disease activity (17.5 +/- 4.4 vs. 15.0 +/- 6.0, respectively), but was different when active acromegalic patients and normal controls were compared (8.1 +/- 1.0; P < 0.05) and when cured acromegalic patients and normal controls were compared (P < 0.05). The GH pulsatile secretion/total GH secretion ratio was higher in normal controls than in acromegalic patients regardless of disease activity. We concluded that 1) the increases in GH pulsatility in active and cured acromegalic patients are similar, but most of the 24-h GH secretion is nonpulsatile; 2) half of the GH secretion in normal subjects occurs during pulses; 3) cured acromegalic patients, even those with normal GH and insulin-like growth factor I levels, do not recover a normal GH secretory pattern.

Acromegaly↗
PubMed1995

No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms.

The mechanism(s) of tumorigenesis for the majority of adrenocortical neoplasms remain unknown. G-Protein-coupled receptors were recently proposed as candidate protooncogenes. That activating mutations of this class of receptors might be important for tumor induction or progression of endocrine neoplasms was strengthened by the recent identification of such mutations in hyperfunctioning thyroid adenomas. To examine whether the ACTH receptor (ACTH-R) gene could be an oncogene in human adrenocortical tumors, we amplified by the polymerase chain reaction and directly sequenced the entire exon of the ACTH-R gene in 25 adrenocortical tumors (17 adenomas and 8 carcinomas) and 2 adrenocortical cancer cell lines. We found no missense point mutations or even silent polymorphisms in any of the tumors and cell lines studied. We conclude that activating mutations of the ACTH-R gene do not represent a frequent mechanism of human adrenocortical tumorigenesis.

Adolescent↗
PubMed1995

A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty.

Familial male-limited precocious puberty (FMPP) is an autosomal dominant gonadotropin-independent disorder. Affected males generally develop signs of precocious puberty in early childhood. They typically show Leydig cell hyperplasia and increased testosterone production typical for their age, whereas circulating LH concentrations remain prepubertal. Several dominant point mutations of the LH receptor gene were identified in pedigrees with familial male-limited precocious puberty and were shown to cosegregate with the disease. Here we report a novel heterozygote point mutation in the LH receptor gene of a Brazilian boy with gonadotropin-independent precocious puberty. This mutation substitutes alanine 568 with valine at the carboxyterminus of the third cytosolic loop of the LH receptor. The unoccupied mutant receptors confer constitutive activation of adenyl cyclase activity when expressed in COS-7 cells, resulting in 4-fold higher cAMP concentrations over baseline compared with cells expressing an equivalent number of wild-type receptors. The affinity of the mutant receptors to 125I-labeled human LH was not altered compared with the wild type. Mutations of the homologue alanine residue in the alpha 1-adrenergic (in vitro), FSH (in vitro), and TSH (naturally occurring) receptors also result in constitutive adenyl cyclase activation, suggesting that this alanine residue is crucial for signal transduction and a potential site for upregulatory/oncogenic mutations in G-protein coupled receptors.

Alanine↗
PubMed1995

Estimation of body fat and lean tissue distribution by dual energy X-ray absorptiometry and abdominal body fat evaluation by computed tomography in Cushing's disease.

Body composition determined by dual energy x-ray absorptiometry and the abdominal visceral fat component determined by computed tomographic scanning were examined in women with Cushing's disease and compared with those in obese women with the same anthropometric parameters and those in nonobese women. Patients with Cushing's had no increase in total body fat or the trunk region (android) component, but had a higher intraabdominal fat area compared to the obese subjects. The total lean tissue mass was slightly reduced in Cushing's compared to that in the obese subjects due to a significant decrease in the muscle of the legs and arms; the reduced amounts of fat and lean tissue masses in the arms were the most significant findings in hypercortisolism. The body mineral and bone calcium contents were slightly reduced in Cushing's compared to those in the obese controls. Thus, although obese subjects had more fat and lean tissue and mineral masses than their normal weight counterparts, the Cushing's patients, with the same total fat mass and its components (except in the arms) as obese individuals, present total lean tissue and fractions, including body mineral and bone calcium contents, similar to those in nonobese subjects due to the depletion of the protein depots, as seen in hypercortisolism.

Absorptiometry, Photon↗
PubMed1994

The effect of hypocaloric diet with and without D-fenfluramine treatment on growth hormone release after growth hormone-releasing factor stimulation in patients with android obesity.

Basal and stimulated growth hormone (GH) secretions are impaired in obesity, and partial restoration of the GH response to various stimuli is observed after weight loss. The aim of the present study was to investigate whether D-fenfluramine, a serotoninergic agent, would increase the GH response to growth hormone-releasing factor (GRF) as compared with placebo in obese android patients. The subjects were 17 patients with android obesity (four men and 13 women) aged 21 to 58 years with a body mass index (BMI) ranging from 32.0 to 52.2 kg/m2 and an abdominal-gluteal ratio greater than 1.0. The following four GRF (1-44) tests were performed: T-30 (control), T0 (after 30 days of a hypocaloric diet), T1 (after 30 days of either placebo or D-fenfluramine 15 mg twice daily), and T2 (after 30 additional days of placebo or D-fenfluramine). The hypocaloric diet was maintained during the T1 and T2 periods. At each test, the serum GH response to GRF was measured at frequent intervals, and the peak GH response and the GH area under the curve were calculated. Serum insulin concentrations were also assayed before GRF stimulation, and the insulin to GH ratio was obtained. The D-fenfluramine-treated group had a mean +/- SEM GH peak level after GRF significantly higher at T1 (43.3 +/- 8.2 micrograms/L) and T2 (50.9 +/- 9.2 micrograms/L) compared with the placebo group. Likewise, the mean integrated areas of GH response were significantly higher for the D-fenfluramine-treated group as compared with the placebo group at both T1 and T2 of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin-receptor tyrosine kinase activity is decreased in erythrocytes from non-obese patients with NIDDM.

