Biomedical subjects

R S Weinstock

Publications and source records attributed to R S Weinstock.

36 records · Page 2Linked to original sources

PubMed1992

Role of protein kinase C in insulin's regulation of c-fos transcription.

One of insulin's actions is the induction of DNA synthesis and cell division, but little is known about the molecular mechanisms involved. Previous studies indicate that insulin stimulates cell division and regulates the expression of several genes in rat H4IIE (H4) hepatoma cells. One of these genes is the proto-oncogene c-fos, a cellular gene whose deregulation has been implicated in the process of cellular differentiation and division. We have shown that insulin induces transcription of the c-fos gene in H4 cells. In the present study, the phorbol ester, phorbol 12-myristate 13-acetate (PMA), stimulated c-fos transcription in a rapid and dose-dependent manner with an 800% increase in transcription following 15-30 min of addition. This increase in c-fos transcription was transitory, returning towards baseline transcription rates within 120 min. PMA stimulated the translocation of protein kinase C (PKC) from the cytoplasm to the membrane in H4 hepatoma cells, as evidenced by a 77% decrease in cytosolic PKC and a 29% increase in membrane PKC activity following 10 min of treatment. Insulin addition to H4 cells for 10 min also resulted in a 31% decrease in cytosolic PKC activity, suggesting a translocation response. When H4 cells were pretreated with PMA for 24 h, there was a decrease of 20-45% in both cytosolic and membrane PKC activity and a complete loss of PMA's induction of c-fos transcription. Thus, the cells were functionally desensitized to further PMA addition. When cells were pretreated with PMA for 24 h, the insulin-induced increase in transcription of c-fos was reduced by 50%. Western blot analysis indicated that the PKC-beta isozyme followed a translocation pattern almost identical with that of total PKC activity. These results suggest that a PMA-sensitive form of PKC is preferentially lost upon PMA pretreatment and that this PKC subtype may be necessary for insulin to fully induce c-fos gene expression.

Animals↗

PubMed1992

Short- and long-term effects of insulin on tyrosine aminotransferase gene expression.

In the present study the relationship between changes in tyrosine aminotransferase (TAT) enzyme activity, cytoplasmic mRNA levels, and gene transcription in response to both short- and long-term exposure to insulin was investigated. Insulin acutely inhibited transcription of the TAT gene by 50% in serum-deprived rat H4 hepatoma cells. Following this initial 50% decrease in transcription, there was a 2.5-fold induction in TAT activity that could not be accounted for by a concomitant increase in TAT mRNA levels. Insulin had no effect on the half-life of TAT mRNA. Insulin exposure for short periods of time also inhibited the glucocorticoid- and cAMP-induced transcription of the TAT gene. Like insulin, protein synthesis inhibitors acutely inhibited basal and glucocorticoid-induced TAT transcription. TAT activity gradually returned toward basal levels after 8 h of insulin treatment. A second insulin-induced increase in TAT activity (3.5-fold above basal levels) was observed by 24 h of insulin treatment. This second phase of insulin-induced TAT activity was associated with elevated levels of TAT transcription and TAT mRNA levels, and therefore, unlike the earlier stimulation, could be accounted for by changes in gene expression. Thus, the insulin-mediated regulation of the TAT gene in H4 cells is complex. Different transcriptional and post-transcriptional mechanisms are likely to be involved in the biphasic responses to insulin.

Animals↗

PubMed1992

Regulation of beta-actin gene transcription by insulin and phorbol esters.

Insulin and the phorbol ester, phorbol 12-myristate 13-acetate, induce beta-actin gene transcription in H4 cells. This occurred rapidly, with a maximum 15-fold stimulation following 15 min of insulin (5 x 10(-9) M) or phorbol ester (1 microgram/ml) exposure. The increase in beta-actin transcription was transitory, returning to baseline within 120 min. Pretreatment of cells with phorbol ester for 24 h, reducing functional protein kinase C activity, abolished the ability of phorbol esters to increase beta-actin transcription. When insulin was added to phorbol ester-pretreated cells the insulin-induced increase in beta-actin transcription was reduced by 40-60%. These findings support our hypothesis that a common regulatory signal is utilized by both insulin and phorbol esters for the complete induction of specific genes.

Actins↗

PubMed1992

The regulation of p33 gene expression by insulin and calcium ionophores.

