Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We examined the cooperative effect of a newly synthesized oral hypoglycaemic agent, KAD-1229 with glucose on insulin, glucagon and somatostatin secretion in the isolated perfused pancreas of the rat. 2. KAD-1229 stimulated concentration-dependently the first phase of insulin secretion without the second phase in the presence of 2.8 mM glucose, while it stimulated both the first and the second phase of insulin release in the presence of 5.6 mM glucose. It was confirmed that the first phase of insulin release is depolarization-induced release with no other additional signal transduction. 3. KAD-1229 also enhanced insulin release evoked by 16.7 mM glucose, a concentration known to inhibit the ATP-sensitive K+ current completely. 4. A low concentration (2.8 mM) of glucose stimulated somatostatin release transiently, while a higher concentration (16.7 mM) of glucose exerted a sustained stimulation. KAD-1229 stimulated somatostatin secretion in a concentration-dependent manner irrespective of glucose concentrations. 5. When glucagon release was stimulated with 2.8 mM glucose, KAD-1229 inhibited this hypoglycaemia-induced glucagon secretion. 6. When pancreata from rats pretreated with streptozotocin (STZ) 60 mg kg-1 were perfused, the basal secretion of glucagon was markedly elevated, and the glucagon response to the low glucose was abolished. Further, the insulin and somatostatin responses to KAD-1229 were largely attenuated. KAD-1229 showed transient enhancement followed by inhibition of the glucagon release from the STZ-pretreated rat pancreas. 7. We conclude that KAD-1229 stimulates insulin and somatostatin release, while it inhibits glucagon release following transient stimulation.
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PMID:Effect of a non-sulphonylurea hypoglycaemic agent, KAD-1229 on hormone secretion in the isolated perfused pancreas of the rat. 873 79

The regulation of clonal rat insulinoma (RINm5F) cell proliferation and hormone accumulation was investigated with the aim of identifying putative compounds capable of inducing differentiation, i.e. decreased growth and increased insulin accumulation, by the tumor cells. In particular, interest was focused on the role of a number of peptides as well as pharmacological probes modulating various signal transduction systems and which have been shown to regulate normal beta-cell proliferation and insulin accumulation. Growth hormone stimulated insulin accumulation and inhibited DNA synthesis, whereas galanin and insulin-like growth factor I caused a moderate suppression of insulin accumulation but did not affect proliferation, while epidermal growth factor, transforming growth factor beta, platelet-derived growth factor, acidic and basic fibroblast growth factor, bradykinin and somatostatin were virtually inactive on all parameters tested. Exogenous prostaglandins E2 and F1 alpha were inactive, while the cycloxygenase inhibitor indomethacin slightly suppressed insulin accumulation. The cytokine IL-1 beta caused a significant decrease in both beta-cell mitogenesis and insulin accumulation, effects that were mediated through nitric oxide generation. The vitamin A derivative retinyl acetate slightly inhibited serum-stimulated DNA synthesis, but did not affect insulin accumulation. The vitamin E alpha-tocopherol significantly enhanced insulin release but did not affect mitogenesis. By contrast, gamma-tocopherol was inactive on both these parameters. The alpha-adrenergic agonist clonidine evoked a slight inhibition of serum-stimulated DNA synthesis, without influencing insulin accumulation, whereas phenylephrine did not affect any of these parameters. Carbamylcholine increased insulin accumulation, but not cell proliferation, whereas the adenylyl cyclase activator forskolin suppressed mitogenesis but did not affect insulin accumulation. Inhibition of protein kinase C with staurosporine or prolonged treatment with phorbol ester suppressed DNA synthesis, as did the tyrosine kinase inhibitor genistein. Stimulating Ca2+ influx by closing ATP-dependent K+ channels with glibenclamide enhanced DNA synthesis, while opening of these channels with diazoxide suppressed cell growth. Conversely, preventing Ca2+ influx by the Ca2+ channel antagonist D-600, chelating intracellular Ca2+ by fura-2 AM or inhibiting the Ca2+/calmodulin-dependent protein kinase by calmidazol resulted in a decreased DNA synthesis. On the other hand, uncontrolled influx or mobilization of Ca2+ by ionomycin or thapsigargin resulted in an arrested DNA synthesis. The present paper shows that RINm5F insulinoma cell proliferation and insulin accumulation can be modulated by various peptidergic and pharmacological agents regulating certain signal transduction pathways. However, mitogenesis in the insulinoma cells seemingly is controlled in a vastly different manner in comparison to that in normal beta-cells. The most spectacular finding in this screening study, i.e. that growth hormone, contrarily to its effect on normal beta-cells, suppresses insulinoma cell growth, merits further elucidation of the underlying mechanisms. Possibly the hormone might become of utility in a clinical setting in the treatment of patients with insulin-producing tumors.
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PMID:Regulation of insulinoma cell proliferation and insulin accumulation by peptides and second messengers. 880 83

