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Biomedical subjects

J R Givens

Publications and source records attributed to J R Givens.

At least 19 recordsLinked to original sources
PubMed2001

Formation of intermediate transcription initiation complexes at pfliD and pflgM by sigma(28) RNA polymerase.

The sigma subunit of prokaryotic RNA polymerase is an important factor in the control of transcription initiation. Primary sigma factors are essential for growth, while alternative sigma factors are activated in response to various stimuli. Expression of class 3 genes during flagellum biosynthesis in Salmonella enterica serovar Typhimurium is dependent on the alternative sigma factor sigma(28). Previously, a novel mechanism of transcription initiation at the fliC promoter by sigma(28) holoenzyme was proposed. Here, we have characterized the mechanism of transcription initiation by a holoenzyme carrying sigma(28) at the fliD and flgM promoters to determine if the mechanism of initiation observed at pfliC is a general phenomenon for all sigma(28)-dependent promoters. Temperature-dependent footprinting demonstrated that promoter binding properties and low-temperature open complex formation are similar for pfliC, pfliD, and pflgM. However, certain aspects of DNA strand separation and complex stability are promoter dependent. Open complexes form in a concerted manner at pflgM, while a sequential pattern of open complex formation occurs at pfliD. Open and initiated complexes formed by holoenzyme carrying sigma(28) are generally unstable to heparin challenge, with the exception of initiated complexes at pflgM, which are stable in the presence of nucleoside triphosphates.

Bacterial Proteins↗
PubMed1994

Enhanced adrenocortical activity as a contributing factor to diabetes in hyperandrogenic women.

The high incidence of non-insulin-dependent diabetes mellitus (NIDDM) in women with polycystic ovarian syndrome (PCO) is believed to occur secondary to the insulin resistance associated with their androgenicity. In the present study, we have examined the interrelationships between glucose tolerance, androgenicity, and various in vivo and in vitro parameters of insulin sensitivity in 11 obese PCO patients with NIDDM, 14 PCO patients without diabetes, and 14 weight-matched controls. Both groups of PCO patients were hypertestosteronemic, hyperinsulinemic, and insulin-resistant when compared with a group of weight-matched controls. However, PCO patients with NIDDM differed from those without diabetes in that they had elevated basal and corticotropin-stimulated adrenal steroids (cortisol, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]). The hyperglycemia of our diabetic patients was not related to their elevated testosterone levels or to their degree of insulin resistance, but was significantly and positively correlated with adrenal hypersecretion, which in turn was associated with postreceptor defects in insulin action. These findings would suggest that enhanced adrenocortical activity may be an important factor underlying the development of NIDDM in women with PCO.

Adrenal Cortex↗
PubMed1992

Lipoprotein abnormalities in hirsute women. II. Compensatory responses of insulin resistance and dehydroepiandrosterone sulfate with obesity.

OBJECTIVE: The purpose of our study was to further understand interrelationships between insulin, androgens, obesity, and apolipoprotein metabolism. STUDY DESIGN: In this University cross-sectional observational study for hypothesis generation, 53 women with hirsutism-hyperandrogenism were ternately divided according to body mass index into the following groups: 22 to 28 (n = 17), 29 to 36 (n = 19), 37 to 61 (n = 17), and 16 controls. Mean hormone and clinical parameters were compared by using the Student t test, analysis of variance, and Pearson correlation. RESULTS: Dehydroepiandrosterone sulfate correlated negatively with fasting insulin (r = 0.4, p < 0.05) and reached significance in those most obese. Unbound testosterone concentrations were 24.7, 38.9, and 31.9 ng/dl, respectively. Dehydroepiandrosterone sulfate concentrations were 2.8, 2.3, and 2.3 micrograms/dl, respectively; their ratios were 13.4, 18.6, and 20.4, respectively, even though mean fasting insulin concentrations (reflecting insulin resistance) were 13.0, 20.4, and 42.6 microU/ml, respectively. Although more atherogenic apolipoprotein profiles and higher fasting insulin concentrations were found with greater body weight, lipid-insulin interrelationships may reflect dehydroepiandrosterone sulfate interaction. CONCLUSIONS: We hypothesize that dehydroepiandrosterone sulfate dampens the effect of insulin resistance, which in turn is reflected in apolipoprotein profiles in women with hirsutism/hyperandrogenism.

Adaptation, Physiological↗
PubMed1991

Suppression of circulating delta 4-androstenedione and dehydroepiandrosterone sulfate during oral glucose tolerance test in normal females.