We have previously shown that insulin induces p33 transcription and mRNA levels in serum-deprived rat H4 hepatoma cells. In the current study, the effects of the calcium ionophores A23187 and ionomycin on the regulation of p33 gene expression were examined. When H4 cells were incubated with A23187 or ionomycin (1 microM) for 90-300 min, 700-900% and 400-600% increases in p33 mRNA levels were observed. The effects of ionophore and insulin together on p33 mRNA levels were not additive. Insulin-induced increases in p33 mRNA levels were diminished at low concentrations of extracellular calcium, but were unchanged by the calcium channel blocker verapamil. The chelation of intracellular calcium using 20 and 60 microM quin2-AM resulted in 50% and 90% reductions in insulin-induced p33 mRNA levels. When transcription assays were performed, A23187 treatment for 15-180 min increased p33 transcription 300-400%. The lesser effect of A23187 on transcription compared to that on mRNA levels was also true for insulin treatment. Similar results were obtained using ionomycin. Insulin- and A23187-induced p33 transcription was reduced by quin2-AM to below basal levels. These studies show that calcium ionophores stimulate p33 gene expression and suggest that changes in intracellular calcium can alter insulin's induction of this gene.

Animals↗

PubMed1991

Reliability and validity of the appraisal of diabetes scale.

The present research evaluated the psychometric properties of a brief self-report instrument designed to assess appraisal of diabetes. Two hundred male subjects completed the Appraisal of Diabetes Scale (ADS) and provided blood samples that were subsequently assayed to provide an index of glycemic control (i.e., glycosylated hemoglobin). Subjects also completed either (a) additional measures of diabetes-related health beliefs, diabetic daily hassles, perceived stress, diabetic adherence, and psychiatric symptoms or (b) the ADS on two additional occasions. Results indicated that the ADS is an internally consistent and stable measure of diabetes-related appraisal. The validity of the measure was supported by correlational analyses which documented the relationship between the ADS and several related self-report measures.

Adaptation, Psychological↗

PubMed1990

Decreased induction of an hepatic mRNA by phorbol esters after insulin desensitization.

Insulin and phorbol esters rapidly induce the transcription and cytoplasmic accumulation of a specific mRNA (p33) in rat hepatoma cells. We have studied the effects of insulin desensitization on the regulation of p33 gene expression by insulin and phorbol esters. Insulin desensitization is associated with down-regulation of the insulin receptor and post-receptor defects. When cells were treated with insulin (5 x 10(-7) M) for 24 h, a greater than 50% reduction in insulin binding was observed and insulin's stimulation of p33 transcription and cytoplasmic mRNA levels was prevented. The induction of p33 gene transcription and mRNA levels by phorbol esters was also decreased. Beta-tubulin gene expression was unaffected by insulin or phorbol esters and the stimulatory effect of dexamethasone on p33 gene expression was not impaired. Since insulin desensitization impaired phorbol esters' induction of p33 gene expression, one intracellular defect in insulin-desensitized cells may include an alteration in protein kinase C-dependent events.

Animals↗

PubMed1990

Desmopressin and indomethacin therapy for nephrogenic diabetes insipidus in patients receiving lithium carbonate.

Individuals receiving lithium carbonate commonly have nephrogenic diabetes insipidus. There is no effective and practical treatment for this condition. We have found that large doses of desmopressin (DDAVP) may provide effective therapy without adverse effects. A recent report showed that indomethacin improved nephrogenic diabetes insipidus that had persisted after the lithium therapy was discontinued. We have provided additional evidence that indomethacin may be effective, even when treatment with lithium is continued. We also have shown that indomethacin together with desmopressin can markedly decrease polyuria, though indomethacin must be used with care because it may impair renal function.

Adult↗

PubMed1989

Bone mineral density in women with type II diabetes mellitus.

Bone mineral density (BMD) was assessed in 28 women with type II diabetes mellitus and compared to 207 age-matched nondiabetic women. Mean BMD, as measured by dual-photon absorptiometry, 1.12 +/- 0.3 g/cm2 (+/- SEM), was similar to the mean BMD of control subjects, 1.06 +/- 0.1 g/cm2. Only 1 of the 28 diabetic patients had a BMD less than 0.95 g/cm2 ("fracture threshold"), whereas 25% of the control subjects had a BMD below that level. When diabetic and control subjects were matched for weight as well as age, the data continued to show similar BMD among both groups. Moreover, the disparity between the proportion of weight-matched controls (25%) and diabetic subjects (1 of 28) with a BMD below the fracture threshold persisted. Among the group of 17 diabetic subjects receiving insulin, there was a positive relationship between BMD and insulin dose. There was no significant relationship between BMD, duration of diabetes, or hemoglobin Alc. Thus, women with type II diabetes are not at increased risk for diminished BMD and may be protected against bone loss.