We hypothesized that altered insulin secretory patterns in obese (fa/fa) Zucker rats might be caused by changes in downstream stimulus-secretion coupling events, such as ATP-dependent potassium (KATP) channel activity. The functions of KATP-dependent and -independent pathways of insulin secretion were therefore compared in lean and fa/fa Zucker rat isolated islets. KATP channel function was normal in fa/fa rat islets, as assessed by responsiveness to direct channel inactivators glybenclamide and quinine and by the receptor-mediated response to epinephrine and somatostatin. Altered sensitivity to glucose and mannoheptulose were explained by upstream alterations in glucose metabolism documented earlier. Despite normal inactivation of KATP channels by ATP depletion of fa/fa rat islets, glucose-stimulated insulin secretion was not inhibited, leading to studies of a putative KATP-independent pathway. When islets were depolarized by incubating with 30 mM potassium and 0.25 mM diazoxide to bypass KATP channels, glucose elicited a concentration-dependent response in both phenotypes. This response required glucose metabolism and Ca2+, as proven by experiments with nonmetabolizable glucose analogs and calcium chelation, but was only partially inhibited by a glycolytic inhibitor. Intermediates or products of oxidative metabolism are likely involved because alpha-ketoisocaproate also elicited a KATP-independent insulin response. The pattern of responses was similar in lean and fa/fa rat islets, indicating that neither of these pathways explains the insulin secretion by fa/fa rat islets depleted of ATP. In conclusion, phenotype-related differences in KATP channel function were consistent with upstream changes in glucose metabolism in fa/fa rat islets. Further studies are required to understand the basis of insulin secretion in ATP-depleted islets from fa/fa rats.
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PMID:KATP channel-dependent and -independent pathways of insulin secretion in isolated islets from fa/fa Zucker rats. 888 46

Several agonists including norepinephrine, somatostatin, galanin, and prostaglandins inhibit insulin release. The inhibition is sensitive to pertussis toxin, indicating the involvement of heterotrimeric Gi and/or Go proteins. Receptors for the different agonists have different selectivity for these G proteins. After G protein activation, the alpha- and beta gamma-subunits dissociate and interact with multiple targets to inhibit release. These include 1) the ATP-sensitive K+ channel and perhaps other K+ channels, 2) L-type voltage-dependent Ca2+ channels, 3) adenylyl cyclase, and 4) a "distal" site late in stimulus-secretion coupling. The latter effect, which may be exerted close to the final stage of exocytosis, is the most powerful of the individual inhibitory mechanisms. G protein action on the target molecules is determined by the individual G proteins activated and their specificity for the targets. The L-type Ca2+ channel is inhibited by G(o)-1. Adenylyl cyclase is inhibited by Gi-2 and Gi-3. The distal inhibition can be exerted by Gi-1, Gi-2, Gi-3, and G(o)-2. Thus there is both selectivity and promiscuity in G protein action in the beta-cell. These characteristics allow an inhibitory ligand to be effective at multiple targets and to act differentially from other inhibitory ligands.
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PMID:Mechanisms of inhibition of insulin release. 899 78

