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N. R. H. BOYD, D. B. JACKSON, STELLA HOLLINGSWORTH, MARY L. FORSLING and T. CHARD

SUMMARY

A method is described for the extraction and concentration of oxytocin from urine, satisfactory for the radioimmunoassay of this peptide. The recovery of added oxytocin was 64·8 ± 12·6 (s.d.)% from urine samples with an osmolality less than 770 mosm./kg, and 44·9 ± 13·5% for urine samples of greater osmolality. Infusions of oxytocin at a rate of 1 mu./min into male and female volunteers showed a direct relationship between the volume of urine and the total amount of oxytocin excreted during any 1-h period. Extracts of normal male urine contained an immunoreactive material which behaved identically with synthetic oxytocin in two systems of chromatography.

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A V Lee, C-N Weng, J G Jackson and D Yee

Abstract

Estrogen and IGF-I are potent mitogens for most breast cancer cell lines, and although their signaling pathways contrast, there is considerable interaction between them. Recent evidence indicating that IGF-I can alter estrogen receptor (ER) action led us to investigate whether an inhibitor of IGF-I action, IGF-binding protein-1 (IGFBP-1), could affect transcriptional activation of ER. First, we confirmed that tamoxifen (TAM) could inhibit IGF-I-mediated proliferation of MCF-7 cells. Although TAM can increase IGFBP-3 expression in MCF-7 cells, and this binding protein has been shown to be able to inhibit IGF action, TAM had no effect on IGF-I-stimulated tyrosine phosphorylation of IGF-I receptor or the downstream signaling molecule, insulin receptor substrate-1. Therefore, to confirm that IGF-I was affecting transcriptional activation of ER, we utilized a gene reporter assay using a single consensus estrogen response element (ERE-tk-luc) upstream ofluciferase. As expected, estradiol (E2; 1 nm) increased transcriptional activation three- to fivefold from the ERE in three ER-positive breast cancer cell lines (MCF-7, ZR-75 and T47D). A 2·5- to 4-fold increase was also seen with IGF-I (5 nm). TAM (1 μm) effectively blocked activation by E2 and IGF-I, indicating disruption of ER-mediated transcription. As expected, human recombinant IGFBP-1 (80 nm) completely inhibited IGF-I-mediated activation of ER, however, IGFBP-1 also caused a significant decrease in E2-mediated activation. We also noticed that IGF-I increased the activity of all plasmids that we cotransfected including TATA-luc, SV40-luc and pGLBasic. This effect was post-transcriptional, as it was not affected by actinomycin D (2 μg/ml), while we were able to completely inhibit E2-mediated transcriptional activation of ERE-tk-luc. Unlike the complete inhibition of ER-mediated transcriptional activation by actinomycin D, IGF-I-mediated transactivation was reduced by only 50%, indicating that the activation by IGF-I represented both transcriptional and post-transcriptional effects. This study confirmed that IGF-I can cause transcriptional activation of endogenous ER in human breast cancer cells, and inhibition of ER action by IGFBP-1 suggests that IGF-I signaling may be necessary for maximal ER activation.

Journal of Endocrinology (1997) 152, 39–47

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S B Bowes, N C Jackson, D Papachristodoulou, A M Umpleby and P H Sönksen

Abstract

The net catabolic effect of glucocorticoids on protein metabolism is well documented but the acute and chronic effect of glucocorticoids on protein breakdown remains controversial. In the present studies protein breakdown was measured by the release of tyrosine from the isolated soleus and extensor digitorum longus (EDL) muscles of control rats and rats treated with corticosterone (10 mg/100 g body weight/day) for 5 days.

The effect of corticosterone in arresting growth was confirmed since corticosterone-treated rats weighed significantly less than control rats after 2, 3, 4 and 5 days of treatment (P<0·001). Furthermore, the weights of soleus and EDL muscles from corticosterone-treated rats were significantly reduced (P<0·001, at least P<0·05 respectively) compared with muscles from control rats on days 3–5.

