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ABSTRACT
We have previously reported a lack of effect of a depolarizing concentration of K+ on the release of vasoactive intestinal polypeptide (VIP) from the perifused rat hypothalamus, and suggested that this was due to the presence of an endogenous inhibitor of the release of VIP. In this study we report that the VIP response to K+ was restored if the hypothalami were obtained from animals killed during the dark phase of the light–dark cycle. Adrenaline blocked the K+-stimulated release of VIP when used at a concentration of 0·1 μmol/l; however, at a higher concentration (10 μmol/l) adrenaline stimulated the basal release of VIP. The use of specific receptor antagonists indicated that this dual effect of adrenaline was mediated through two distinct receptors, a stimulatory β-receptor and an inhibitory α2-receptor. The suggestion that adrenaline might be the endogenous inhibitor of the release of VIP, mediating the diurnal variation in the effect of K+, was supported by studies where 50 mmol K+/l was perifused concomitantly with an α2-antagonist, restoring the VIP response to K+ in light-phase hypothalami. In conclusion, adrenaline has a dual role in the control of VIP release and may function to inhibit the K+-stimulated release of VIP in our system.
J. Endocr. (1988) 116, 335–341
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ABSTRACT
During pregnancy, in women and the rat, there is a resetting of the plasma osmolality–arginine vasopressin relationship (Posmol/PAVP) such that a decrease in Posmol is maintained without suppression of PAVP. This occurs at a time when relaxin is detectable in plasma. The hypothesis tested here was that relaxin could alter the Posmol/PAVP in the non-pregnant rat. One group of ovariectomized rats (n = 15) was treated for 7 days with intravenous synthetic human relaxin (10 μg/h) in 10 pi 0·9% (w/v) NaCl. Controls were two groups of rats either with no treatment (n = 15) or treated with vehicle alone (n = 15). One-third of each group received hypertonic saline (0·4 mol NaCl/l, 2 ml/100 g body weight i.p.) on day 7, and one-third were deprived of water for the final 24 h. All rats were killed by decapitation and blood was collected rapidly (<40 s) for hormone and osmolality assays. The Posmol in all relaxin-treated rats was significantly (P < 0·001) lower than that in both control groups, but the PAVP was unchanged. The log PAVP/Posmol regression line was significantly shifted in elevation (P <0·001) but not in slope. Thus treatment of ovariectomized rats with relaxin caused changes in fluid balance which mimic those occurring in normal pregnancy.
Journal of Endocrinology (1993) 137, 505–510
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SUMMARY
A partially purified fraction of human thyroid-stimulating hormone (DEAE-II) was further purified by ion-exchange chromatography on IRC-50, gel-filtration on Sephadex G-100 and finally chromatography on DEAE-cellulose. Two fractions were obtained which were high in thyroid-stimulating activity (8·3 and 7·3 units human Research Standard A/mg) and were comparable in potency to other preparations of the human hormone reported in the literature. They were also electrophoretically heterogeneous as were the preparations of other workers. Lipolytic activity toward cells obtained from human or rat adipose tissue was demonstrated for all fractions containing thyroid-stimulating activity, the two activities being roughly parallel. It is concluded that both thyroid-stimulating and lipolytic activities are probably present in the same protein molecule, but it is unlikely that the latter activity is of physiological significance.
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Search for other papers by ANNE STOCKELL HARTREE in
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SUMMARY
Attempts to isolate, free of thyroid-stimulating hormone (TSH), the peptide(s) responsible for the lipolytic activity of a fraction of acetone-dried human pituitary powder are described. It was not found possible to separate the lipolytic and TSH activities, even by isoelectric focusing which gave fractions consisting predominantly of single protein components. In the four lipolytic fractions isolated by electrofocusing, the two activities paralleled one another. It is therefore concluded that the TSH present is responsible for the lipolytic activity of this human pituitary fraction, though some evidence suggests that luteinizing hormone (LH), which is a minor contaminant, might also be lipolytic.
The minimum effective lipolytic concentration of the most potent fraction isolated was in the range 0·1–1·0 μg/ml. This is far in excess of plasma concentrations of TSH or LH encountered physiologically. Hence the lipolytic action of these molecules is unlikely to be of physiological significance.
Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.