Adult↗

PubMed1988

Sustained pectin ingestion: effect on gastric emptying and glucose tolerance in non-insulin-dependent diabetic patients.

The effects of sustained pectin ingestion on gastric emptying, glucose tolerance, and hormone responses were studied in 12 stable, non-insulin-dependent (type 2) diabetic patients. Patients were placed on a 2400 kcal, low-fiber (3 g) diet for 2 wk, followed by 4 wk of an isocaloric diet supplemented with 20 g apple pectin/d. Gastric-emptying half-time, plasma glucose, glucagon, and human pancreatic polypeptide levels were determined. Gastric-emptying half-time was prolonged 43% (p less than 0.025) by pectin supplementation and returned to normal 3 d after its discontinuation. Fiber supplementation decreased the incremental area under the glucose tolerance curve from 34.8 +/- 3.0 to 27.9 +/- 3.2 mmol/L (p less than 0.01) but did not affect hormonal responses to a meal. Sustained pectin ingestion slowed the gastric-emptying rate and improved glucose tolerance; however, a direct relationship could not be demonstrated between changes in gastric emptying and changes in the incremental area under the glucose curve (r = 0.22).

Adult↗

PubMed1988

Regulation of 1,25 (OH)2D synthesis in hypoparathyroidism and pseudohypoparathyroidism.

We examined the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] synthesis in patients with hypoparathyroidism (n = 5) and pseudohypoparathyroidism (n = 5) by administration of parathyroid extract (PTE) and N6,O2-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP) and by phosphorus deprivation with antacids. In response to PTE, patients with hypoparathyroidism increased serum 1,25(OH)2D from 17 +/- 5 to 30 +/- 5 (SD) pg/ml (P less than 0.01). An approximate doubling of the 1,25(OH)2D concentration also occurred following dbcAMP infusion or phosphorus deprivation (serum phosphorus 4.4 +/- 0.5 to 2.6 +/- 1.1, P less than 0.01). Serum phosphorus and 1,25(OH)2D concentrations were inversely correlated (r = -0.73, P less than 0.001). Patients with pseudohypoparathyroidism had negligible responses to PTE with respect to urinary adenosine 3', 5'-cyclic monophosphate excretion, serum phosphorus concentration, or 1,25(OH)2D synthesis. They did show a rise in serum 1,25(OH)2D from 17 +/- 4 to 44 +/- 5 pg/ml (P less than 0.001) in response to dbcAMP infusion. During phosphorus deprivation, serum phosphorus decreased from 4.1 +/- 0.8 to 3.2 +/- 1.2 mg/dl (P less than 0.05), but there was no change in serum 1,25(OH)2D concentration or any correlation between serum phosphorus and 1,25(OH)2D levels. Although reduction in mean serum phosphorus levels was generally not as great in patients with pseudohypoparathyroidism, one such patient attained serum phosphorus of 1.2 mg/dl and still did not increase serum 1,25(OH)2D concentration. In addition to an abnormal parathyroid hormone receptor-adenylate cyclase complex, patients with pseudohypoparathyroidism appear to have an abnormal renal 1 alpha-hydroxylase, which does not respond appropriately to phosphate deprivation.

Adolescent↗

PubMed1988

Transcriptional regulation of a rat hepatoma gene by insulin and protein kinase-C.

Both insulin and phorbol esters rapidly stimulated the cytoplasmic accumulation of a specific mRNA (designated p33) in a time- and dose-dependent manner in serum-deprived rat H4 hepatoma cells. When cells were pretreated with phorbol esters to produce a deficiency in protein kinase-C, the ability of further phorbol ester addition to stimulate p33 mRNA accumulation was abolished. However, after pretreatment of H4 cells with phorbol esters, insulin still induced cellular p33 mRNA concentrations, but to a lesser degree. The primary effect of phorbol esters was to increase transcription of the p33 gene, and this was abolished after pretreatment with phorbol esters. In previous work, insulin was shown to stimulate p33 gene transcription, but this effect was insufficient to account for the level of insulin-induced p33 mRNA production. The transcriptional effect of insulin was further reduced by phorbol ester pretreatment. Insulin must, therefore, regulate p33 gene expression by at least two pathways, at least one of which may be modulated by protein kinase-C.

Animals↗

PubMed1988

Rapid development of nephrotic syndrome, hypertension, and hemolytic anemia early in pregnancy in patients with IDDM.

