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

We have previously shown that the two nonallelic insulin genes in Xenopus laevis are expressed differentially during neurulation in prepancreatic embryos (Shuldiner et al., 1991, Proc. Natl. Acad. Sci. USA 88, 7679-7683). We now examine pancreatic expression with alterations in ambient temperature, glucose administration, fasting and feeding, somatostatin analog treatment, as well as during postmetamorphic growth. Insulin I and II mRNAs were quantitated by slot blot hybridization with specific probes and were expressed as the number of copies (x 10(8)) per 5 micrograms total RNA +/- SEM. Frogs maintained at 12 degrees showed no significant changes when compared to frogs maintained at 20 degrees. There was a coordinate decrease in insulin I and II mRNA levels in frogs maintained at 29 degrees (Ins I 20, 3.41 +/- 0.34 vs Ins I 29, 2.39 +/- 0.17; Ins II 20, 2.59 +/- 0.36 vs Ins II 29, 1.67 +/- 0.09; P < 0.05). When compared to fasting animals, both insulin I and II mRNA levels decreased slightly in frogs given repeated intraperitoneal injections of glucose and in those fed ad libitum; there were no changes after a single dose of glucose or in frogs given somatostatin. When compared to young frogs (6 to 24 months), older frogs (36 months) had higher insulin I and II mRNA levels (e.g., Ins I 6mo, 2.14 +/- 0.15 vs Ins I 36mo, 3.68 +/- 0.43; Ins II 6mo, 1.21 +/- 0.06 vs Ins II 36mo, 3.26 +/- 0.38; P < 0.05). Further, there was a modest reduction in the percentage of insulin I mRNA with aging (e.g., 6 months 63.6 +/- 3.1% vs 36 months 53.9 +/- 2.7%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The two nonallelic Xenopus insulin genes are expressed coordinately in the adult pancreas. 752 1

The cAMP-responsive element (CRE)-binding transcription factor CREB confers basal as well as cAMP- and calcium-induced transcription. Activation of CREB occurs by phosphorylation on serine-119 stimulating its transactivating potency. However, the regulation of CREB-DNA binding by posttranslational modification is not established. In this study, using binding and functional assays, the interaction of CREB with pancreatic islet cell-specific enhancer elements of the rat somatostatin (SMS-UE), glucagon (Glu-G3) and insulin I genes (Ins-E1) was investigated, which share a functional regulatory sequence, PISCES, with islet-specific activity. CREB bound to the SMS-UE. Bacterially expressed recombinant CREB bound equally well to the SMS-UE and to the somatostatin CRE. However, cellular CRE-binding proteins with CREB-like immunoreactivity recognized the SMS-UE markedly less well than the somatostatin CRE suggesting the existence of a posttranslational modification of CREB that alters its binding specificity.
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PMID:Interaction of the transcription factor CREB with pancreatic islet cell-specific enhancer elements. 761 87

A pancreatic islet cell-specific enhancer element in the rat glucagon gene, Glu-G3, contains two domains, one of which, domain A, has been shown to be necessary for Glu-G3 activity. In the present study, the functions of the isolated domain A of Glu-G3 were investigated by using transient reporter fusion gene expression and DNA binding assays. A single copy of domain A was transcriptionally inactive in glucagon-producing islet cell lines, whereas it did confer activity when combined with domain B, suggesting that Glu-G3 may be a bipartite element. Multiple copies of domain A did function independently as transcriptional enhancer in phenotypically distinct islet cell lines but not in several nonislet cell lines. Sequences (PISCES, pancreatic islet cell-specific enhancer sequences), similar to that of domain A of Glu-G3 and present in cell-specific control elements of the rat insulin I (Ins-E1) and rat somatostatin genes (SMS-UE), are shown to be required for transcriptional activity of these elements. In addition, a protein was detected in islet cell lines that bound to the PISCES motifs within Glu-G3, Ins-E1, and SMS-UE. These results support the view that cell-specific control elements of the glucagon, insulin, and somatostatin genes share a functional regulatory sequence, PISCES, and provide direct evidence for the existence of an islet-specific, PISCES-binding transcription factor or closely related proteins being involved in the coordinate expression of islet hormone genes.
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PMID:Transcriptional activity of domain A of the rat glucagon G3 element conferred by an islet-specific nuclear protein that also binds to similar pancreatic islet cell-specific enhancer sequences (PISCES). 778 13

