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P A Martin
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A Faulkner
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Abstract

The effects of intravenous somatostatin-28 (S28) infusion on glucose-stimulated and glucagon-like peptide-1(7–36)amide (GLP-1)-augmented insulin secretion were studied in sheep. S28 was infused via a jugular catheter for 15 min at a rate of 1·1 pmol/kg/min either alone or together with GLP-1 and/or glucose. S28 infusion did not significantly lower circulating basal insulin concentrations in fed sheep. Glucose-stimulated insulin secretion was significantly inhibited by S28 infusion, serum concentrations decreasing from about 200 to 150 pmol/l. GLP-1 significantly augmented glucose-stimulated insulin secretion, serum concentrations increasing from about 230 to 280 pmol/l. S28 completely counteracted this effect of GLP-1. S28 infusion also significantly decreased the circulating concentrations of glucose-dependent insulinotrophic polypeptide (GIP) and GLP-1 in fed sheep (from about 110 to 45 pmol/l for GIP and from about 25 to 15 pmol/l for GLP-1). The physiological implications of these observations are discussed with particular reference to the ruminant. It is concluded that S28 may have an important endocrine role in the control of insulin secretion and regulation of nutrient partitioning.

Journal of Endocrinology (1996) 151, 107–112

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P. A. Martin
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A. Faulkner
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J. P. McCarthy
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ABSTRACT

Plasma concentrations of gastric inhibitory polypeptide (GIP) were measured in preruminant goat kids before and after consumption of milk, skimmed milk or solutions of milk fat, lactose, glucose or casein plus lactose. GIP concentrations increased significantly within 1 h of consumption of milk or milk fat, and were elevated for the remainder of the 5-h sampling period. The integrated mean change in GIP concentration during this period did not differ between these two meals. GIP levels were slightly increased above basal values 5 h after skimmed milk consumption, probably reflecting the absorption of a small amount of fat, but overall there was no significant GIP response to this or to any of the other test meals. The marked increase in GIP concentration after a milk feed indicates a physiological role for the hormone in preruminants but, in contrast to the situation in simple-stomached animals, carbohydrate absorption does not elicit GIP secretion in the preruminant goat. The data strongly suggest that fat is the major nutrient to stimulate GIP secretion in these animals.

Journal of Endocrinology (1993) 138, 167–173

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J. P. McCarthy
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A. Faulkner
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P. A. Martin
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D. J. Flint
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ABSTRACT

Plasma concentrations of gastric inhibitory polypeptide (GIP)-like activity were determined in sheep before and after refeeding following a 48-h fast. Plasma concentrations increased significantly after feeding, from about 250 pg/ml to about 550 pg/ml. Other metabolites in plasma also increased at this time, reflecting the absorption of nutrients from the gastrointestinal tract. Significant increases were observed in the plasma concentrations of acetate, β-hydroxybutyrate and triacylglycerol. By comparing the time-courses of the changes in concentration of GIP and other metabolites in plasma, possible sites of secretion and secretagogues of GIP in ruminant animals are proposed. The results demonstrate that GIP is secreted in response to nutrient absorption in adult ruminants and that, as in simple-stomached animals, the absorption of long-chain free fatty acids plays an important role in this secretion.

Journal of Endocrinology (1992) 134, 235–240

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G. B. Martin
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P. L. Taylor
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A. S. McNeilly
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ABSTRACT

Previous work has shown that treatment of ewes with steroid-free bovine follicular fluid (bFF), a rich source of inhibin, partially inhibits the increase in mean plasma concentrations of LH induced by ovariectomy. The present experiment was designed to test the hypothesis that this effect was a reflection of reduced LH pulse amplitude which would only be expressed at high (pharmacological) doses of bFF. To do this, we assessed the dose–response to bFF of the secretion of FSH and LH pulses in intact and acutely ovariectomized ewes.

In intact ewes, a low dose of bFF (0·2 ml s.c. every 8 h) had no detectable effect on the secretion of FSH, an intermediate dose (0·6 ml s.c. every 8 h) depressed FSH concentrations for about 24 h and a high dose (1·8 ml s.c. every 8 h) reduced FSH concentrations to undetectable levels. In ewes treated with 1·8 ml bFF, FSH concentrations also remained undetectable after ovariectomy and did not increase until treatment was withdrawn. In ewes treated with 0·6 ml bFF, FSH concentrations were maintained at normal intact levels for about 32 h following ovariectomy but then rose to normal ovariectomized levels. In ewes treated with 0·2 ml bFF, FSH concentrations increased immediately after ovariectomy but more slowly than in control ovariectomized ewes. Profiles of LH pulses were recorded after ovariectomy, during and after the withdrawal of bFF treatment. In ewes treated with the highest dose (1·8 ml s.c. every 8 h), mean LH levels and pulse amplitude were lower than in control ewes and increased significantly following withdrawal of treatment. None of the other pulse variables measured (apparent half-life, pulse interval, nadir) were significantly affected. The lower doses did not significantly affect LH secretion.

