Biomedical subjects

C A Stuart

Publications and source records attributed to C A Stuart.

At least 37 records · Page 2Linked to original sources

PubMed1993

Rat tail suspension causes a decline in insulin receptors.

Decreased muscular activity results in weakness and muscular atrophy. Coincident with this protein catabolic state is glucose intolerance and hyperinsulinemia. Rats were tail suspended for 7 to 14 days to accomplish unloading of the hindlimbs. Insulin resistance was documented in these animals by a 14 day tail suspension-related 26% increase in serum glucose in spite of a 253% increase in serum insulin concentration. Microsomal membranes were prepared from hindlimb muscles and specific binding of insulin and insulin-like growth factor I (IGF-I) were determined in these membranes. Insulin binding was decreased by 27% at 7 days and by 21% at 14 days. In contrast, IGF-I binding was unchanged at 7 days and was increased by 24% at 14 days. Liver membrane insulin receptors also had declined by 14 days of suspension, suggesting that the change in insulin receptors was a generalized, humorally-mediated phenomenon. These data suggest that tail suspension in rats results in insulin resistance, hyperinsulinemia, a decline in insulin receptors in liver and muscle, and a relative increase in muscle membrane IGF-I receptors. These data are consistent with the hypothesis that resistance to insulin's effects on protein metabolism in skeletal muscle may contribute to the protein catabolism associated with decreased muscular activity.

Animals↗

PubMed1992

Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics.

Stable isotope tracers and indirect calorimetry were used to evaluate whole-body energy, glucose, lipid, and amino acid metabolism in a patient with generalized lipodystrophy during basal conditions and in response to insulin therapy. The results were compared with those obtained in previous studies in normal volunteers. The basal rate of glucose production (33.7 mumol/kg.min) was three times higher than normal. The basal rate of glycerol appearance in blood, an index of lipolysis, was 60% greater than normal when expressed per kilogram body weight (3.82 mumol/kg.min), but was more than 10 times normal when expressed per kilogram body fat mass (123.2 mumol/kg.min) because of the marked decrease in body fat in our patient (3% of total body weight). Leucine rate of appearance, an index of protein breakdown, and nonoxidative leucine disposal, an index of protein synthesis, were also greater than normal. Resting energy expenditure (REE) was 30% greater than normal. The effect of insulin infusion on these metabolic parameters was markedly blunted. These metabolic abnormalities help explain many of the clinical findings such as hyperglycemia, hypertriglyceridemia, fat depletion, hepatomegaly, and steatosis observed in patients with lipodystrophy. Ineffective insulin function in many tissues appears to be an important factor in the pathophysiology of lipodystrophy.

Adult↗

PubMed1992

Specific binding sites for insulin in the human myometrium and leiomyomas of the uterus.

OBJECTIVE: To investigate whether there are increased binding sites for insulin in the leiomyomas of the uterus. STUDY DESIGN: Samples of myomas and myometrium were obtained from seven patients with myomas at the time of hysterectomy. Binding studies were performed with [125I] insulin. RESULTS: The percent total binding of [125I] insulin in the myomal tissues (mean +/- SE 20.7% +/- 2.3%/100 micrograms protein) was significantly higher (P less than 0.01) than that in the myometrium (14.7% +/- 1.3%/100 micrograms protein). Scatchard analysis revealed that the increase in binding is because of increase in receptor affinity. CONCLUSIONS: There is increased binding of insulin in the myomas because of increase in receptor affinity. This could increase the sensitivity of the biological response of the myomal cells to insulin.

Adult↗

PubMed1992

Assessment of patients with acanthosis nigricans skin lesion for hyperinsulinemia, insulin resistance and diabetes risk.

