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)

The cytoplasmic Ca2+ concentration ([Ca2+]i) was continuously monitored in single glucagon-producing alpha 2-cells isolated from the mouse pancreas and later identified by immunostaining. Up to 60% of the alpha 2-cells exhibited spontaneous [Ca2+]i oscillations (frequency 0.1-0.3/min) in a medium containing 3 mM glucose. In originating from a basal level of 60-100 nM, reaching peak values of 300-400 nM and promptly disappearing after blocking voltage-dependent Ca2+ channels with methoxyverapamil, the oscillations resembled those in insulin-releasing beta-cells stimulated by glucose. The oscillatory activity was suppressed when combining elevation of glucose to 20 mM with the addition of 2-2000 ng/ml insulin. Whereas 10 mM of L-arginine or l-glycine transformed the oscillations into sustained elevation of [Ca2+]i, there was no response to 1 mM tolbutamide or 0.1-1 mM gamma-aminobutyric acid. The observations that alpha 2-cells differ from islet cells secreting insulin and somatostatin in responding to adrenaline with mobilisation of intracellular calcium can be used for their rapid identification. It is suggested that the oscillations reflect periodic entry of Ca2+ due to variations of the membrane potential.
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PMID:Suppression of Ca2+ oscillations in glucagon-producing alpha 2-cells by insulin/glucose and amino acids. 861 35

Adrenaline and somatostatin inhibit insulin secretion via pertussis toxin (PTX)-sensitive mechanisms. Since glucose-stimulated release involves inhibition of ATP-sensitive K+ (K+ATP) channels and activation of Ca2+ influx, we took advantage of the glucose-sensitive, insulin-secreting cell line INS-1 to investigate whether inhibitors of insulin release modulate membrane voltage and K+ATP channel activity in cell-attached patch-clamp experiments. We found that adrenaline, through alpha2-adrenoceptors, and somatostatin counteracted glucose-induced depolarization and action potentials. As expected, these effects were mediated via PTX-sensitive G proteins since PTX pretreatment of the cells eliminated the effects of adrenaline and somatostatin on membrane voltage. When INS-1 cells were activated by adding both the K+ATP channel inhibitor tolbutamide and the adenylyl cyclase activator forskolin, adrenaline and somatostatin still repolarized the plasma membrane. Single-channel measurements in the cell-attached mode revealed that tolbutamide closed a 40 to 70 pS K+ channel which was neither reopened by adrenaline nor by somatostatin. In parallel cell preparations, insulin secretion was measured by radioimmunoassay. Insulin release induced by glucose, forskolin and tolbutamide was abolished by adrenaline. In contrast, somatostatin attenuated insulin secretion by only 30%. After comparing the potency of adrenaline and somatostatin on membrane voltage and on insulin secretion, it is concluded that the repolarizing effect of adrenaline on membrane voltage is not sufficient to explain its potent inhibitory effect on insulin secretion.
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PMID:Adrenaline-, not somatostatin-induced hyperpolarization is accompanied by a sustained inhibition of insulin secretion in INS-1 cells. Activation of sulphonylurea K+ATP channels is not involved. 866 72

Pancreatic AR42J cells are derived from acinar cells and express both exocrine and neuroendocrine properties. We have recently shown that these cells convert into insulin-producing cells in vitro after treatment with activin A and betacellulin. Here, we investigated the effect of hepatocyte growth factor (HGF) in those cells. When AR42J cells were incubated with HGF, DNA synthesis was attenuated, and the amylase content was reduced in a concentration-dependent manner. HGF-treated cells extended processes, but bundle formation was not observed using an antibody against tubulin. Reverse both insulin and pancreatic polypeptide (PP) were expressed in HGF-treated, but not naive, AR42J cells. Immunocytochemical analysis indicated that approximately 3% of the HGF-treated cells were stained with antiinsulin antibody, and some were also stained with anti-PP antibody. When AR42J cells were exposed to a combination of activin A and HGF, cells extended longer processes, and over 10% of them were stained with antiinsulin antibody. In these cells, messenger RNAs for insulin, PP, glucose transporter 2, and glucokinase, but not those for glucagon or somatostatin, were expressed. A subclone of AR42J cells, AR42J-B13, was obtained. Most of the AR42J-B13 cells converted to insulin-producing cells after the incubation with activin A and HGF. Insulin secretion was augmented by tolbutamide, depolarizing concentrations of potassium, carbachol, and glucagon-like peptide-1 in these cells. These results indicate that HGF reduces the acinar cell-like property of AR42J cells and converts them into insulin-producing cells. The effect of HGF was markedly enhanced by activin A.
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PMID:Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. 875 73