It was concluded that FSH secretion can be inhibited for short periods by low doses of inhibin and that a dose of 0·6 ml bFF every 8 h is approximately equivalent to normal ovarian output. However, another factor, possibly oestrogen, is also involved in the long-term regulation of plasma FSH concentrations. The inhibitory effect of bFF on LH pulse amplitude was only observed at the highest dose, suggesting that it is a pharmacological effect and that it is unlikely that inhibin plays a major role in the control of tonic LH secretion.

J. Endocr. (1987) 114, 73–79

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G. A. Lincoln
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F. J. P. Ebling
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G. B. Martin
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ABSTRACT

The role of endogenous opioid peptides in the inhibitory control of pulsatile LH secretion was studied in adult Soay rams at different stages of the seasonal reproductive cycle, entrained by an artificial lighting regimen of alternating 16-week periods of long and short days. The LH responses to the acute administration of naloxone (opioid antagonist) and morphine (opioid agonist) were measured in intact rams (n = 7), testosterone-implanted castrated rams (n = 8) and castrated rams (n = 8) to assess the interaction between photoperiod and gonadal steroids in the opioid control of LH secretion.

In the intact and testosterone-implanted castrated rams, naloxone (1·7 mg/kg i.v.) increased and morphine (1·0 mg/kg i.v.) decreased mean LH concentrations and LH pulse frequency during the sexually active phase under short days, but these effects were reduced or absent during the inactive phase under long days. The changes in the LH responses occurred in close parallel with the photoinduced changes in endogenous LH secretion. In the castrated rams receiving no supplementary testosterone, plasma LH concentrations were permanently raised and there were only minor changes related to the photoperiod. Naloxone (1·7 mg/kg) induced transient increases in LH secretion at all stages, and morphine (1·0 mg/kg) failed to suppress LH levels under both short and long days. LHRH stimulation tests revealed that there were changes in LH release related to the induced reproductive cycle in the intact and testosterone-implanted rams but not in the castrated rams; these changes in the responsiveness of the pituitary gonadotrophs to LHRH could not account for the changes in the LH response to the opiate drugs.

These results illustrate that an endogenous opioid mechanism is involved in the tonic inhibition of LH secretion acting to regulate the pulsatile release of LHRH from the hypothalamus. This system can be shown to be functional in a steroid-dependent manner in the sexually active phase of the seasonal cycle, but not in the inactive phase of the cycle when non-opioidergic mechanisms are presumed to predominate in the inhibition of LH secretion.

J. Endocr. (1987) 115, 425–438

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B. T. MARTIN
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B. A. COOKE
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W. P. BLACK
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SUMMARY

A competitive protein-binding method for the measurement of progesterone in plasma of human subjects was investigated. The purification steps necessary to achieve good accuracy, precision and specificity were determined. It was found that one paper chromatographic separation of unwashed ethyl acetate plasma extracts was sufficient, providing that the sample contains a minimum of 1 ng. progesterone. Water blank values equivalent to 0·05 ng. progesterone were consistently obtained. The concentrations of progesterone found in plasma during the follicular and luteal phases of the menstrual cycle and in male plasma were 0·14 ± 0·14, 0·82 ± 0·74 and 0·022 ± 0·015 (s.d.) μg./100 ml., respectively.

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A P D Lord
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A A Martin
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F J Ballard
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L C Read
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Abstract

The net transfer of 125I-labelled insulin-like growth factor (IGF)-I from the blood to the distal small intestine was measured in anaesthetized lambs using a non-recirculating vascular-perfused intestine. To determine whether IGF-binding proteins (IGFBPs) reduce net IGF transfer, radio-labelled IGF-I was compared with two analogues, des(1–3)IGF-I and LR3IGF-I, which show reduced affinity for IGFBPs. Radiolabelled IGF-I, des(1–3)IGF-I or LR3IGF-I (1 ng/ml plasma) was infused for 45 min into the arterial supply of a 10 cm intestinal segment, either in the absence of added unlabelled peptide (high specific activity) or in the presence of a 100-fold excess of unlabelled homologous peptide (low specific activity) to achieve different proportions of free and complexed peptide. Very little degradation of radiolabelled peptides was detected in plasma, with 3–10% degradation in the intestinal tissue. Less than 5% of radiolabelled IGF-I remained as free peptide in the efferent venous plasma of the perfused segment at both specific activities. Bound radio-labelled IGF-I was found by size-exclusion chromatography mainly in the 30–50 kDa region, with a smaller proportion in the 150 kDa peak. The net intestinal transfer of IGF-I, calculated as the sum of the proportions of infused tracer recovered from intestinal tissue, luminal contents and lymph, was 3·46 ± 0·22% (s.e.m.) and 3·49 ± 0·93% when infused at high and low specific activities respectively. The analogues differed from IGF-I with up to ninefold higher concentrations of free radio-labelled peptide in venous plasma of the perfused intestinal segment, and corresponding decreases in binding to the 30–50 kDa binding proteins. Notwithstanding these marked differences in the plasma levels of free peptide, net intestinal transfer was very similar for the three peptides, as was the extent of degradation in the intestinal tissue. The lack of correlation between binding to 30–50 kDa binding proteins and net intestinal transfer suggests that association with 30–50 kDa plasma binding proteins is not a rate-limiting determinant of net IGF transfer to intestinal tissue.

