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Biomedical subjects

A E Kitabchi

Publications and source records attributed to A E Kitabchi.

At least 37 records · Page 2Linked to original sources
PubMed1994

Evidence for a defect in insulin metabolism in hyperandrogenic women with polycystic ovarian syndrome.

It has been well established that the hypertestosteronemia of patients with polycystic ovarian syndrome (PCO) is associated with hyperinsulinemia and insulin resistance. We have recently noted a disparity between serum levels of insulin and C-peptide in certain hypertestosteronemic women with PCO and hypothesized a possible association between testosterone and insulin metabolism. Therefore, we have studied insulin clearance (baseline steady-state ratios of C-peptide to insulin) in 15 obese PCO women, 12 weight-matched controls (OC), and nine lean controls (LC), and examined the interactions of testosterone and insulin metabolism by examining the correlations between testosterone and insulin clearance and by studying the direct in vitro actions of testosterone on T-lymphocyte insulin binding and degradation. We found that the C-peptide to insulin ratio at baseline and T-lymphocyte insulin degradation of the PCO group were twofold below the LC and OC values. Basal C-peptide to insulin ratios and insulin-degradative activities were significantly and negatively interrelated (r = .56, P < .01), and both of these parameters were highly correlated (P < .01) with basal testosterone levels (r = .49 for basal C-peptide to insulin and r = -.61 for insulin degradation). In experiments where testosterone was added to cell cultures, insulin degradation was impaired in a biphasic fashion. We conclude that (1) elevated testosterone levels may contribute to impairments in insulin metabolism, and (2) the hyperinsulinemia of hyperandrogenic women may occur in part from defects in insulin clearance and peripheral tissue insulin degradation.

Adult↗
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↗
PubMed1993

Case report: amelioration of insulin resistance in diabetes with dehydroepiandrosterone.

In hyperandrogenic females, the ratio of dehydroepiandrosterone (DHEA) to testosterone may be an important determinant of insulin sensitivity. This study involved changes in insulin sensitivity and glucose metabolism with therapeutic manipulation of DHEA (S)/testosterone in a female patient with non-insulin-dependent diabetes and hyperandrogenism. Therapeutic intervention included 1-month treatment with 0.25 mg dexamethasone at bedtime and 1-month dexamethasone + DHEA. Insulin sensitivity and glucose tolerance were assessed before and after each treatment regimen by examining: 1) fasting and oral glucose tolerance test glucose and insulin levels, 2) hypoglycemic response to intravenous insulin, and 3) erythrocyte insulin receptor binding. With dexamethasone alone, DHEAS, testosterone, and their ratio were reduced with a concomitant increase (30%) in oral glucose tolerance test insulin levels and a decrease (33%) in erythrocyte insulin binding. With DHEA + dexamethasone, the ratio of DHEAS/testosterone increased 16-fold along with a marked improvement in insulin sensitivity, as determined by a more than 30% reduction in fasting and oral glucose tolerance test insulin levels, a threefold stimulation of the rate of glucose disappearance with intravenous insulin, and a 30% increase in insulin binding. DHEA improved insulin sensitivity and reduced fasting and oral glucose tolerance test glucose levels and ameliorated the diabetic state. The ratio of DHEAS/testosterone is an important regulator of insulin sensitivity and glucose tolerance and that DHEA therapy may be beneficial in the treatment of certain forms of insulin resistance.

Adolescent↗
PubMed1991

Role of adrenal and gonadal androgens in insulin action and metabolism.

In a previous report we found extreme hyperinsulinemia associated with high testosterone levels in patients with polycystic ovarian syndrome (PCO) and normal insulin levels in a small group of patients with elevated dehydroepiandrosterone (DHEA). From these observations, we hypothesized that DHEA and testosterone may have opposing actions on insulin sensitivity. To test this hypothesis, we studied insulin sensitivity in vivo and in vitro in a) obese PCO women with elevated testosterone, b) obese patients with adult-onset adrenal hyperplasia (AH) and high levels of DHEA, c) weight-matched obese controls, and d) lean controls. Insulin sensitivity was determined by insulin responses to a standard OGTT, hypoglycemic responses to an IV insulin tolerance test (ITT), red blood cell (RBC) insulin binding and receptor kinase activity, and phytohemagglutinin (PHA)-activated T-lymphocyte (T-cell) insulin binding and PDH insulin sensitivity. In PCO patients, we found that basal and glucose-challenged insulin levels were significantly greater than, and hypoglycemic responses to IV insulin, significantly lower than, weight-matched control values. However, AH patients had insulin values significantly below, and hypoglycemic responses significantly above, those of the weight-matched controls. Their values were, in fact, comparable to those observed for the lean control subjects. Similar findings were observed with insulin binding and PDH insulin sensitivity. Insulin sensitivity in all study subjects was found to be negatively correlated to testosterone and positively correlated to DHEA and, more significantly, to the ratio of DHEA/testosterone. These data would suggest that, in females, DHEA and T may have opposing actions on insulin sensitivity. We conclude that in females insulin sensitivity in vivo and in vitro is modulated, at least in part, by the ratios of DHEA to testosterone.

Adrenal Glands↗
PubMed1991

Pseudonormoglycemia in diabetic ketoacidosis with elevated triglycerides.