Extending a series of previous investigations on the regulatory interaction of insulin and androgens, this study tests the hypothesis that the physiological insulinemia after oral glucose suppresses circulating dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), and androstenedione (delta 4A) delta 4 in normal women. Accordingly, seven normal weight, ovulatory women were randomized to receive first either a 75 g glucose dose or a sham control for diurnal rhythm consisting of distilled water at 1700 h. After this insulin stimulus, DHEA-S suppressed below sham control at 90 and 120 min (P less than 0.05) whereas delta 4A suppress at 60, 90, and 120 min (P less than 0.05). Furthermore, as serum insulin increased after glucose, DHEA-S (r2 = 0.351, P less than 0.05) and delta 4A (r2 = 0.314, P less than 0.05) decreased in an inverse linear relationship with insulin. There was no significant suppression below sham at any point in time for DHEA, testosterone, or cortisol. Thus, the endogenous serum insulin response after oral glucose in normal women is associated with suppression of serum DHEA-S and delta 4A with absence of testosterone and cortisol suppression.

Administration, Oral↗
PubMed1991

Opposing actions of dehydroepiandrosterone and testosterone on insulin sensitivity. In vivo and in vitro studies of hyperandrogenic females.

It has been hypothesized that the androgens testosterone and dehydroepiandrosterone (DHEA) may have opposing actions on insulin sensitivity. To test this hypothesis, we selected patients with polycystic ovary syndrome (PCO) and hypertestosteronemia and a group of individuals with adrenal hyperplasia (AH) and elevated DHEA and studied their 1) insulin and glucose responses to a 75-g oral glucose tolerance test, 2) insulin resistance by hypoglycemic responses to a standard dose of intravenous (IV) insulin, and 3) insulin binding and pyruvate dehydrogenase (PDH) responsiveness to insulin in phytohemagglutinin (PHA)-activated T lymphocytes. PCO patients exhibited elevated basal and glucose-challenged insulin levels and had blunted hypoglycemic responses to IV insulin. Conversely, AH patients had hypoglycemic responses to IV insulin significantly greater than and basal and glucose-challenged insulin levels lower than the PCO patients and weight-matched control subjects. In vitro, T-lymphocyte insulin binding of the PCO patients was 40-60% below control values; in AH patients, insulin binding and PDH insulin sensitivity were above those of the control subjects. Testosterone levels in all study subjects were negatively correlated to T-lymphocyte insulin binding and positively correlated to basal insulin, insulin area under the curve (AUC), and insulin-glucose indices. DHEA levels were positively correlated to insulin binding and inversely related to basal insulin, insulin AUC, and insulin-glucose indices. In all instances, the parameters of insulin sensitivity were more strongly correlated to individuals' ratios of DHEA to testosterone than to either of these androgens alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocortical Hyperfunction↗
PubMed1990

Bimodal correlation between the circulating insulin level and the production rate of dehydroepiandrosterone: positive correlation in controls and negative correlation in the polycystic ovary syndrome with acanthosis nigricans.

The objective of this study was to define the relationship among the circulating insulin level (IRI), the MCR of dehydroepiandrosterone (MCR-D), and the production rate of DHEA (PR-D) in 10 women with the polycystic ovary syndrome and acanthosis nigricans (PCOS-AN). Seven normal weight and 10 obese women served as controls. Measurement of the MCR-D and PR-D was accomplished by iv saline infusion (0.9% NaCl solution) on day 1 as a control and a 4-h iv dehydroepiandrosterone (unlabeled) infusion (1 mg/h) was performed on day 2. Mean MCR-D was more than 2-fold higher in the obese controls compared to the normal weight controls. However, the plasma concentration of DHEA(PC-D) was not significantly different in the normal and obese control women, since the PR-D was increased proportionately to the MCR-D. The MCR-D and the PR-D were coupled through insulin in the control women, and their correlation coefficients with IRI were positive and identical (0.77 and 0.73, respectively). In contrast, IRI was negatively correlated with PR-D in the PCOS-AN women. Also, unlike the control women, there was minimal or no change in the MCR-D across a broad range of IRI in the PCOS-AN women. Thus, the MCR-D and PR-D were not coupled in these women.

Acanthosis Nigricans↗
PubMed1990

Sensitivity of pyruvate dehydrogenase to insulin in activated T lymphocytes. Lack of responsiveness to insulin in patients with polycystic ovarian disease and diabetes.