Acanthosis nigricans is a skin lesion characterized by thickening and apparent darkening of the keratin layer of the skin, usually on the neck and axillae. Recent studies reveal that this disorder is directly associated with hyperinsulinemia. A major implication of hyperinsulinemia is insulin resistance--a primary factor in the development of type II diabetes mellitus. Prolonged hypersecretion of insulin presumably leads to pancreatic exhaustion and subsequent glucose intolerance that can progress to type II diabetes. Prospective studies of individuals with acanthosis nigricans have shown very high prevalence rates of type II diabetes. Prevalence studies among adolescents have shown that the lesion appears early in life and is a common finding in some ethnic groups. These data suggest that acanthosis nigricans is an easily detected empirical marker for elevated risk of type II diabetes. The lesion can appear long before the onset of glucose intolerance. Thus, including acanthosis nigricans screening in a comprehensive disease-prevention program can help identify people at risk for type II diabetes prior to the actual onset of glucose intolerance, as well as individuals with undiagnosed diabetes. Interventions that reduce insulin resistance include weight loss and regular physical activity.

Acanthosis Nigricans↗

PubMed1992

Increased steroid production by the ovarian stromal tissue of postmenopausal women with endometrial cancer.

An increase in ovarian steroid secretion could play a role in the pathogenesis of endometrial cancer in postmenopausal women. The present study was undertaken to investigate steroid production by isolated ovarian stromal tissues of postmenopausal women with endometrial cancer and to study the effect of LH and insulin on ovarian steroidogenesis in postmenopausal women. Ovarian stromal tissue was obtained from 10 postmenopausal women with endometrial cancer and 8 women without cancer. The stroma was incubated in either the medium alone or the medium to which was added LH (50 ng/mL) or insulin (500 ng/mL). The ovarian stroma of postmenopausal women with cancer released significantly more androstenedione (A), testosterone, and dehydroepiandrosterone than that of women without cancer. Addition of LH resulted in a significant increase in A, testosterone, dehydroepiandrosterone, and progesterone release compared to that with vehicle alone. Addition of insulin stimulated the release of A from the ovarian stroma of women with cancer, but had no effect on the normal postmenopausal ovarian stroma. These results indicate that the ovarian stroma of postmenopausal women with endometrial cancer secrete significantly greater amounts of androgens than those of women without cancer and that both LH and insulin may be important factors contributing to this increase in ovarian steroidogenesis.

Aged↗

PubMed1992

Alteration in human mononuclear leucocytes following space flight.

Reduced in vitro mitogen-stimulated proliferative responses have routinely been observed from astronauts' mononuclear leucocytes following space flight. This study investigated the effect of space flight on subpopulations of peripheral blood mononuclear cells from 30 shuttle astronauts prior to launch, upon landing and 3 days after flight. The total number of peripheral blood leucocytes, granulocytes and monocytes were increased after space flight (5.7 +/- 0.2 versus 7.0 +/- 0.2; 3.1 +/- 0.1 versus 5.0 +/- 0.1; and 0.16 +/- 0.02 versus 0.25 +/- 0.28 x 10(3) cells/mm3, respectively) whereas lymphocytes were decreased (2.2 +/- 0.1 versus 1.7 +/- 0.1 x 10(3) cells/mm3). Flow cytometry analysis on Ficoll-Hypaque isolated mononuclear cells upon landing revealed significant decreases in T-inducer (CD4+, Leu-8+; 32 +/- 2 versus 23 +/- 2%) and T-cytotoxic lymphocytes (CD8+, CD11b-; 17 +/- 1 versus 12 +/- 1%), and increases in monocytes (CD14+; 13 +/- 1 versus 21 +/- 1%) compared to pre-flight and post-flight samples whereas B cells (CD19+), T-helper (CD4+, Leu-8-) and T-suppressor (CD8+, CD11b+) populations did not change. Additional phenotypic analysis of these mononuclear leucocytes from 10 crew members upon landing revealed a reduction in natural killer (NK) cells (CD16+ or CD56+; 9 +/- 1 versus 3 +/- 1%) and an increase in monocytes that were negative for insulin and insulin-like growth factor-1 (IGF-1) receptor expression. Flow cytometric analysis indicated these hormone receptor negative monocytes were smaller and less granular than receptor positive monocytes. Therefore, a novel population of monocytes may be released into the peripheral blood during the stress of space flight or upon landing. These findings may explain some of the diverse in vitro immunological and endocrine changes observed in crew members following space flight.

Adult↗

PubMed1991

Specific binding sites for insulin and insulin-like growth factor I in human endometrial cancer.