In recent years, the prognosis for a successful pregnancy has greatly improved for women with insulin-dependent diabetes mellitus (IDDM) who are under good glycemic control and free of complications such as vascular disease and nephropathy. We report the rapid development of severe nephrotic syndrome, malignant hypertension, and microangiopathic hemolytic anemia during the first trimester of pregnancy in a 29-yr-old woman with IDDM of 18 yr duration. Our patient had no pregestational history of retinopathy or hypertension and only minimal proteinuria. Significant improvement in blood glucose levels had been achieved over the 6 mo before conception. Kidney biopsy performed before the termination of pregnancy at 10 wk gestation revealed diabetic nephropathy. No other etiology for her renal disease could be found. An arteriole was noted to have entrapped red blood cell fragments and platelet thrombi, revealing the probable source of her hemolytic process. By 8 wk postpartum, her nephrotic syndrome and hemolysis had completely resolved. At 3 mo postgestation, the patient's hypertension was still present but less severe. Her serum creatinine has continued to decrease toward normal. This is the first report of a woman with IDDM in White's classification C who developed a toxemia-like syndrome during the first trimester of pregnancy, attributable to the underlying diabetic state.

Adult↗

PubMed1986

Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism.

In six patients with pseudohypoparathyroidism (PHP) who were deficient in guanine nucleotide-binding stimulatory protein (Ns) activity, the response to endogenous arginine vasopressin (AVP) was tested during water deprivation. Hourly plasma osmolality (Posm), urinary osmolality (Uosm), and urinary AVP (UAVP) values were compared to those in normal subjects. The Uosm vs. Posm and the UAVP vs. Uosm relationships of the patients were all within the normal range. Four patients with Ns-deficient PHP were subjected to maintained water loads and infused with AVP at three different rates for 1 h each to assess their responses to exogenous AVP. Urinary volume and osmolality values from the final 30 min of each infusion rate were measured. All volume values except 1 were within 1.6 SD of normal, and all osmolality values except 1 were within 1.1 SD of normal. In conclusion, these studies indicate that these six patients with Ns-deficient PHP are not resistant to the antidiuretic (cAMP-mediated) action of endogenous or exogenous AVP, in contrast to the previously documented resistance of patients with Ns-deficient PHP to the actions of PTH, TSH, glucagon, and gonadotropins.

Adolescent↗

PubMed1977

Right and left ventricular compliance in the hereditary cardiomyopathy of the Syrian hamster.

Ventricular pressure-volume curves were examined in 10 pre-oedematous cardiomyopathic Syrian hamsters, aged 120 d, and 10 oedematous cardiomyopathic hamsters, aged 210 d, and compared with 10 and 8 age-matched controls, respectively. Previous studies had shown filling pressures and cardiac output to be normal in the pre-oedematous stage. In contrast, the oedematous stage was characterised by elevated filling pressures and increased cardiac output, raising the question whether this stage represents true myocardial failure or circulatory congestion associated with decreased ventricular compliance. Compliance, defined as dV/dP, was derived simulataneously for both ventricles from post-mortem pressure-volume curves from 0 to 2.66 kPa (0 to 20 mmHg). Left ventricular tissue elastic modulus, E, defined as dsigma/depsilon or the incremental stress (sigma) for an increment of strain (epsilon), was derived from the compliance curves and certain linear dimensions of the heart. At isobaric intervals, compliance did not differ between control and myopathic ventricles. At pressures corresponding to previously measured, naturally prevailing end-diastolic pressures, the myopathic ventricles were significantly dilated in both stages; end-diastolic compliance was normal in pre-oedematous hamsters, but was significantly decreased in the oedematous animals. Left ventricular elastic modulus was elevated at all values of sigma in both groups of myopathic animals.

Animals↗

PubMedDate not supplied

Diet and exercise in the treatment of obesity: effects of 3 interventions on insulin resistance.