We have examined insulin binding, and insulin receptor associated tyrosine kinase activity in detergent solubilized and Ricin II-agarose purified receptor preparations from erythrocytes of obese and non-obese subjects with normal glucose tolerance and non-obese patients with NIDDM. Insulin receptor activity, as assessed by [125I Tyr A14] insulin binding, was significantly lower in erythrocyte preparations from the obese group when compared with similar preparations from non-obese subjects, with either normal glucose tolerance or NIDDM. The affinity of the receptor for insulin, however, was reduced in both obese subjects and patients with NIDDM as compared to non-obese subjects with normal glucose tolerance. Insulin receptor tyrosine kinase activity, measured in the absence (basal) and presence of insulin (0.3-3000 nM), was decreased in obese and NIDDM subjects with normal glucose tolerance and in patients with NIDDM. Insulin sensitivity, measured as the dose of insulin required for half-maximal activation of kinase activity, however, was comparable among three groups. In contrast, insulin-stimulated tyrosine kinase activity, when normalized to insulin binding activity, was unchanged in both non-obese and obese subjects with normal glucose tolerance, but was reduced approximately 60% in the NIDDM group. These findings indicate that the functional behavior of insulin receptor-kinase signaling system is markedly impaired in non-obese patients with NIDDM. Furthermore, the insulin receptor-tyrosine kinase defect (i.e. decrease in activity) observed in patients with NIDDM is probably related to a reduction in coupling efficiency between insulin binding and the activation of the receptor tyrosine kinase activity.

Adult↗
PubMed1994

Calcium and prolactin secretion in humans: effects of the channel blocker, verapamil, in the spontaneous and drug-induced hyperprolactinemia.

The effects of the intravenous administration of a calcium channel blocker, verapamil (0.0833 mg/min for 2-3 h after a 5 mg bolus) on prolactin (PRL) and thyrotropin (TSH) circulating levels were assessed in 7 normal subjects and in 17 patients with hyperprolactinemia (11 with prolactinoma and 6 sulpriride-induced). In the normal group a non-significant increase in PRL levels occurred (mean +/- SEM = 11.7 +/- 2.9 micrograms/l verapamil vs. 8.5 +/- 1.4 micrograms/l saline). In this control group the peak response of PRL and TSH to TRH (thyrotrophin releasing hormone) during verapamil or saline was also determined: PRL = 112.0 +/- 27.0 micrograms/l on verapamil vs. 53.6 micrograms/l on saline, p = 0.02; TSH 7.1 +/- 0.7 microU/l on verapamil vs. 9.0 +/- 0.6 mU/l on saline, p = 0.01. In the hyperprolactinemic subjects verapamil induced opposite effects on PRL levels, the prolactinoma group exhibiting an increase in the mean values (168.5 +/- 22.3 micrograms/l vs. 150.8 +/- 23.6 micrograms/l on saline, p = 0.04) whereas in the sulpiride-induced there was a reduction in the mean PRL levels (61.1 +/- 13.8 micrograms/l vs. 78.5 +/- 19.3 micrograms/l on saline, p = 0.002). In both groups of hyperprolactinemic patients no effects on TSH levels were observed. The authors discuss the possibility that the divergent effects of verapamil in hyperprolactinemia of different etiologies could be related to the balance between dopamine and calcium channel effects on hypothalamus and/or pituitary.

Adult↗
PubMed1994

Calcium-dependent protein kinase-C activity in human adrenocortical neoplasms, hyperplastic adrenals, and normal adrenocortical tissue.

The calcium- and phospholipid-dependent protein kinase-C (PKC) is a critical enzyme of cellular signal transduction. In this report we studied calcium-dependent total PKC activity in eight adrenocortical carcinomas (group 1), nine adrenocortical adenomas (group 2), six hyperplasias (group 3), and five human normal adrenal tissues (group 4). The PKC activity assay was based on phosphorylation of a specific synthetic peptide from myelin basic protein. The specificity of the assay was confirmed by using an inhibitor peptide common to alpha-, beta-, and gamma-isoenzymes of PKC. The median value in group 1 was 1.15 pmol 32P/min.micrograms protein (range, 0.55-2.19), that in group 2 was 1.2 (range, 0.74-2.7), that in group 3 was 0.915 (range, 0.6-1.7), and that in group 4 was 1.22 (range, 0.6-3.95). The calcium-dependent total PKC activity was similar in the four groups studied. We did not find any correlation between urinary total cortisol, serum cortisol, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, aldosterone, and estradiol concentrations and PKC activity. These findings suggest that the calcium-dependent PKC activity is not elevated in adrenocortical tumors and is not a useful marker of adrenocortical malignancy.

Adolescent↗