Insulin and insulin-like growth factor I are known to be mitogenic and therefore may play a role in the development of endometrial cancer. We undertook this study to investigate whether human endometrial cancer tissue has receptors for these substances. Endometrial cancer tissue samples were obtained at hysterectomy from 10 women with endometrial cancer, and control endometrial tissue was collected from normal cycling women undergoing hysterectomy for nonendocrine problems. Binding studies with iodine 125-insulin and [125I]insulin-like growth factor I revealed the presence of specific binding sites for insulin and insulin-like growth factor I in both normal endometrium and endometrial cancer tissue. The percent binding of [125I]insulin in the endometrial cancer tissue (mean +/- SE 2.4% +/- 0.5%/100 micrograms protein) was not significantly different from that in normal endometrium (3.5% +/- 1%/100 micrograms protein). On the contrary, the percent total binding of [125]insulin-like growth factor I in the endometrial cancer (5.3% +/- 1.5%/100 micrograms protein) was significantly (p less than 0.04) higher than that observed in normal endometrium (2.1% +/- 0.4%/100 micrograms protein). There was a significant positive correlation between the histologic grade of the tumor and the insulin-like growth factor I binding (r = 0.865, p less than 0.02). The affinity constants for the high-affinity receptors were similar in the normal and neoplastic endometrium. These results indicate that insulin and insulin-like growth factor I may play a role in the growth and development of endometrial cancer.

Adult↗

PubMed1991

Insulin-like growth factor-I binds selectively to human peripheral blood monocytes and B-lymphocytes.

Insulin-like growth factor-I (IGF-I) is a potential modulator of responses to a variety of immunological challenges. Previous studies have suggested that specific IGF-I receptors are present on peripheral blood leukocytes, including polymorphonuclear leukocytes, lymphocytes, and monocytes. We sought to determine what type of IGF receptor was present on peripheral blood mononuclear cells and which types of cells possessed these receptors. Binding of [125I]IGF-I to mononuclear cells was inhibited by both unlabeled IGF-I and insulin, insulin being 200-fold less potent than IGF-I. Covalent affinity labeling with [125I]IGF-I, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, revealed a specific binding species with an apparent mol wt of 130 kDa. Two color flow cytometric analysis of mononuclear cells stained with mouse monoclonal antibodies specific for the human IGF-I receptor, the human insulin receptor, and monoclonal antibodies directed against specific monocyte and lymphocyte subset cell surface antigens revealed that both IGF-I receptors and insulin receptors were present on nearly all monocytes and B-lymphocytes, but were present on only 2% of T-lymphocytes. We conclude from these data that among human peripheral blood nonactivated mononuclear cells, IGF-I binds to specific type I IGF receptors found predominantly on monocytes and B-lymphocytes.

Antibodies, Monoclonal↗

PubMed1990

Specific binding sites for insulin-like growth factor I in the ovarian stroma of women with polycystic ovarian disease and stromal hyperthecosis.

Women with polycystic ovarian disease and hyperthecosis have hyperinsulinemia and insulin resistance. It is possible that insulin in supraphysiologic concentration exerts its steroidogenic action on ovarian stromal cells through insulin-like growth factor I receptors. We undertook this study to investigate whether the ovarian stroma of women with hyperthecosis has specific binding sites for insulin or insulin-like growth factor I. Ovarian stromal tissue was obtained from seven women with normal ovulatory cycles and from five women with hyperthecosis of the ovaries. Binding studies with insulin tagged with iodine 125 and insulin-like growth factor I tagged with iodine 125 revealed specific binding sites both for insulin and insulin-like growth factor I in the ovarian stroma. The binding of insulin tagged with iodine 125 in the ovarian stroma of women with hyperthecosis (3.4% +/- 1.1% (+/- SE) per 100 micrograms protein) was significantly (p less than 0.04) lower than that observed in normal premenopausal women (8.3% +/- 1.6% per 100 micrograms protein). By contrast, the specific binding of insulin-like growth factor I tagged with iodine 125 in the ovarian stroma of women with hyperthecosis (7.1% +/- 1.7% per 100 micrograms protein) was higher than that observed in the ovarian stroma from normal women (4.5% +/- 1.7% per 100 micrograms protein), although the difference was not statistically significant. The affinity constants for these high-affinity receptors were similar (1.2 to 3.6 x 10(9) L/mol) in the two groups of women. These results indicate that (1) the ovarian stroma has specific binding sites both for insulin and for insulin-like growth factor I; (2) in women with hyperthecosis, the ovarian stroma has decreased binding sites for insulin but has normal concentrations of insulin-like growth factor I receptors; and (3) in women with hyperthecosis, stimulation of ovarian androgen synthesis by insulin may be mediated through the insulin-like growth factor I receptors.