BACKGROUND: In short-term studies, diet and exercise both improve insulin sensitivity. OBJECTIVE: To determine the effects of a 48-week supervised diet and exercise program on weight and insulin sensitivity after initial weight loss and weight maintenance, and then subsequent weight regain over 96 weeks. METHODS: Forty-five obese women were randomly assigned to 1 of 3 treatment groups: (1) diet alone, (2) diet and aerobic training, and (3) diet and strength training. All subjects received the same 48-week group behavior modification program and diet (approximately 3879 kJ/d [approximately 925 kcal/d] for the first 16 weeks; approximately 6276 kJ/d [approximately 1500 kca/d] thereafter). Exercising subjects were provided 3 supervised exercise sessions per week for the first 28 weeks and 2 sessions weekly until week 48. During weeks 48 to 96, subjects were unsupervised. Oral glucose tolerance tests were performed at baseline and weeks 16, 24, 44, and 96. RESULTS: Subjects across the 3 conditions achieved a mean weight loss of 13.8 kg by week 16, which was associated with decreased insulin levels (61.8% of baseline) There were no significant differences among groups in changes in body mass index, which is a measure of weight in kilograms divided by the square of the height in meters, weight, glucose tolerance, or insulin levels at weeks 16, 24, and 44. No additional beneficial effect of aerobic or strength exercise on insulin resistance, as reflected by serum insulin levels before and after a glucose load, was demonstrated. The 22 subjects who were studied at week 96 maintained a loss of approximately 10% of initial weight. Insulin levels, however, had returned to pretreatment levels. CONCLUSIONS: This study confirms the beneficial effect of weight reduction on hyperinsulinemia in obese individuals. Participation in supervised exercise did not result in additional improvement in weight loss or insulin sensitivity. We also observed a marked increase in insulin levels with only partial weight regain. Determining the amount of sustained weight loss necessary for continued improvement in insulin sensitivity will require further study.

Adult↗

PubMedDate not supplied

Severe hyperkalemia in two patients with diabetes after cosyntropin administration.

Some patients with diabetes mellitus are at increased risk for the development of hyperkalemia. Included in this group are patients with glucose-induced hyperkalemia who may have renal insufficiency, hyporeninemic hypoaldosteronism, or other impediments to the release or action of aldosterone. In an unusual demonstration of this abnormality, two patients with diabetes, who form the basis of our report, became markedly hyperglycemic and hyperkalemic after cosyntropin administration. To our knowledge, this complication of adrenocorticotropic hormone (ACTH) stimulation testing has not been previously reported. It should therefore be emphasized that the use of cosyntropin as a diagnostic agent can provoke severe hyperglycemia and hyperkalemia in a susceptible subgroup of patients with diabetes mellitus.

Aldosterone↗

PubMedDate not supplied

Olfactory dysfunction in humans with deficient guanine nucleotide-binding protein.

The guanine nucleotide-binding stimulatory protein (Gs) couples hormone-receptor interaction to the activation of adenylate cyclase and the generation of cyclic AMP. Studies using frog neuroepithelium indicate that the sense of smell is mediated by a Gs-adenylate cyclase system, and this prompted us to test olfaction in the only known model of Gs deficiency in the animal kingdom, Gs-deficient (type 1a) pseudohypoparathyroidism (PHP), which occurs in humans. Such patients are resistant to the cAMP-mediated actions of several hormones. (Although Henkin has reported disturbances in the sense of smell in six patients with PHP, currently available biochemical measurements such as the cAMP response to parathyroid hormone (PTH) and determination of Gs activity were not reported and olfactory testing was limited.) In the present study, we found that all Gs-deficient patients had impaired olfaction when compared with PHP patients who had normal Gs activity (type 1b PHP, in which patients are resistant only to the action of PTH in the kidney). This is the first evidence of human olfactory impairment which can be related to Gs deficiency and suggests that Gs-deficient PHP patients may be resistant to cAMP-mediated actions in other non-endocrine systems.

Cyclic AMP↗

PubMedDate not supplied

Central diabetes insipidus due to herpes simplex in a patient immunosuppressed by Cushing's syndrome.

OBJECTIVE: To describe a patient immunocompromised by Cushing's syndrome in whom central diabetes insipidus developed as a complication of herpes simplex involvement of the hypothalamus. METHODS: We present a case, including results of laboratory and histopathologic studies, in which herpes simplex was established as the causative agent for central diabetes insipidus. RESULTS: A woman with ectopic corticotropin-dependent Cushing's syndrome, diabetes mellitus, carcinoid tumor, and a history of thyroid cancer had the precipitous onset of seizure and fever, and hypotonic polyuria and progressive hypernatremia developed. Central diabetes insipidus was diagnosed and successfully treated with desmopressin. Nevertheless, the patient's condition deteriorated and she died. Autopsy revealed herpes simplex encephalitis involving the magnicellular neurons of the hypothalamus. CONCLUSION: Central diabetes insipidus caused by viral infections has been reported in immunosuppressed patients, such as those with acquired immunodeficiency syndrome (AIDS). To our knowledge, this is the first report of a herpes infection causing diabetes insipidus in a patient immunosuppressed by Cushing's syndrome. This case demonstrates that, in patients with Cushing's syndrome, diabetes insipidus may develop as a result of herpes simplex infection of the hypothalamus.

Cushing Syndrome↗