1. Receptor-dependent internalization of somatostatin (SRIF) agonists has been a matter of controversy probably because [125I]Tyr11-SRIF-14 is rapidly degraded. We have studied the internalization of a stable somatostatin analogue, [125I]-BIM-23027, in a neuronal cell line, Neuro2A, which natively expresses somatostatin sst2 receptors. 2. Incubation of Neuro2A cells with [125I]-BIM-23027 at 37 degrees C resulted in a time-dependent internalization of the ligand, which reached a maximum at 30 min. Acid-washing showed that cell-surface binding of the ligand accounted for only 34% of total binding at this time. Internalization was dramatically reduced at 15 degrees C. 3. Internalization of [125I]-BIM-23027 was prevented by inclusion of unlabelled somatostatin receptor agonists in a concentration-dependent manner. The IC50 values for inhibition of [125I]-BIM-23027 internalization were approximately 100 fold lower than for inhibition of [125I]-BIM-23027 binding to membrane homogenates but followed the same rank order of potencies. 4. Disruption of G-protein coupling by treatment with pertussis toxin caused a 60% reduction in internalization of ligand. A combination of antimycin (50 nM) and deoxyglucose (50 mM) pretreatment, which leads to a depletion of cellular ATP, decreased internalization of [125I]-BIM-23027 by 66% of control and increased the proportion of surface-bound ligand. Hypertonic sucrose, which prevents clathrin-mediated endocytosis, reversibly abolished the internalization of ligand without increasing the proportion bound at the cell surface. 5. After internalization of [125I]-BIM-23027, approximately half of the ligand was recycled back to the extracellular medium within 20 min at 37 degrees C. This finding suggests that the intracellular content of [125I]-BIM-23027 reaches a steady state which is determined by the rates of both internalization and recycling of the ligand. In contrast to studies in which the internalization of [125I]-Tyr11-SRIF-14 was examined, neither internalized nor recycled [125I]-BIM-23027 was degraded to its component amino acids. 6. These findings indicate that the somatostatin agonist, [125I]-BIM-23027, is internalized in a receptor-dependent manner which involves clathrin-coated pits in Neuro2A cells. Furthermore, much of the internalized ligand is rapidly recycled back to the extracellular medium without undergoing significant degradation.
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PMID:Somatostatin receptors in Neuro2A neuroblastoma cells: ligand internalization. 911 98

A variety of cells including cardiac myocytes and neuronal cells possess inwardly rectifying K+ (Kir) channels through which currents flow more readily in the inward direction than outward. These K+ channels play pivotal roles in maintenance of the resting membrane potential, in regulation of the action potential duration, in receptor-dependent inhibition of cellular excitability, and in the secretion and absorption of K+ ions across cell membrane. Recent molecular biological dissection has shown that the DNAs encoding Kir channels constitute a new family of K+ channels whose subunits contain two putative transmembrane domains and a pore-forming region. So far, more than ten cDNAs of Kir channel subunits have been isolated and classified into four subfamilies: 1) IRK subfamily (IRK1-3/Kir1.1-1.3), 2) GIRK subfamily (GIRK1-4/Kir3.1-3.4), 3) ATP-dependent Kir subfamily (ROMK1/Kir1.1, K(AB)-2/Kir4.1), and 4) ATP-sensitive Kir subfamily (uKATP-1/Kir6.1, BIR/Kir6.2). Xenopus oocytes injected with the cRNAs of IRKs elicit classical Kir channel currents. GIRKs, as heteromultimers, compose the G protein-gated Kir (KG) channels, which are regulated by a variety of Gi/Go-coupled inhibitory neurotransmitter receptors such as m2-mus-carinic, serotonergic (5HT1A), GABAB, somatostatin and opioid (mu, delta, kappa) receptors. ROMK1 and KAB-2 are characterized with a Walker type-A ATP-binding motif in their carboxyl termini, and may be involved in K+ transport in renal epithelial and brain glial cells. uKATP-1 and BIR form with sulfonylurea receptors, the so-called ATP-sensitive K+ channels. Thus, it is a feature of the Kir channel family that each subfamily plays a specific physiological functional role. The (Na+)-activated Kir channels identified electrophysiologically in neurons and cardiac myocytes have not yet been cloned. In this review, we overviewed the current understandings of the features of the molecular structures and functions of the four main subfamilies of Kir channels.
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PMID:Inwardly rectifying potassium channels: their molecular heterogeneity and function. 915 40

