Islet secretion of immunoreactive thyrotropin-releasing hormone and the 'paracrine-like' effects of its exogenous administration
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Abstract. In order to know more about the secretory pattern of islet TRH in response to glucose and its possible physiological relevance, the release of this hormone as well as that of insulin, glucagon, and somatostatin was radioimmunologically measured. Whereas the secretion of immunoreactive insulin and somatostatin by incubated rat islets is known to be dose-dependently stimulated by glucose, that of glucagon and TRH was inhibited by glucose. Similarly, palmitate dose-dependently inhibited islet glucagon and TRH release. Exogenous TRH exerted strong and dose-dependent effects on islet secretion of the other hormones at the same concentration range at which its hypophysiotropic effects are produced (10 −10 to 10 −8 mol/l). It inhibited the insulin response to glucose and blocked that of glucagon, whereas it enhanced glucose-induced stimulation of somatostatin. These results are suggestive of a possible paracrine inhibitory role of islet TRH, either directly exerted on the secretion of insulin and glucagon or partially mediated through the stimulation of somatostatin release.In the rat, hypoglycaemia inhibits growth hormone secretion, but the mechanism is unclear. To investigate this further, we have studied the effects of glucose and 2-deoxy-D-glucose on somatostatin and LHRH release from rat hypothalamic fragments incubated in vitro. Glucose (1.35–22 mM) was added to glucose-free medium and 5 and 50 mM 2-deoxy-D-glucose were added to medium containing 5.5 mM glucose. Medium somatostatin and LHRH levels were measured by RIA. Somatostatin and LHRH released diluted in parallel with synthetic somatostatin and LHRH. Sephadex gel filtration demonstrated two molecular forms of somatostatin, 70% coeluting with somatostatin-14 and 30% with somatostatin-28; LHRH coeluted with synthetic LHRH. KC1 (30–100 mM) resulted in release of somatostatin and LHRH; this was reduced in calcium-free medium. Basal and K+-stimulated somatostatin release were significantly increased by reducing glucose levels (r = -0.6, p < 0.001). Basal LHRH was not influenced by glucose. Basal and K+-induced somatostatin release were significantly increased by 2-deoxy-D-glucose (p < 0.05), while LHRH levels remained unchanged. Our results demonstrate that basal and K+-induced somatostatin release from rat hypothalamic fragments are modulated by local glucose concentrations, and this effect is specific as it is not paralleled by LHRH changes. We suggest that the reduction in growth hormone secretion during hypoglycaemia in the rat might be mediated, at least in part, via a direct effect of glucose on somatostatin release.
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We have found that canine and rat hepatocytes convert (125I)iodoTyr10-glucagon to a peptide metabolite lacking the NH2-terminal three residues of the hormone. The peptide is released into the cell incubation medium and its formation is unaffected by a variety of lysosomotropic or other agents. Use of specific radioimmunoassays and gel filtration demonstrated in both normal subjects and in chronic renal failure patients a plasma peptide having the properties of the hormone fragment identified by cell studies. Studies of the dog revealed a positive gradient of the fragment across the liver and no differential gradient of the fragment and glucagon across the kidney. We conclude that the glucagon fragment arises from the cell-mediated processing of the hormone on a superficial aspect of the hepatocyte, the glucagon fragment identified during experiments in vitro represents the cognate of a peptide formed during the hepatic metabolism of glucagon in vivo, and measurement of the fragment by COOH-terminal radioimmunoassays could lead to an understimulation of hepatic glucagon extraction.
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Ketogenesis
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NON-SELECTIVE INHIBITION OF BASAL GLUCAGON RELEASE BY [d-CYS14]-ANALOGUES OF SOMATOSTATIN IN THE RAT
The effects of two [D-Cys14]-analogues of somatostatin on basal plasma levels of glucagon, insulin and glucose were determined in unanaesthetized rats to re-examine a glucagon-selective action of these peptides which has been claimed by others. Somatostatin, [D-Cys14]-somatostatin and [D-Trp8, D-Cys14]-somatostatin caused a short-lasting, dose-dependent decrease of plasma glucagon and insulin but they had no significant influence on plasma glucose. Glucagon and insulin reached the nadir 2 min after intravenous injection of the peptides (dose range 1--10 micrograms/kg) or 5 min after subcutaneous administration (30 and 300 micrograms/kg). At the nadir, insulin was decreased to a greater extent than glucagon and the effecer the nadir and at high doses, the time-course of some effects of the analogues on either glucagon or insulin differed from that of somatostatin. Thus, these [D-Cys14]-analogues may show partial kinetic dissociation of effects on glucagon and insulin but they are not truly selective inhibitors of glucagon release.
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Pituitary somatostatin receptors. Characterization by binding with a nondegradable peptide analogue.