Enterostatin is a pentapeptide generated by trypic digestion of procolipase in the small intestine. Both peripheral and central administration of this peptide to rats has been shown to reduce food intake, this reduction being due to specific suppression of fat intake. In perifused pancreatic rat islets, enterostatin has been shown to inhibit the insulin response to a high glucose concentration. In the present study, we have investigated the effect of exogenous enterostatin on insulin, glucagon, and somatostatin secretion by the isolated perfused rat pancreas. Enterostatin, at 100 mmol/l, inhibited the insulin response to 9 mmol/l glucose (by 70%), 0.1 mmol/l tolbutamide (by 40%), and 5 mmol/l arginine (by 70%). Enterostatin had no effect on glucagon and somatostatin release at a maintained glucose level (5.5 mmol/l) or in response to 5 mmol/l arginine. Finally, preinfusion of the rat pancreas with a high enterostatin concentration (500 nmol/l) did not alter the insulin response to glucose, an observation that would rule out a toxic effect of this peptide on the beta-cell. In summary, in the perfused rat pancreas, enterostatin, at putatively physiological concentrations, inhibits insulin secretion without affecting glucagon or somatostatin output, thus pointing to a direct effect of enterostatin on the beta-cell and not through an alpha-cell or delta-cell paracrine effect. Because enterostatin is generated in the small intestine after feeding, it might play a role in the enteroinsular axis as an anti-incretin agent.
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PMID:Effect of enterostatin on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. 877 15

Excessive secretion of peptides causes the clinical syndromes associated with functional gastro-intestinal tumours. The somatostatin analogue octreotide acetate inhibits peptide release from a variety of tumours. This study investigated the interactions of calcium and somatostatin analogues on peptide release in two patients, one with a glucagonoma (patient A) and one with an insulinoma (patient B). Peptide responses were evaluated before (fasting levels) and after provocative tests (a 4-hour calcium infusion, an intravenous tolbutamide infusion, a secretin bolus and a standard test meal) in the absence and presence of octreotide acetate treatment (100 micrograms subcutaneously every 8 h). Patients A and B had elevated fasting plasma levels of glucagon and insulin, respectively, which were reduced by octreotide therapy by 73 and 50%, respectively. The peak provoked levels and calculated values for peptide synthesis were lower after octreotide therapy. In both patients, tolbutamide provoked most peptide release, and calcium infusion was the least susceptible to the effects of octreotide therapy. Calcium appears to inhibit octreotide suppression of glucagon and insulin secretion in patients with glucagonoma and insulinoma, respectively. Calcium may stimulate peptide release from endocrine tumours by suppressing the inhibitory effects of endogenous somatostatin. Normalisation of serum calcium, either surgically or pharmacologically, may improve the effectiveness of somatostatin analogue therapy.
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PMID:Calcium reverses octreotide inhibition of insulin and glucagon levels in patients with insulinoma and glucagonoma. 881 73

Oscillatory Ca2+ signaling was studied in human somatostatin-releasing pancreatic delta cells identified by immunostaining. A ratiometric fura-2 technique was used for measuring cytoplasmic concentrations of Ca2+ and Sr2+ in delta cells exposed to the respective cation. Rhythmic activity in terms of slow (frequency, 0.1 to 0.4 per minute) oscillations from close to the basal level was seen in the presence of 3 to 20 mmol/L glucose during superfusion with medium containing 2.6 to 5 mmol/L Ca2+ or 5 mmol/L Sr2. These oscillations could be transformed into a sustained increase by decreasing extracellular Ca2+ or adding 1 mmol/L tolbutamide or 20 nmol/L glucagon. Addition of glucagon to a medium containing 20 mmol/L glucose resulted in the generation of short (< 30 seconds) transients, which disappeared upon exposure to 100 nmol/L of the intracellular Ca(2+)-adenosine triphosphatase (ATPase) inhibitor thapsigargin. When analyzing small aggregates of islet cells, it became evident that oscillatory activity in delta cells can be synchronous with that in adjacent non-delta cells. It is concluded that secretion of pancreatic somatostatin in man involves Ca2+ signaling similar to that regulating the pulsatile release of insulin.
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PMID:Oscillatory Ca2+ signaling in somatostatin-producing cells from the human pancreas. 910 36