Journal of Endocrinology (1994) 141, 505–515

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A P D Lord
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L C Read
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P C Owens
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A A Martin
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P E Walton
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F J Ballard
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Abstract

Halothane anaesthesia in young sheep results in greatly increased plasma binding capacity for radiolabelled insulin-like growth factor (IGF), as demonstrated using size-exclusion chromatography. Most of the increased binding was at an estimated molecular mass range of 30–50 kDa, with a smaller increase evident at 130–150 kDa. These changes were not evident in control animals which had food withheld for the same period. The progressive increase in plasma radioligand binding during anaesthesia was the net result of a rise in circulating levels of a 29–31 kDa IGF-binding protein (IGFBP), as shown by ligand blotting, and declining plasma concentrations of IGF-I and IGF-II. Recovery from anaesthesia was accompanied by the restoration of plasma IGFs and the IGFBP towards pre-anaesthesia concentrations. The induced IGFBP was provisionally identified as IGFBP-1 because it bound anti-IGFBP-1 antiserum but not antibodies against IGFBP-2, IGFBP-3 or IGFBP-4. The elevation of plasma IGFBP-1 immunoreactivity was associated with reduced concentrations of glucose and insulin, the regulators of IGFBP-1 in humans and rats. These results suggest that IGF experiments that require anaesthesia but assume that the anaesthetised state is representative of conscious sheep should be reassessed. A similar situation may occur with other mammalian species.

Journal of Endocrinology (1994) 141, 427–437

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P. B. GREENBERG
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T. J. MARTIN
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R. A. MELICK
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P. JABLONSKI
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J. McK. WATTS
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SUMMARY

The metabolic clearance rate (MCR) of porcine calcitonin in six gilts was 13·0 ± 0·7 (s.e.m.) ml/min/kg and in four isolated, perfused pig livers was 16·1 ± 1·1 ml/min, with constant infusions of porcine calcitonin and measurement of calcitonin concentration by radioimmunoassay.

After single injections of 125I-labelled porcine calcitonin, the MCR of 125I-labelled porcine calcitonin was 29·2 ± 2·8 ml/min in six isolated, perfused pig livers.

125I-labelled salmon calcitonin was cleared at a slower rate than porcine calcitonin after single injections into the gilt. 125I-Labelled human calcitonin and 125I-labelled salmon calcitonin were not significantly cleared by the isolated, perfused pig liver.

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A. P. D. Lord
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A. A. Martin
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P. E. Walton
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F. J. Ballard
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L. C. Read
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ABSTRACT

Heparinized samples of plasma, cerebrospinal fluid (CSF) and lymph from intestinal, prescapular and popliteal lymph nodes were collected from young lambs in order to characterize and compare the insulin-like growth factor-binding proteins (IGFBPs) in extracellular fluids with those from the circulation. Prior to collection and analysis, the superiority of heparin for plasma preparation was established over EDTA and citrate or the use of serum, according to the extent of IGF-I and IGF-II binding achieved in the high molecular mass IGFBP region in vitro. The IGFBPs were characterized by ligand blotting and competitive binding techniques using radiolabelled IGF-I, IGF-II and the truncated IGF analogue, des(1–3)IGF-I, as well as by ligand blotting of fractions after Superose 6 chromatography of incubations of fluids with labelled factors. This combined analysis demonstrated an IGF-II-specific binding protein at approximately 250 kDa that was present in plasma and each lymph type and presumably represented the soluble type-2 IGF receptor; a complex of 130 kDa containing 52 kDa and 46 kDa binding proteins that was labelled by all three IGF peptides was particularly evident in plasma and intestinal lymph and was probably a complex between IGFBP-3 and the acid-labile subunit; and a group of binding proteins that chromatographed as IGF complexes at approximately 50 kDa. This last group contained IGFBP bands of 52, 46, 35, 28 and 23·5 kDa in plasma and all lymphs as well as an IGF-II-specific band of 22 kDa in prescapular and popliteal lymphs. CSF differed qualitatively from plasma and lymph in that the 52/46 kDa IGFBP bands were undetectable in this fluid; the 35 kDa band was the predominant binding protein, and neither this nor the 28, 23·5 and 22 kDa proteins bound des(1–3)IGF-I to any significant extent. The 52,46 and 28 kDa bands in plasma and lymph did bind this ligand. Immunoblots using antisera against bovine IGFBP-2 showed binding at 35 kDa in all fluids as well as several bands at lower molecular masses. Taken together these results show not only marked differences in the binding protein profiles of sheep plasma, lymph and CSF, but both qualitative and quantitative differences between intestinal, prescapular and popliteal lymphs. We speculate that the differences between lymphs may result from tissuespecific release of binding proteins into extracellular fluid.

Journal of Endocrinology (1991) 129, 59–68

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