Somatostatin receptors in the rat pituitary gland were characterized by binding analysis with a radioiodinated high affinity somatostatin analogue, 125I-Tyr1[D-Trp8]somatostatin. Receptor binding of this derivative reached equilibrium at 30 min and was maintained at a plateau for at least 60 min. Two L-Trp8- labeled somatostatin analogues. 125I-Tyr1- and [125I-Tyr11]somatostatin, displayed less stable and lower specific uptake and higher nonspecific binding. In contrast to the rapid degradation of the L-Trp8 ligands during binding assay, 125I-Tyr1]D-Trp8]somatostatin retained more than 80% of its binding activity after 90 min of incubation with pituitary particles. Pituitary particles bound 125I-Tyr1]D-Tyr8]somatostatin with high affinity (Ka = 8.6 +/- 1.2 X 10(9) M-1) and capacity of 54.4 +/- 2.6 fmol/mg. These binding sites showed specificity for the native peptide and its active analogues, and other peptide hormones, including angiotensin II, thyrotropin-releasing hormone, vasopressin, oxytocin, substance P, and gonadotropin-releasing hormone, did not inhibit tracer binding. A good correlation was observed between the binding affinities of several somatostatin analogues and their potencies as inhibitors of growth hormone release in rat pituitary cells. These findings emphasize the physiological importance of the pituitary somatostatin receptor in mediating the inhibitory action of the peptide on growth hormone release. The use of Tyr1[d-Trp8]somatostatin as a labeled ligand permits accurate determinations of the binding affinity and concentration of receptors for somatostatin in the normal pituitary gland and provides a basis for further studies of somatostatin receptor regulation and receptor-mediated cellular effects of the tetradecapeptide.
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Somatostatin was infused for 6 h into seven normal subjects with and without a replacement dose of glucagon. The addition of glucagon to somatostatin resulted in a 30-40% rise in plasma glucagon, whereas plasma insulin declined by 40-50% in both treatment groups. Plasma glucose and glucose production initially increased 2-fold with glucagon replacement, and subsequently declined by 2-3 h to levels comparable to those observed with somatostatin alone. After 6 h plasma glucose and glucose kinetics were no different whether or not glucagon was present. The rise in blood ketones after somatostatin was not exaggerated by glucagon replacement. We conclude that glucagon lack is not a modifying factor in the late hyperglycemic and hyperketonemic response to prolonged infusions of somatostatin.
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Microgram
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Gastrointestinal hormone
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Growth hormone (GH) is secreted as pulses in vivo. To understand the signals governing this periodicity, we have established a perifusion-based model of pulsatile GH release. Male rat anterior pituitaries were dispersed and perifused with pulses of human growth hormone-releasing factor-(1--40) (GHRF), with or without a continuous or discontinuous somatostatin tonus. An experiment was composed of a 1-h base-line collection followed by four 3-h cycles; each contained single or paired 10-min infusion(s) of 3 nM GHRF. In testing the impact of somatostatin, the protocol was identical except that 0.3 nM somatostatin was added 30 min into the base-line period and then was either continued throughout the study or withdrawn during the periods of GHRF infusion. GH base lines with somatostatin were lower than vehicle base lines (P less than 0.05). GHRF pulses generated consistent peaks of GH release between 200 and 300 ng. min-1. (10(7) cells)-1, and these peaks were not altered by continuous somatostatin. In contrast, withdrawal of somatostatin during GHRF administration elicited markedly higher GH peaks (P less than 0.05) and more total GH release (P less than 0.05). This response could not be accounted for by the additive effects of GHRF and somatostatin withdrawal.
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Glucagon is a hormone generated as a result of post translational modifications during proglucagon processing. The hormone's amino acid sequence is found in several proglucagon peptides, including the hormones glicentin and oxyntomodulin. In addition, glucagon’s sequence is similar to incretin hormones such as glucagon-like peptide-1 (GLP-1). The similar sequence homology between glucagon and these peptide hormones has created challenges in specifically measuring glucagon concentrations. Current commercially available glucagon assays have been proven to cross-react with oxyntomodulin, glicentin, and other proglucagon peptides. In addition, researchers often report higher cross-reactivity values than the manufacturers, which further complicates accurately measuring glucagon levels. To address this need, ALPCO has developed the STELLUX® Chemi Glucagon ELISA for the quantitative determination of glucagon in EDTA plasma and cell culture samples. This assay has an excellent sensitivity and is capable of measuring post-prandial glucagon levels in both rodents and humans. Most importantly, this assay specifically measures glucagon without any cross-reactivity to other proglucagon peptides including glicentin and oxyntomodulin. In the current study, ALPCO’s ELISA was compared to competitor A’s ELISA to further investigate how differences in specificity contribute to final calculated concentrations of the analyte. A panel of 16 samples of human, mouse, and rat EDTA plasma were assayed on both products and an overall R2 of 0.988 and slope of 1.337 was shown. The consistently higher recovery in values using the competitor ELISA may be explained through its known cross-reactivity with oxyntomodulin and/or glicentin. However, the correlation between the two assays would allow for a seamless transition from the competitor ELISA to the ALPCO ELISA within or between projects. Disclosure C. Caillouette: Employee; Self; Alpco. B.K. McDermott: None. J.M. Cacicedo: Employee; Self; Alpco. B. Bell: Employee; Self; Alpco. C. Wisherd: Employee; Self; Alpco.
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