Adult↗

PubMed1990

Skeletal effects of sodium fluoride during hypokinesia.

This study tested the capacity of fluoride (F) to prevent the disuse-associated reduction in bone formation/growth. Suspending young male Wistar rats by the tail for 2-2.5 weeks reduced femoral cortical (P less than 0.05) and trabecular (P less than 0.01) bone areas. Tetracycline labelling showed that the decrement in cortical area was largely due to a reduction in the percent periosteal mineralizing surface (PsMS). Periosteal mineral apposition rate (PsMAR) was not affected. Endosteal mineralizing surface (EsMS) and mineral apposition rate (EsMAR) were significantly stimulated spontaneously during the second week of suspension. F treatment (5 mg/kg/day i.p.) prevented the loss in bone area, and established a trend toward increased PsMS without affecting EsMS and EsMAR. None of these changes are associated with alterations in serum Ca, P or osteocalcin. F treatment in hypokinetic animals caused a decrease in serum PTH (-21% compared to control; P = 0.001). We conclude that F prevents the development of hypokinetic osteopenia in rats.

Animals↗

PubMed1990

Effect of dietary protein on bed-rest-related changes in whole-body-protein synthesis.

To determine whether increasing dietary protein could exert a beneficial effect on bed-rest-related protein catabolism, two groups of normal subjects were subjected to 7 d of bed rest while taking isocaloric diets containing either 0.6 or 1.0 g protein.kg body wt-1.d-1. Whole-body-leucine turnover, leucine oxidation, and nonoxidative leucine disappearance were measured by use of a constant infusion of 1-13C-leucine. Before bed rest, the higher-protein diet resulted in a 14% decrease in whole-body-leucine turnover and a 28% decrease in leucine oxidation, but net nonoxidative leucine disappearance was not different on the two diets. A 24% decrease in nonoxidative leucine disappearance was seen in subjects assigned to the lower-protein diet, who had been on bed rest, but on the higher-protein diet, leucine kinetics were unchanged by bed rest. Bed rest does not cause an increase in whole-body-protein breakdown, but decreased whole-body-protein synthesis is demonstrable when dietary protein is low. This decrease is prevented by a higher dietary amount of protein.

Adult↗

PubMed1990

Whole body and plasma protein synthesis in exercise and recovery in human subjects.

The effect of 4 h of exercise at 40% of maximal oxygen consumption (VO2 max) on protein metabolism was assessed in normal volunteers maintained on a diet containing 42 kcal.kg-1.day-1 and either 0.9 or 2.5 g protein.kg-1.day-1. Primed constant infusions of [1,2-13C]-leucine and [15N]glycine enabled the quantitation of whole body protein turnover and also the fractional synthetic rates (FSR) of albumin, fibrinogen, and fibronectin. In subjects who did not exercise, the fractional synthetic rates (%/day) on normal and high-protein intakes, respectively, were as follows: albumin, 10 +/- 1 and 9 +/- 1; fibrinogen, 21 +/- 3 and 18 +/- 1; and fibronectin, 31 +/- 3 and 34 +/- 3. Neither exercise nor recovery had an effect of whole body protein turnover or on albumin FSR, but the FSR of fibronectin was significantly elevated at the end of exercise, and fibrinogen was significantly elevated in recovery. Dietary protein intake had no major effect on the response to exercise. Thus, in response to exercise, there is a stimulation of the synthesis of some acute phase proteins, which may be a mechanism whereby nitrogen resulting from muscle protein breakdown is spared.

Amino Acids↗

PubMed1990

Effect of exercise and recovery on muscle protein synthesis in human subjects.