We have characterized the phosphoinositide metabolism in a polyoma-BK-virus-transformed rat pancreatic islet cell line which has highly malignant characteristics, expresses viral T-antigen and has lost insulin-secreting capacity. After incorporation with [3H]inositol to isotopic equilibrium, all inositol metabolites were analyzed. When compared with normal pancreatic islets, increased levels of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3), inositol 1,3,4-trisphosphates and inositol tetrakisphosphate (Ins-P4), and decreased levels of phosphatidylinositol monophosphate (PIP) and phosphatidylinositol bisphosphate (PIP2) were found. The Ins-1,4,5-P3/PIP2 ratio increased, whereas the PIP2/PIP ratio was not altered after the transformation. In the pancreatic islet cell line there was a stable accumulation of inositol phosphates at 3.3 mM glucose. Glucose, KCl, cholecystokinin (CCK) and carbachol with and without LiCl were all without effect on the accumulation of inositol phosphates. Somatostatin inhibited the accumulation of inositol phosphates but a Ca(2+)-free/EDTA solution did not. Preincubation with cholera toxin or pertussis toxin inhibited the accumulation of inositol phosphates at 3.3 mM glucose except for Ins-P4, whereas no effect was observed on the phosphoinositides. NaF stimulated the accumulation of inositol phosphates, with a concomitant decrease in the phosphoinositides, whereas neomycin was without effect on the inositol phosphates. In normal pancreatic islets, pertussis toxin inhibited the CCK-induced increase in Ins-1,4,5-P3, whereas no effect was seen at 3.3 mM glucose. Finally, pertussis toxin inhibited the CCK-induced increase in the Ins-1,4,5-P3/PIP2 ratio in normal pancreatic islets. The same inhibition was also found in the pancreatic islet cell line at 3.3 mM glucose. We conclude that in the transformed pancreatic islet cell line the phosphoinositide hydrolysis is constitutively activated at the level of phospholipase C, with a substantial loss of regulatory control.
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PMID:Phosphoinositide metabolism in a polyoma-BK-virus-transformed pancreatic islet cell line: evidence for constitutively activated phospholipase C. 838 59

In a subset of patients with non-insulin-dependent diabetes mellitus an 8-base pair (bp) repeat was found from -322 to -315 in the 5'-flanking region of the insulin gene. This 8-bp repeat is inserted into a sequence that is highly homologous to a sequence motif, called PISCES (pancreatic islet cell-specific enhancer sequences), found within cell-specific enhancer elements of the rat insulin I (Ins-E1, from -332 to -285), rat glucagon (Glu-G3) and rat somatostatin (SMS-UE) genes. The PISCES motif confers pancreatic islet-specific activity and is recognized by an islet-specific transcription factor (PISCES-BP). The consequences on functional activity and on protein binding of the 8-bp repeat sequence in the human insulin promoter was investigated. When fused to a reporter gene and transiently transfected into an insulin-producing islet cell line, the 8-bp repeat decreased basal transcriptional activity of the human insulin promoter (from -366 to +42) whereas the induction of promoter activity by cAMP was unaffected. The isolated rat Ins-E1 element was sufficient to confer basal transcriptional activity to a minimal promoter; the corresponding fragments of the normal and variant human insulin genes (from -329 to -288), however, were not. Using nuclear extracts in an electrophoretic mobility shift assay, it was found that PISCES-BP recognizes rat Ins-E1, but PISCES-BP binding to the corresponding normal and variant human insulin promoter fragments was not detectable and weak, respectively. However, a nuclear protein was found that binds to the variant but not normal human sequence. These data suggest that the 8-bp repeat in the variant human insulin promoter found in patients with non-insulin-dependent diabetes mellitus allows the binding of a nuclear protein that interferes with promoter function.
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PMID:Nuclear protein binding and functional activity of a variant insulin gene found in non-insulin-dependent diabetes mellitus. 881 39