A 24-year-old newly diagnosed male patient with diabetes presented with diabetic ketoacidosis (DKA) (pH 7.16, HCO3 6.0) and extreme hypertriglyceridemia (239.35 mmol/L). The diagnosis of DKA was delayed because of the apparent depression of the true serum glucose (to 11 mmol/L). He was treated with intravenous (IV) insulin and rehydration, which normalized his pH, HCO3, and triglyceride levels. To the authors' knowledge, this is both the highest triglyceride level recorded and the first report of a high triglyceride level as the apparent cause of a factitiously low glucose level.

Adult↗
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↗
PubMed1989

Identification of insulin intermediates and sites of cleavage of native insulin by insulin protease from human fibroblasts.

We have studied the time sequence degradation of native insulin by insulin protease from human fibroblast using multiple steps involving purification of the products by high performance liquid chromatography, determination of peak composition by amino acid sequence analysis, and confirmation of structure by mass spectrometry and thus elucidated the sites of cleavage of insulin by human insulin protease. We observed that as early as 0.5 min of incubation, three major new peptide peaks, intact insulin, and four smaller peptide peaks can be detected. The major peptides are portions of the insulin molecule, with the amino ends of the A and B chains or the carboxyl ends of the A and B chains still connected by disulfide bonds. Peptide peak I is A1-13-B1-9. Peptide peak II is A1-14-B1-9. Peptide peak III is A14-21-B14-30. The smaller peptide peaks are A14-21-B17-30, A15-21-B14-30, A15-21-B10-30, and A14-21-B10-30. The major peptide bond cleavage sites therefore consist of A13-14, A14-15, B9-10, B13-14, and B10-17. With longer incubation times, peptide peak II appears to lose the A14 tyrosine to form peptide peak I. This peptide I, which is the amino end of the A and B chains, is not further degraded even after 1.5 h of incubation. With longer incubation times, the peptides containing the carboxyl ends of the A and B chains are further degraded to form products from cleavage at the A18-19, B14-15, B25-26, and a small amount of A19-20, B10-11, and B24-25 cleavage and the emergence of 2-5-amino acid peptide chains, tyrosine, alanine, histidine, and leucine-tyrosine. We conclude, based on the three-dimensional structure of insulin, that human insulin protease recognizes the alpha-helical regions around leucine-tyrosine bonds and that final degradation steps to small peptides do not require lysosomal involvement.

Amino Acid Sequence↗
PubMed1988

Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma.

Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma are two of the most common acute complications of diabetes. The pathophysiologic changes that occur in both disease states represent an extreme example of the super-fasted state. The physiology of the fed and fasted state, evaluation, therapeutic issues, recommendations for therapy, immediate follow up care, and complications of therapy are reviewed for both syndromes.

Diabetic Coma↗
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↗
PubMed1987

Increased insulin binding of erythrocytes and insulin sensitivity in adrenal insufficiency.

We have studied 125I-insulin binding to erythrocytes (RBC) in five patients with hypoadrenocortisolism, and compared to 17 normal subjects and in nine patients with Cushing's syndrome. In another study insulin sensitivity index (ISI) was measured by the IV insulin tolerance test in four patients with hypoadrenocortisolism (1.82 +/- 0.15 mg/dL/min), and compared to 19 normal subjects and 23 patients with Cushing's syndrome (1.56 +/- 0.1 mg/min/dL). Mean insulin binding in hypocortisolism was 17.9 +/- 0.7%, and was significantly higher (P less than .01) than in normal subjects (12.0 +/- 1.4%) and was significantly (P less than .001) decreased toward normal (11.8 +/- 1.47) during replacement therapy. Increased binding in untreated hypoadrenocortisolism was due to elevated high affinity site receptor concentration as compared to the treated patients (0.10 +/- 0.015 v 0.053 +/- 0.003 nmol/L,P less than .01). These results suggest that increased insulin binding in chronic hypoadrenocortisolism may be attributed to increased insulin binding to the receptor, which can revert to normal by replacement therapy. The role of increased insulin binding to increased insulin sensitivity in hypoadrenocortisolism is discussed.

Adrenal Insufficiency↗
PubMed1987

Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus.

Insulin requirements, C-peptide levels, and serum lipids have been assessed in 12 obese, insulin-requiring (greater than 60 U/day) patients with type II diabetes mellitus, in a randomized crossover fashion with two treatment regimens: NPH alone and combined NPH and tolazamide, over a period of 3 months each, with maintenance of weight and glycemic control (HgA1, 2hpp and mean 24h glucose profile) at comparable levels. Serum cholesterol improved in both groups compared to their respective baseline values (p less than 0.05). In addition, serum triglyceride was lower (p less than 0.05) in the combined therapy as compared with NPH alone therapy. Insulin requirements were decreased by 23% (p less than 0.002) in the combined therapy group, without significant change in weight, glycemic control, or C-peptide levels. However, C-peptide increments in the combined therapy group were significantly higher than the baseline by 70% (p less than 0.02). NPH plus tolazamide therapy as compared with NPH alone lowers insulin requirement in obese, type II diabetic women without significant alteration in glycemic control, possibly by an increased tissue sensitivity to insulin, and decreases serum triglyceride levels.

Adult↗
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↗