The modulation of a cloned neuronal calcium channel was studied in a human embryonic kidney cell line (HEK293). The HEK293 cells were stably transfected with the alpha1Ed cDNA, containing the pore forming subunit of a neuronal class E calcium channel. Inward currents of 25 +/- 1.9 pA/pF (n = 79) were measured with the cloned alpha1Ed-subunit. The application of the peptide hormone somatostatin, carbachol, ATP or adenosine reduced the amplitude of Ca2+ and Ba2+ inward currents and exhibited a slowing of inactivation. This inhibitory effect by somatostatin was significantly impaired after pre-incubating the transfected cell line with pertussis toxin (PTX). Internal perfusion of the cells with the G-protein-inactivating agent GDP-beta-S or with the permanently activating agent GTP-gamma-S also attenuated the somatostatin effect. The inhibition indicates that modulation of the alpha1Ed-mediated Ca2+ current involves pertussis toxin-sensitive G-proteins. The block of Ca2+ and Ba2+ inward currents by somatostatin is also found in cells expressing a truncated alpha1Ed-subunit which lacks a 129-bp fragment in the C-terminus. This fragment corresponds to the major structural difference between two native human alpha1E splice variants. As somatostatin inhibits inward currents through both, the cloned alpha1Ed- and the truncated alpha1Ed-DEL-subunit, the hormone-mediated modulation is independent from the presence of the 129-bp insertion in the C-terminus.
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PMID:Receptor-mediated modulation of recombinant neuronal class E calcium channels. 918 73

The aim of this study was to obtain pharmacological evidence for the presence and participation of K+ channels in amphibian pancreatic islets. Pancreases from the toad Bufo arenarum were thus incubated with activators or blockers of K+ channels and the immunoreactive insulin released into the medium was measured by radioimmunoassay. Two K(+)-ATP channel openers (diazoxide and BPDZ44) inhibited; while a K(+)-ATP channel blocker (tolbutamide) and metabolizable sugars (glucose, glyceraldehyde) significantly stimulated the output of insulin. Although a nonmetabolizable sugar (galactose) failed to increase insulin release, dinitrophenol decreased the secretagogue effect of glucose. By contrast, although somatostatin and clonidine blocked the release of insulin, tetraethylammonium significantly stimulated secretion. For each compound tested, the effects on both insulin secretion and B-cell K+ channel activity were similar to those observed in the mammalian pancreas. These findings point to the existence of mammalian-like K+ channels in the B-cells of some amphibians.
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PMID:Effect of activators and inhibitors of K+ channels on insulin secretion in the amphibian pancreas. 922 48

Kir6.2, a member of the inward rectifier K+ channel family, is a component of the ATP-sensitive K+ (K[ATP]) channel considered to play a key role in glucose-induced insulin secretion. We studied the distribution of Kir6.2 in mouse pancreas at the cellular level. The sites of Kir6.2 mRNA expression were determined by in situ hybridization histochemistry with a digoxigenin (DIG)-labeled antisense cRNA probe. The hybridization signal was unevenly present throughout the islets of Langerhans, while no distinct signal was detected in exocrine acinar cells. This distribution was confirmed by another cRNA probe complementary to a different region of Kir6.2 mRNA. In situ hybridization and immunofluorescence staining of serial sections with the anti-insulin, the anti-glucagon, and the anti-somatostatin antibodies showed Kir6.2 mRNA to be present in alpha-, beta-, and delta-cells. Furthermore, immunofluorescence staining with antibody raised against Kir6.2 revealed that Kir6.2 protein is localized within the pancreatic islets and is not found in exocrine pancreas. Kir6.2 was further shown to be located together with insulin, glucagon, or somatostatin. The positive staining of Kir6.2 appeared concentrated along the contour of each islet cell, suggesting that Kir6.2 is at the plasma membrane of islet cells. These results suggest that Kir6.2, as a component of K(ATP) channels, is an important molecule in the regulation of all the release of insulin, glucagon, and somatostatin.
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PMID:Localization of the ATP-sensitive K+ channel subunit Kir6.2 in mouse pancreas. 928 44

The neonatal disorder persistent hyperinsulinemic hypoglycemia of infancy (PHHI) arises as the result of mutations in the subunits that form the ATP-sensitive potassium (KATP) channel in pancreatic beta cells, leading to insulin hypersecretion. Diazoxide (a specific KATP channel agonist in normal beta cells) and somatostatin (octreotide) are the mainstay of medical treatment for the condition. To investigate the mechanism of action of these agents in PHHI beta cells that lack KATP currents, we applied patch clamp techniques to insulin-secreting cells isolated from seven patients with PHHI. Five patients showed favorable responses to medical therapy, and two were refractory. Our data reveal, in drug-responsive patients, that a novel ion channel is modulated by diazoxide and somatostatin, leading to termination of the spontaneous electrical events that underlie insulin hypersecretion. The drug-resistant patients, both of whom carried a mutation in one of the genes that encode KATP channel subunits, also lacked this novel K+ channel. There were no effects of diazoxide and somatostatin on beta cell function in vitro. These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom KATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI treatment.
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PMID:Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin. 931 91


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