In animals receiving total parenteral nutrition (TPN), infection impairs net hepatic glucose uptake (NHGU) by 40% and induces mild hyperinsulinemia. In the normal animal, the majority of the glucose taken up by the liver is diverted to lactate, but in the infected state, lactate release is curtailed. Because of the hyperinsulinemia and reduced NHGU, more glucose is utilized by peripheral tissues. Our aims were to determine the role of infection-induced hyperinsulinemia in 1) limiting the fall in NHGU and hepatic lactate release and 2) increasing the proportion of glucose disposed of by peripheral tissues. Chronically catheterized dogs received TPN for 5 days via the inferior vena cava. On day 3, a fibrin clot with a nonlethal dose of E. coli was placed into the peritoneal cavity; sham dogs received a sterile clot. On day 5, somatostatin was infused to prevent endogenous pancreatic hormone secretion, and insulin and glucagon were replaced at rates matching incoming hormone concentrations observed previously in sham or infected dogs. The TPN-derived glucose infusion was adjusted to maintain a constant arterial plasma glucose level of approximately 120 mg/dl. after a basal blood sampling period, the insulin infusion rate was either maintained constant (infected time control, Hi-Ins, n = 6; sham time control, Sham, n = 6) or decreased (infected + reduced insulin, Lo-Ins; n = 6) for 180 min to levels seen in noninfected dogs (from 23 +/- 2 to 12 +/- 1 microU/ml). Reduction of insulin to noninfected levels decreased NHGU by 1.4 +/- 0.5 mg x kg(-1) x min(-1) (P < 0.05) and nonhepatic glucose utilization by 4.8 +/- 0.8 mg x kg(-1) x min(-1) (P < 0.01). The fall in NHGU was caused by a decline in HGU (Delta-0.6 +/- 0.4 mg x kg(-1) x min(-1)) and a concomitant increase in hepatic glucose production (HGP, Delta0.8 +/- 0.5 mg x kg(-1) x min(-1)); net hepatic lactate release was not altered. Hyperinsulinemia that accompanies infection 1) primarily diverts glucose carbon to peripheral tissues, 2) limits the fall in NHGU by enhancing HGU and suppressing HGP, and 3) does not enhance hepatic lactate release, thus favoring hepatic glucose storage. Compensatory hyperinsulinemia plays a critical role in facilitating hepatic and peripheral glucose disposal during an infection.
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PMID:Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN. 1091 21

K cells are a subpopulation of enteroendocrine cells that secrete glucose-dependent insulinotropic polypeptide (GIP), a hormone that promotes glucose homeostasis and obesity. Therefore, it is important to understand how GIP secretion is regulated. GIP-producing (GIP/Ins) cell lines secreted hormones in response to many GIP secretagogues except glucose. In contrast, glyceraldehyde and methyl pyruvate stimulated hormone release. Measurements of intracellular glucose 6-phosphate, fructose 1,6-bisphosphate, and pyruvate levels, as well as glycolytic flux, in glucose-stimulated GIP/Ins cells indicated that glycolysis was not impaired. Analogous results were obtained using glucose-responsive MIN6 insulinoma cells. Citrate levels increased similarly in glucose-treated MIN6 and GIP/Ins cells. Thus pyruvate entered the tricarboxylic acid cycle. Glucose and methyl pyruvate stimulated 1.4- and 1.6-fold increases, respectively, in the ATP-to-ADP ratio in GIP/Ins cells. Glyceraldehyde profoundly reduced, rather than increased, ATP/ADP. Thus nutrient-regulated secretion is independent of the ATP-dependent potassium (K(ATP)) channel. Antibody staining of mouse intestine demonstrated that enteroendocrine cells producing GIP, glucagon-like peptide-1, CCK, or somatostatin do not express detectable levels of inwardly rectifying potassium (Kir) 6.1 or Kir 6.2, indicating that release of these hormones in vivo may also be K(ATP) channel independent. Conversely, nearly all cells expressing chromogranin A or substance P and approximately 50% of the cells expressing secretin or serotonin exhibited Kir 6.2 staining. Compounds that activate calcium mobilization were potent secretagogues for GIP/Ins cells. Secretion was only partially inhibited by verapamil, suggesting that calcium mobilization from intracellular and extracellular sources, independent from K(ATP) channels, regulates secretion from some, but not all, subpopulations of enteroendocrine cells.
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PMID:Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent. 1267 50

