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J. D. GREEN and G. W. HARRIS

There is little doubt that the secretory activity of the adenohypophysis is to some extent under the control of the nervous system [see Marshall, 1936, 1942; Brooks, 1939]. Two hypotheses have been advanced by various authors to explain this neural control: first, that the glandular cells possess a direct secretor-motor nerve supply, or secondly, that a humoral relay transmits the nervous stimuli from the hypothalamus by means of the hypophysial portal vessels.

The nerve supply of the hypophysis is derived from several sources. A sympathetic supply was first described by Bourgery in 1845. It consists of a few fine twigs passing from the carotid plexus to the pars distalis. The method of termination of these fibres and their function remain doubtful. Possibly they end on gland cells and are secretomotor, but more probably they end on blood vessels and are vasomotor. It is certain, however, that they do not subserve

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N. K. Green, J. A. Franklyn, J. A. O. Ahlquist, M. D. Gammage and M. C. Sheppard

ABSTRACT

The effect of tri-iodothyronine (T3) treatment on myocardial levels of α and β myosin heavy chain (MHC) mRNAs in the rat was defined in vivo and in vitro. Dose–response experiments were performed in intact hypothyroid and euthyroid rats; in addition, studies in vitro examined the effect of T3 on MHC mRNAs in neonatal cardiac myocytes in primary culture. Specific α and β MHC mRNAs were determined by Northern blot and dot hybridization to oligonucleotide probes complementary to the 3′ untranslated regions of the MHC genes. An increase in myocardial β MHC mRNA was demonstrated in hypothyroidism, accompanied by a reduction in α MHC mRNA. Marked differences in the sensitivity of α and β MHC mRNAs to T3 replacement were found; a dose-dependent increase in α mRNA was evident at 6 h after T3 treatment, in the absence of consistent effects on β mRNA, whereas 72 h after T3 replacement was commenced, stimulatory effects of T3 on α MHC mRNA, evident at all doses, were accompanied by a dose-dependent inhibition of β MHC mRNA. No effect of thyroid status on actin mRNA was found, indicating the specificity of MHC gene regulation. T3 treatment of cardiac myocytes in vitro exerted similar actions on MHC mRNAs to those found in vivo, with a more marked influence on α than β MHC mRNA. These studies of the action of T3 in vivo and in vitro have thus demonstrated specific effects of T3 on pretranslational regulation of the α and β MHC genes, influences which differ not only in terms of stimulation or inhibition, but also in magnitude of effect.

Journal of Endocrinology (1989) 122, 193–200

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J. SKARDA, C. D. GREEN, R. P. G. AISBITT and J. M. BARRY

The parenchymal cells of cultured mammary tissue from C3H mice in late pregnancy can be stimulated to synthesize DNA and to divide by the addition of insulin to the culture medium (Stockdale & Topper, 1966), which need contain only glucose, amino acids and inorganic salts (Green, Skarda & Barry, 1971). Insulin also stimulates the formation of glucose-6-phosphate dehydrogenase and apparently does this by stimulating the uptake of glucose by the tissue (Green et al. 1971). The results reported here suggest that insulin stimulates DNA synthesis by a different mechanism.

Figure 1 shows that with insulin, maximum incorporation of [3H]thymidine into DNA over 22 h of culture occurs at a glucose concentration of about 80 mg/100 ml or a fructose concentration of 500 mg/100 ml. Without insulin there is little incorporation, even with the high concentrations

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C. D. GREEN, J. SKARDA, R. P. G. AISBITT, M. E. TRENCH and J. M. BARRY

Organ culture of mammary tissue from pregnant mice is normally performed in the defined but complex Medium 199 (Rivera & Bern, 1961; Stockdale, Juergens & Topper, 1966). We have recently reported the use of a much simpler medium containing only inorganic salts, amino acids and glucose (Green, Skarda & Barry, 1971). This medium allows precise studies to be made of substrate requirements of the tissue at different stages of culture. The stimulation by insulin of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities, and of DNA synthesis, was identical when mammary tissue was cultured in Medium 199 and in our simplified medium (Green et al. 1971). We report here that the simplified medium is also as satisfactory as Medium 199 for certain responses that require prolactin and hydrocortisone.

Batches of 20 explants (about 7 mg of tissue) from the mammary glands of pregnant C3H mice were cultured in 5 ml of

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N. K. Green, M. D. Gammage, J. A. Franklyn and M. C. Sheppard

ABSTRACT

Effects of thyroid status on expression of a variety of myocardial genes, such as those encoding contractile proteins, have been reported, as well as interactions between thyroid hormones and developmental and haemodynamic regulation of contractile protein synthesis. In addition, it is clear that developmental and haemodynamic factors regulate expression of specific proto-oncogenes, including c-myc, c-fos and H-ras, in the myocardium but the effect of thyroid status on such proto-oncogene products, which are proposed to play a critical signal-transducing role in the heart, has been previously unexplored.

In order to determine whether changes in thyroid status are associated with changes in expression of these putative intracellular signals, we examined the effect of hypothyroidism and tri-iodothyronine (T3) treatment on myocardial levels of c-myc, c-fos and H-ras mRNAs in the rat. The induction of hypothyroidism was associated with a marked increase in myocardial c-myc, c-fos and H-ras mRNAs, changes reversed by 72 h of T3 replacement. Administration of T3 to euthyroid rats had no significant effect on myocardial c-myc or c-fos mRNAs, but inhibition of H-ras mRNA by T3 was evident. These observations demonstrating influences of thyroid status on expression of specific proto-oncogenes suggest that thyroid hormones, as well as exerting direct effects on expression of functionally important myocardial genes, also interact with the cellular transduction pathways mediated by the products of the c-myc, c-fos and H-ras genes.

Journal of Endocrinology (1991) 130, 239–244

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W. A. Ratcliffe, E. Green, J. Emly, S. Norbury, M. Lindsay, D. A. Heath and J. G. Ratcliffe

ABSTRACT

Parathyroid hormone-related protein (PTHrP) was measured in human and bovine milk by radioimmunoassay (RIA) and bioassay, and the molecular forms characterized by gel chromatography and immunoblotting of affinity-purified PTHrP. Mean immunoreactive PTHrP(1–34) concentrations were 23 and 87 μg/l in human and bovine milk respectively. Bioactive (BIO) PTHrP concentrations determined by cyclic AMP production by ROS 17/2·8 cells correlated significantly (P< 0·001) with those obtained by RIA (BIO = 1·04RIA−3·4, r = 0·939). Gel filtration of human and bovine milk identified several peaks with immunoactivity and bioactivity. Immunoblotting of affinity-purified PTHrP revealed multiple molecular species including components with mobilities similar to those of PTHrP and its subfragments. These studies confirm the presence of immuno- and bioactive PTHrP in milk and suggest that post-translational processing is complex and variable.

Journal of Endocrinology (1990) 127, 167–176

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B D Green, N Irwin, V A Gault, C J Bailey, F P M O’Harte and P R Flatt

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9–39)amide (Ex(9–39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9–39) was confirmed in ob/ob mice by blockade of the insulin-releasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9–39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucose-stimulated insulin secretion were not significantly affected by chronic Ex(9–39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9–39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucose-lowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.

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J C Parker, K S Lavery, N Irwin, B D Green, B Greer, P Harriott, F P M O’Harte, V A Gault and P R Flatt

Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3–42) and GLP-1(9–36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9–36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3–42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3–42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.