In the EDL muscle tyrosine release was significantly elevated after corticosterone treatment for 2 days (257 ± 21 nmol/g tissue/h, P<0·05), 3 days (205 ± 9 nmol/g tissue/h, P<0·01), 4 days (255 ± 20 nmol/g tissue/h, P<0·005) and 5 days (218 ± 8 nmol/g tissue/h, P<0·05) compared with EDL from control rats (192 ± 13, 171 ± 7, 187 ± 7, 180 ± 12 nmol/g tissue/h respectively). In the soleus muscle, tyrosine release was significantly elevated after corticosterone treatment for 2 days (226 ± 14 nmol/g tissue/h, P<0·001), 3 days (223 ± 16 nmol/g tissue/h, P<0·001) and 4 days (199 ± 10 nmol/g tissue/h, P<0·001) compared with control rats (158 ± 7, 132 ± 6 and 153 ± 7 nmol/g tissue/h respectively). After 5 days there was no significant difference in tyrosine release from soleus muscle between corticosterone-treated (176 ± 15 nmol/g tissue/h) and control rats (157 ± 6 nmol/g tissue/h). Plasma glucose concentrations were not significantly different in rats treated with corticosterone and control rats whilst insulin levels were significantly raised in the corticosterone-treated rats on all days compared with control rats (P<0·05 on day 1; P<0·001 on days 2, 3, 4 and 5). It is suggested that insulin may have prevented hyperglycaemia developing in the corticosterone-treated rats. Results from these studies indicate that the acute effect of glucocorticoids is to increase muscle proteolysis but this is not maintained with longer-term treatment.

Journal of Endocrinology (1996) 148, 501–507

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I. M. D. JACKSON, C. R. M. PRENTICE and MARGARET T. McKIDDIE

Although the clinical association of hypothyroidism and diabetes mellitus is well known (Phair, Bondy & Abelson, 1965; Hecht & Gershberg, 1968) there have been few studies of glucose and insulin metabolism in hypothyroidism before and after treatment; this paper reports our findings in ten such subjects.

Ten patients (9 female, 1 male; aged 43–73 yr.) with obvious clinical hypothyroidism, due to primary thyroid failure confirmed by a combination of serum protein-bound iodine, radioactive iodine studies with thyroid-stimulating hormone stimulation (as appropriate) and thyroid antibody studies, were investigated. None were known to be diabetic. An oral glucose tolerance test (50 g.) before and after treatment was performed, venous blood being removed for determination of blood sugar and plasma insulin levels at 0, 30, 60, 90 and 120 min. The sugar was measured as total reducing substances in a Technicon auto-analyser and plasma insulin by the double antibody radioimmunoassay method of Hales

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Melissa F Jackson, Dung Luong, Dor Dor Vang, Dilip K Garikipati, James B Stanton, O Lynne Nelson and Buel D Rodgers

The natural aging process results in the physiological decline of multiple tissues and organ systems. Changes commonly occur with middle age and include decreased skeletal muscle mass, bone mineral density, cardiac output, and insulin sensitivity, and increased adiposity, all of which can contribute to the onset of sarcopenia, osteoporosis, heart failure, or type 2 diabetes. Recent studies suggest that myostatin may influence many of these systems. We therefore sought to determine whether they are affected by aging, especially in ‘middle-aged’ Mstn −/− mice (12–20 months old (m.o.)). Although body weights were similar in wild-type (WT) and Mstn −/− mice, lean fat-free mass and skeletal muscles composed of predominantly type I, II, and mixed fibers were significantly heavier in Mstn −/− mice. These differences were accompanied by lower total adiposity, especially in female mice, white and brown fat pad weights, and adipocyte size. Hearts were heavier in Mstn −/− mice across a large age range (3–24 m.o.) and exhibited signs of dilated cardiomyopathy at rest, which include lower strain measurements compared with WT myocardium. However, Mstn −/− mice responded better to isoproterenol stress tests with greater increases in fractional shortening and ejection fraction—differences that were again more apparent in females and which are consistent with physiological cardiac hypertrophy. Spleens and kidneys were also smaller, although histologically normal, in Mstn −/− mice. These data together suggest that attenuating myostatin could potentially prevent or possibly treat pathological conditions that develop with age. Additional studies are nevertheless needed to definitively assess potential risks to cardiac function.