Previous studies using indirect means to assess the response of protein metabolism to exercise have led to conflicting conclusions. Therefore, in this study we have measured the rate of muscle protein synthesis in normal volunteers at rest, at the end of 4 h of aerobic exercise (40% maximal O2 consumption), and after 4 h of recovery by determining directly the rate of incorporation of 1,2-[13C]leucine into muscle. The rate of muscle protein breakdown was assessed by 3-methylhistidine (3-MH) excretion, and total urinary nitrogen excretion was also measured. There was an insignificant increase in 3-MH excretion in exercise of 37% and a significant increase (P less than 0.05) of 85% during 4 h of recovery from exercise (0.079 +/- 0.008 vs. 0.147 +/- 0.0338 mumol.kg-1.min-1 for rest and recovery from exercise, respectively). Nonetheless, there was no effect of exercise on total nitrogen excretion. Muscle fractional synthetic rate was not different in the exercise vs. the control group at the end of exercise (0.0417 +/- 0.004 vs. 0.0477 +/- 0.010%/h for exercise vs. control), but there was a significant increase in fractional synthetic rate in the exercise group during the recovery period (0.0821 +/- 0.006 vs. 0.0654 +/- 0.012%/h for exercise vs. control, P less than 0.05). Thus we conclude that although aerobic exercise may stimulate muscle protein breakdown, this does not result in a significant depletion of muscle mass because muscle protein synthesis is stimulated in recovery.

Adult↗

PubMed1990

Insulin infusion acutely augments ovarian androgen production in normal women.

Euglycemic insulin clamp studies were performed at a sustained physiological insulin concentration of 420 +/- 35 pmol/L (60 +/- 5 muU/mL) in five women who had undergone bilateral oophorectomy and in five intact normal women during the follicular phase of their menstrual cycles to determine the relative contributions of the ovary and adrenal glands in insulin-related augmentation of androgen secretion. Normal women increased their plasma dehydroepiandrosterone (DHEA) concentration by 7.3 +/- 0.4 nmol/L (to 239% +/- 15% of basal), but in oophorectomized women DHEA increased by 1.4 +/- 0.4 nmol/L (to 135% +/- 15% of basal). Thus, the acute response in DHEA to insulin infusion in women without ovaries was only 20% of that seen in intact women. The androstenedione response in oophorectomized subjects was 27% of that seen in controls. We conclude that the insulin stimulation of androgen production occurs predominately at an ovarian site.

Adrenal Glands↗

PubMed1990

Receptors for insulin and IGF-I in bovine lens epithelium.

The presence of insulin receptors has not yet been established in lens epithelial cells. Our goal was to understand the involvement of insulin in lens pathology, especially diabetic cataractogenesis. As a first step in this process, we evaluated the presence of insulin receptors in bovine lens epithelium. Insulin bound to insulin receptor with a high affinity (KD 7.0 nM), although this binding of insulin to its receptor could be replaced by IGF-I (KD 41 nM). Similarly IGF-I binding to IGF-I receptor (KD 0.38 nM) could be inhibited by insulin (KD 53.7 nM). SDS-PAGE and subsequent autoradiography of affinity labeled insulin receptor show the presence of a 130 kDa band, indicating that the lens epithelium insulin receptor may be similar to insulin receptors isolated from other tissues.

Affinity Labels↗

PubMed1989

Dexamethasone effects on creatine kinase activity and insulin-like growth factor receptors in cultured muscle cells.

We examined the effects of dexamethasone on creatine kinase (CK) activity and insulin-like growth factor I (IGF-I) binding in two skeletal muscle-derived cell lines (mouse, C2C12; rat, L6) and in one cardiac muscle-derived cell line (rat, H9c2). Dexamethasone treatment during differentiation of cultured cells caused a dose-dependent increase in CK activity as well as an increase in the degree of myotube formation in C2C12 and L6, whereas H9c2 cells did not exhibit significant CK activities during culture or dexamethasone treatment. Dexamethasone treatment of C2C12 did not stimulate proliferation in differentiating cultures, but a dose-dependent increase in the number of nuclei was observed for L6 concomitant with increased CK activity. In L6 the increased CK activity may therefore reflect a dose-dependent increase in proliferation. Short-term (48 hr) treatment of C2C12 with dexamethasone (20 nM) did not appear to alter myoblast fusion but reversibly increased CK activity. In C2C12 the observed increase in CK, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities with dexamethasone treatment suggest modulation of protein expression and/or turnover. Although the data for dexamethasone effects on CK activities varied in each of the cell lines, consistent behavior was observed in all three cell lines when IGF-I binding was examined. IGF-I binding to dexamethasone-treated cells (50 nM for 24 hr the day prior to confluence) resulted in an increased number of available binding sites, with no effect on the binding affinities. Affinity cross linking and autoradiography indicated that the increase in IGF-I binding was the result of dexamethasone up-regulation of type I IGF receptors. Our data for all three muscle cell lines suggest that similar heterologous hormone receptor modulation of type I IGF receptor sites occurs with dexamethasone treatment.