Using phytohemagglutinin-activated T lymphocytes, we studied possible mechanisms responsible for insulin resistance in patients with polycystic ovarian disease (PCO) and acanthosis nigricans (AN) by examining insulin binding to erythrocytes and activated T lymphocytes and T-lymphocyte pyruvate dehydrogenase (PDH) responsiveness to insulin in three groups. These groups of subjects consisted of six PCO-AN patients with normal glucose tolerance, six PCO-AN patients with mild non-insulin-dependent diabetes mellitus (NIDDM), and six weight-matched control subjects. We found that insulin binding to both erythrocytes and activated T lymphocytes was significantly lower in PCO and PCO-NIDDM patients than control subjects but did not differ between the PCO groups. Insulin binding to erythrocytes and T lymphocytes varied inversely with basal insulin. In activated T lymphocytes of PCO-NIDDM patients, PDH responsiveness to both submaximal and maximal insulin concentrations was impaired, the extent of which varied in proportion to their degree of carbohydrate intolerance. In contrast, PDH responsiveness to maximal amounts of insulin in T lymphocytes of PCO patients without NIDDM was similar to the weight-matched control subjects. These data may suggest that lesions at the level of the receptor are primarily responsible for insulin resistance in patients with PCO but that both receptor and postreceptor defects (i.e., PDH responsiveness to insulin) contribute to the insulin-resistant state of PCO patients with NIDDM.

Adolescent↗
PubMed1988

Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding.

We evaluated the insulin response to a standard oral glucose tolerance test (OGTT) and in vitro insulin binding to erythrocytes (RBC) in 26 women from 3 groups: Group NW, normal women (n = 11); Group DS, women (n = 9) with elevated serum DHEAS concentrations, greater than 400 micrograms/dl (greater than 10.84 mumol/L); and Group IR, women (n = 6) with elevated basal plasma insulin concentrations (IRI). There was a significant linear correlation between the area under the insulin response curve (IRI-AUC) and serum testosterone (T) (r = 0.78, p = 0.0001). Using stepwise multiple linear regression, IRI-AUC was characterized as a function of both serum T and DHEAS; positively with T and negatively with DHEAS. In vitro (n = 17), there was a positive correlation between RBC-insulin binding and serum DHEAS (r = 0.54, p = 0.029) and a negative correlation between RBC-binding and T (r = -0.57, p = 0.017). We conclude that DHEAS may enhance insulin binding and action and that DHEAS and T have divergent functional relationships with IRI. DHEAS and T may therefore exert opposing effects on insulin secretion and action.

Dehydroepiandrosterone↗
PubMed1988

Familial polycystic ovarian disease.

Emphasis is placed on the heterogeneity of the phenotypic presentation of PCOD. It is the common expression of an unknown number of disorders and thus is a sign and not a specific diagnosis. Two essential features are arrested follicular maturation and atresia of follicles. Normal folliculogenesis is described, emphasizing that a large number of areas could be subject to derangement causing PCOD. Any interference of the finely balanced sequence of events can lead to PCOD. The genetic defect causing familial PCOD is unknown and the initiating event remains undefined. Three families are described that illustrate four features of familial PCOD. A number of associated disorders such as diabetes, hyperinsulinemia, obesity, and hypertension are described. The potential importance of agents that modulate the LH and FSH activity that may cause PCOD is emphasized. The theoretic means by which similar male and female gonadal abnormalities may be coupled in families through growth factors EGF and alpha TGF are presented.

Androgens↗
PubMed1987

Reduction of hyperinsulinemia and insulin resistance by opiate receptor blockade in the polycystic ovary syndrome with acanthosis nigricans.

We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.

Acanthosis Nigricans↗
PubMed1987

Maintenance of normal circulating levels of delta 4-androstenedione and dehydroepiandrosterone in simple obesity despite increased metabolic clearance rates: evidence for a servo-control mechanism.

To study the effect of obesity on the metabolism of adrenal androgens not bound to testosterone-estradiol-binding globulin, the MCRs of delta 4-androstenedione (A) and dehydroepiandrosterone (DHEA) were determined using constant infusion of unlabeled steroids to steady state in 8 normal weight and 19 obese nonhirsute eumenorrheic women. The blood production rates (PR) were calculated as the product of the MCR and the 24-h integrated serum concentrations (IC). The mean MCR and PR of A and DHEA were significantly higher in the obese women than in the normal weight women. There was, however, no difference in the mean IC of each androgen in the 2 groups. The MCR and PR of A and DHEA were each correlated with the body mass index (BMI; kilograms per m2). The MCR and PR of A and the MCR of DHEA were also correlated with the ratio of waist circumference to hip circumference (WHR). However, the PR of DHEA was not correlated with WHR. There was no correlation between the IC of either androgen and BMI or WHR. However, partial correlation analysis revealed that correction of the BMI for WHR resulted in a significant negative correlation between BMI and IC of A. We conclude that the MCR and PR of A and DHEA were increased in obese nonhirsute eumenorrheic women; there was a strong correlation between BMI and the MCR and PR of A and DHEA; upper segment obesity, as measured by WHR, was correlated with the MCR and PR of A and the MCR of DHEA, but not with the PR of DHEA; and circulating DHEA and A were maintained at normal levels in the obese eumenorrheic women despite an increase in the MCR, which suggests that a servo-mechanism is operative which registers the body size and adjusts the PR according to the MCR.