Whether hyperinsulinemia is required for stimulation of net hepatic glucose uptake (NHGU) by a selective serotonin reuptake inhibitor (SSRI) was examined in four groups of conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental periods (Exp; 0-240 min). During Exp, somatostatin, intraportal insulin [at basal (Ins groups) or 4-fold basal rates (INS groups)], basal intraportal glucagon, and peripheral glucose (to double hepatic glucose load) were infused. In the Fluv-Ins (n = 7) and Fluv-INS groups (n = 6), saline was infused intraportally from 0 to 90 min (P1), and fluvoxamine was infused intraportally at 2 microg x kg(-1) x min(-1) from 90 to 240 min (P2). Sal-Ins (n = 9) and Sal-INS (n = 8) received intraportal saline in P1 and P2. NHGU during P2 was 8.4 +/- 1.4 and 6.9 +/- 2.3 micromol x kg(-1) x min(-1) in Sal-Ins and Fluv-Ins, respectively (not significant), and 13.3 +/- 2.2 and 20.9 +/- 3.1 micromol x kg(-1) x min(-1) (P < 0.05) in Sal-INS and Fluv-INS. Unidirectional (tracer-determined) hepatic glucose uptake was twofold greater (P < 0.05) in Fluv-INS than Sal-INS. Net hepatic carbon retention during P2 was significantly greater in Fluv-INS than Sal-INS (18.5 +/- 2.7 vs. 12.2 +/- 1.9 micromol x kg(-1) x min(-1)). Nonhepatic glucose uptake was reduced in Fluv-INS vs. Sal-INS (20.0 +/- 1.3 vs. 38.4 +/- 5.4 micromol x kg(-1) x min(-1), P < 0.05). Intraportal fluvoxamine enhanced NHGU and net hepatic carbon retention in the presence of hyperinsulinemia but not euinsulinemia, suggesting that hepatocyte-targeted SSRIs may reduce postprandial hyperglycemia.
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PMID:Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs. 1552 92

Slow oscillations and sleep spindles are hallmarks of the EEG during slow-wave sleep (SWS). Both oscillatory events, especially when co-occurring in the constellation of spindles nesting in the slow oscillation upstate, are considered to support memory formation and underlying synaptic plasticity. The regulatory mechanisms of this function at the circuit level are poorly understood. Here, using two-photon imaging in mice, we relate EEG-recorded slow oscillations and spindles to calcium signals recorded from the soma of cortical putative pyramidal-like (Pyr) cells and neighboring parvalbumin-positive interneurons (PV-Ins) or somatostatin-positive interneurons (SOM-Ins). Pyr calcium activity was increased more than threefold when spindles co-occurred with slow oscillation upstates compared with slow oscillations or spindles occurring in isolation. Independent of whether or not a spindle was nested in the slow oscillation upstate, the slow oscillation downstate was preceded by enhanced calcium signal in SOM-Ins that vanished during the upstate, whereas spindles were associated with strongly increased PV-In calcium activity. Additional wide-field calcium imaging of Pyr cells confirmed the enhanced calcium activity and its widespread topography associated with spindles nested in slow oscillation upstates. In conclusion, when spindles are nested in slow oscillation upstates, maximum Pyr activity appears to concur with strong perisomatic inhibition of Pyr cells via PV-Ins and low dendritic inhibition via SOM-Ins (i.e., conditions that might optimize synaptic plasticity within local cortical circuits).
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PMID:Cortical circuit activity underlying sleep slow oscillations and spindles. 3020 14

Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1-5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.
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PMID:Interaction between somatostatin analogues and targeted therapies in neuroendocrine tumor cells. 3201 3


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