Alanine Transaminase↗

PubMed1989

Steroid biosynthesis in the Sertoli-Leydig cell tumor: effects of insulin and luteinizing hormone.

In vitro steroid production by a virilizing Sertoli-Leydig cell tumor of the ovary was studied. For comparison, stromal tissue from the opposite normal ovary was also incubated under similar conditions. The tumor fragments secreted significantly more testosterone (527 +/- 168 versus 48 +/- 29 pg/mg tissue, p less than 0.001), androstenedione (1188 +/- 400 versus 40 +/- 10 pg/mg tissue, p less than 0.001), and dehydroepiandrosterone (419 +/- 132 versus 73 +/- 25 pg/mg tissue, p less than 0.004) than that of normal ovarian stroma. Measurement of steroids in the ovarian venous serum draining the tumor indicated a peripheral ovarian gradient for both delta 4 and delta 5 steroids. Incubation of tumor fragments with luteinizing hormone alone resulted in a significant increase in the secretion of androstenedione and dehydroepiandrosterone (p less than 0.05). Addition of insulin to luteinizing hormone resulted in significantly greater release of androstenedione than that of treatment with luteinizing hormone alone (p less than 0.04). Addition of insulin had no effect on the release of dehydroepiandrosterone. Luteinizing hormone and insulin, either alone or in combination, failed to produce any change in the secretion of testosterone. We conclude that (1) increased testosterone secretion by Sertoli-Leydig cell tumor resulted from increased availability of precursors from both delta 4 and delta 5 pathways; (2) the tumor was responsive to luteinizing hormone with an increase in the secretion of androstenedione and dehydroepiandrosterone; (3) insulin acts synergistically with luteinizing hormone to increase secretion of androstenedione; (4) the tumor has specific binding sites for insulin; and (5) the increased levels of insulin and luteinizing hormone in polycystic ovarian disease may play a role in the pathogenesis of Sertoli-Leydig cell tumor.

Adult↗

PubMed1989

Differentiation between septic and postburn insulin resistance.

Sepsis and extensive burn injury produce clinical syndromes characterized in part by "insulin resistance," but it is unclear if these insulin resistant states are identical. To test if the maximal biological effectiveness of insulin is altered in septic or burned patients, eight septic patients and eight nonseptic patients recovering from severe burn injury were studied using the hyperinsulinemic eukalemic euglycemic clamp technique. Compared with bed-rested controls, the septic patients showed an insulin-induced plasma clearance of potassium, which was 183% higher (P less than .001), and a concomitant glucose clearance, which was 52% lower (P less than .001). Nonseptic burn patients also had a 91% increase in potassium clearance (P less than .05), but their maximal insulin-stimulated glucose uptake was not different from that of bedrested controls. When septic patients were compared with their nonseptic burned counterparts, there was no difference in potassium clearance in response to insulin, but glucose uptake by the septic patients was 47% lower (P less than .001). Insulin infusion completely suppressed hepatic glucose production in both septic patients and in nonseptic burn patients. The percent of whole body glucose uptake that was oxidized was not different between the septic patients and the nonseptic postburn patients in both the basal and insulin-stimulated states (38% and 51% v 38% and 42%, respectively). It is concluded that septic and postburn insulin resistance differ in that peripheral glucose uptake in sepsis, but not nonseptic burn injury, is refractory to pharmacologic insulin stimulation, whereas in both states insulin effectively stimulates potassium uptake.

Adult↗