Adult↗
PubMed1986

Relative sensitivity and responsivity of serum cortisol and two adrenal androgens to alpha-adrenocorticotropin-(1-24) in normal and obese, nonhirsute, eumenorrheic women.

The alpha ACTH-(1-24) threshold dose and the response slope were determined for cortisol (F), delta 4-androstenedione (A), and dehydroepiandrosterone (DHEA) in 10 normal and 16 obese eumenorrheic nonhirsute women matched for age. Each woman received 1 mg dexamethasone at 2300 h and again at 0700 h the next morning. At 0700 h, a continuous alpha ACTH-(1-24) infusion was begun at an initial dose of 30 ng/1.5 m2 body surface area X hr. The ACTH infusion rate was doubled every hour for 5 consecutive h to a maximum dose of 480 ng/1.5 m2 X h. Blood samples were collected for steroid assays before the infusion and at the end of each hour. The ACTH threshold dose was defined as the dose that produced a steroid response significantly above the basal level. The ACTH threshold dose for serum F and DHEA stimulation was not different between the groups, but the threshold dose for A was significantly lower in the obese women. Basal and stimulated serum DHEA to F ratios were significantly higher in the obese women. In both groups, the mean F response slope was significantly higher than that for DHEA, which in turn, was significantly higher than that for A. The mean DHEA response slope was significantly greater in the obese women. The F and A response slopes were not different between the groups. We conclude that the relative responsivity of the steroids to ACTH was the same in both groups: F greater than DHEA greater than A; in the obese women, the ACTH threshold dose for F stimulation was lower (greater sensitivity) than for DHEA or A stimulation; and in the obese women, the ACTH threshold dose for A was significantly lower (increased sensitivity) and the slope of the DHEA response to ACTH was steeper (greater responsivity) than in normal women.

Adrenal Cortex Function Tests↗
PubMed1983

Androgen parameters and their correlation with body weight in one hundred thirty-eight women thought to have hyperandrogenism.

The first objective of this study was to determine which plasma androgen assay or combination of assays would be the most useful in documenting hyperandrogenism in women with hirsutism, acne, oligomenorrhea, or unexplained infertility. Plasma levels of androstenedione (A), total testosterone (T), and dehydroepiandrosterone sulfate (DHEAS) were measured and free T (FTc) was calculated from the measured total T and T-estradiol-binding globulin binding capacity (TeBG-BC) in 138 consecutive women referred to our clinic for hirsutism, acne, oligomenorrhea, and/or unexplained infertility. FTc was elevated in 82% and was most frequently elevated parameter. DHEAS was elevated in 59% of the women, and 93% were noted to have hyperandrogenemia on the basis of a combination of FTc and DHEAS levels. The second objective of this study was to determine whether there was significant correlation between the androgen parameters and any of the clinical features. Body weight was significantly negatively correlated with DHEAS and TeBG-BC in those women with a normal DHEAS level but not in those with an elevated level. A strong positive correlation (simple and partial) was noted between body weight and plasma T levels in the whole group of patients, as well as in those with a normal or an elevated DHEAS level. It is suggested that the relationship between T and body weight is multifaceted. Conceivably, T could influence body mass by effects on food intake or through alterations in intermediary metabolism.

Acne Vulgaris↗
PubMed1983

Human ovarian 17 beta-hydroxysteroid oxidoreductase activity: a comparison of normal and polycystic ovarian tissues.

Ovarian tissue and ovarian venous blood were obtained from women undergoing wedge resection, and ovarian tissue was obtained from normally menstruating women who had an oophorectomy for medical reasons. A morphological evaluation was made of the wedged tissue. 17 beta-Hydroxysteroid oxidoreductase levels were determined as the 17-ketoreductase (17-KR) and 17 beta-dehydrogenase activities in both normal and wedged tissue. Plasma androstenedione (A) and testosterone (T) levels were measured in the ovarian venous blood. Low, but measurable, 17 beta-hydroxysteroid oxidoreductase activity was found in the mitochondria, microsomes, and cytosol. With whole, cell-free homogenates, mean 17-KR activity was not significantly different in normal tissues and polycystic tissues; mean 17-KR activity of corpora lutea was significantly greater than that of the other tissues. Mean 17 beta-dehydrogenase activity was not significantly different from 17-KR activity in the tissues studied. Ovarian venous A levels were higher than the reported mean ovarian venous A levels of normal women with only one exception; approximately half of the ovarian venous T levels were higher than reported mean ovarian venous T levels of normal women. The morphology of the wedge sections did not correlate well with the biochemical data.

17-Hydroxysteroid Dehydrogenases↗