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

The delta-cell line RIN14B was characterized with regard to ATP-regulated K+ (K(ATP)) channel activity and hormone release. By applying the patch-clamp technique, dose-response curves for ATP and the sulfonylurea tolbutamide were obtained in inside-out patches. The concentration causing half-maximal K(ATP) channel inhibition was found to be 23.7 and 27.6 microM for ATP and tolbutamide, respectively. ADP and diazoxide stimulated K(ATP) channel activity, an effect dependent on the presence of intracellular Mg2+. The stimulatory effect of diazoxide also required the presence of ATP. The kinetic properties of the K(ATP) channel were analysed in the presence of ATP, a combination of ADP and ATP and in nucleotide-free solutions. The distribution of K(ATP) channel open time could be described by a single exponential function with a time constant of approximately 30 ms in nucleotide-free and in ATP-containing solutions. The presence of both ATP and ADP resulted in the appearance of an additional time constant of > 150 ms. Single-channel unitary current-voltage (i-V) relation was characterised for the K((ATP) channel present in RIN14B cells. The slope conductance, measured at the reversal potential was found to be 19.1 +/- 2.4 pS. The permeability for K+ ions was calculated to be 0.31 x 10(-13) cm3 x s(-1). We have not been able to confirm the somatostatin releasing profile of the RIN14B cells using radioimmunoassays, nor could we find positive somatostatin stain with immunocytochemical techniques. We conclude that the RIN14B cell line, previously characterized as a somatostatin-secreting cell line, contains K(ATP) channels with properties closely resembling the K(ATP) channel described in the pancreatic beta-cell. However, the cell line appears to have dedifferentiated with regard to the ability to secrete somatostatin, maintaining the highly differentiated function of both insulin biosynthesis and exocytosis.
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PMID:RIN14B: a pancreatic delta-cell line that maintains functional ATP-dependent K+ channels and capability to secrete insulin under conditions where it no longer secretes somatostatin. 927 Dec 25

To study the regulation of growth and differentiated function of insulin-secreting cells, the rat insulinoma cell line INS-1 was cultured in a defined serum-free medium containing prolactin, IGF-I, and triiodothyronine, which was originally reported to maintain insulin secretion of islet cells. Growth and viability, as well as cellular insulin content of INS-1 cells in the defined medium, were comparable to the control cells cultured in the complete medium containing 10% fetal calf serum. However, after a 3-day culture in this medium, insulin secretion in response to glucose, pyruvate, and leucine was markedly blunted compared with the control cells (-78, -68, and -56%, respectively), whereas the response to 30 mmol/l K+ was only slightly decreased. In these cells: 1) nutrient metabolism assessed by tetrazolium salt reduction was reduced in response to pyruvate and leucine, which are mainly metabolized in the mitochondria; 2) oxidation of both [3,4-(14)C]glucose and [1-(14)C]pyruvate was decreased (-22 and -32%, respectively); 3) glucose failed to depolarize the membrane potential, whereas tolbutamide was fully active; 4) video imaging analysis of cytosolic Ca2+ showed a decrease in the population of glucose-responsive cells, while the response to 30 mmol/l K+ was preserved; 5) serum replenishment for 3 days restored glucose-induced insulin secretion. Interestingly, conditioned serum-free medium from rat islets maintained the insulin secretory function of INS-1 cells, although glucagon, somatostatin, and some other factors failed to restore the function. In contrast, conditioned media from HepG2, PC12, and human umbilical vein endothelial cells did not substitute for serum. Thus, the impaired insulin secretion of the cells cultured in the defined medium is best explained by defective mitochondrial metabolism. Islet cells, but not INS-1 cells, produce factors required for normal signal generation by nutrient secretagogues.
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PMID:Glucose-induced insulin secretion in INS-1 cells depends on factors present in fetal calf serum and rat islet-conditioned medium. 928 42

In order to evaluate the role of portal insulin in the modulation of hepatic glucose production (HGP), measurements of plasma glucose and insulin concentrations and both HGP and peripheral glucose disappearance rates were made following an infusion of a dose of tolbutamide (0.74 mg x m(-2) x min[-1]) in healthy volunteers that does not result in an increase in peripheral vein insulin concentrations or metabolic clearance rate of glucose. The results showed that the infusion of such a dose of tolbutamide was associated with a significant and rapid decline in both HGP (from 9.0 +/- 0.5 to 7.7 +/- 0.5 micromol x kg(-1) x min(-1) or delta = -13.8 +/- 4.5%; p < 0.001 compared to saline) and plasma glucose concentration (from 5.1 +/- 0.2 to 4.4 +/- 0.1 mmol/l or delta = -13.0 +/- 2.1%; p < 0.01 compared to saline). Since neither HGP nor fasting glucose fell when tolbutamide-stimulated insulin secretion was inhibited by the concurrent administration of somatostatin, it indicated that tolbutamide by itself, does not directly inhibit HGP. Finally, HGP fell by 26.3 +/- 6.0% at 10 min after a dose of tolbutamide that elevated both peripheral and portal insulin concentrations, at a time when HGP had barely increased (delta = +6.9 +/- 5.3%). The difference in the magnitude of the two responses was statistically significant (p < 0.03), providing further support for the view that insulin can directly inhibit HGP, independent of any change in flow of substrates from periphery to liver.
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PMID:Evidence that insulin can directly inhibit hepatic glucose production. 938 22


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