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. Acute effects of amino acids, hormones and drugs on transplantable rat insulinoma cells were examined after 2-3 days culture in RPMI-1640 (11.1 mM glucose) to eliminate necrotic cells and counter prior hypoglycaemia. 2. At 2.6 mM Ca2+, rat insulinoma cells (greater than 95% viability) released 48-97 ng insulin/10(6) cells during 60 min incubations with uptake of 1.0-1.8 nmol 45Ca/10(6) cells. 3. Insulin release and 45Ca uptake by rat insulinoma cells were not modified by arginine, leucine, 2-ketoisocaproate, tolbutamide, glibenclamide, somatostatin, adrenaline, noradrenaline, diazoxide or cyproheptadiene. 4. Responsiveness to acetylcholine (stimulation of insulin release and 45Ca uptake) and to GIP (stimulation of insulin release) was demonstrated. Thiol reagents (CMBS, CPDS and DTNB) and agents affecting microtubules-microfilaments (colchicine, vinblastine and cytochalasin B) enhanced insulin release. 5. The results suggest that rat insulinoma cells exhibit a generalized defect in the regulation of insulin release by nutrients, hormones and drugs which act in pancreatic B-cells by alteration of cellular Ca2+. Responsiveness to agents affecting insulin release through alternative mechanisms appears to be retained.
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PMID:Effects of amino acids, hormones and drugs on insulin release and 45Ca uptake by transplantable rat insulinoma cells maintained in tissue culture. 283 46

We have evaluated the potential of the clonal insulin-secretory cell line HIT-T15 as a model system for investigating stimulus-secretion coupling in pancreatic B cells. In contrast to other cell lines, HIT cell insulin secretion was consistently stimulated 2- to 3-fold by D-glucose. The maximally effective concentration of glucose was 10 mmol/l; between 2 and 10 mmol/l glucose the increase in insulin release was paralleled by an increased rate of glucose oxidation. The main characteristics of glucose-stimulated insulin release by HIT cells were essentially similar to those of normal islets. Thus, the response was specific for metabolizable sugars (D-mannose and D-glyceraldehyde stimulated insulin release but L-glucose and D-galactose were ineffective); markedly dependent on extracellular Ca2+ concentration; potentiated by forskolin, glucagon, acetylcholine and 12-O-tetradecanoyl phorbol 13-acetate; inhibited by adrenaline or somatostatin; showed a biphasic pattern of release in perifusion experiments, with both phases being potentiated by forskolin. The secretory response of the HIT cells to amino acids was also similar to that of normal islets. Thus, L-leucine and its deamination product 2-ketoisocaproate were effective stimuli, whereas L-isoleucine and L-glutamine were ineffective. Insulin release from HIT cells could also be evoked by the sulphonylureas glibenclamide and tolbutamide and by an increase in concentration of extracellular K+ to 40 mmol/l. The content of cyclic AMP in HIT cells was increased modestly by glucose but not by an increase in extracellular K+. Forskolin elicited a 4-fold increase in cyclic AMP content. We conclude that HIT cells retain the essential features of the insulin secretory response of normal B cells and represent an important tool for further biochemical characterization of the secretory system.
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PMID:Insulin secretory responses of a clonal cell line of simian virus 40-transformed B cells. 302 78

To study the effect of insulin on leucine kinetics, three groups of conscious dogs were studied after an overnight fast (16-18 h). One, saline-infused group (n = 5), served as control. The other two groups were infused with somatostatin and constant replacement amount of glucagon; one group (n = 6) received no insulin replacement, to produce acute insulin deficiency, and the other (n = 6) was constantly replaced with 600 muU/kg per min insulin, to produce twice basal hyperinsulinemia. Hepatic and extrahepatic splanchnic (gut) balance of leucine and alpha-ketoisocaproate (KIC) were calculated using the arteriovenous difference technique. l,4,5,[(3)H]Leucine was used to measure the rates (micromoles per kilogram per minute) of appearance (Ra) and disappearance (Rd), and clearance (Cl) of plasma leucine (milliliters per kilogram per minute). Saline infusion for 7 h resulted in isotopic steady state, where Ra and Rd were equal (3.2+/-0.2 mumol/kg per min). Acute insulin withdrawal of 4-h duration caused the plasma leucine to increase by 40% (P < 0.005). This change was caused by a decrease in the outflow of leucine (Cl) from the plasma, since Ra did not change. The net hepatic release of the amino acid (0.24+/-0.03 mumol/kg per min) did not change significantly; the arterio-deep femoral venous differences of leucine (-10+/-1 mumol/liter) and KIC (-12+/-2 mumol/liter) did not change significantly indicating net release of the amino and ketoacids across the hindlimb. Selective twice basal hyperinsulinemia resulted in a 36% drop in plasma leucine (from control levels of 128+/-8 to 82+/-7 mumol/liter, P < 0.005) within 4 h. This was accompanied by a 15% reduction in Ra and a 56% rise in clearance (P < 0.001, both). Net hepatic leucine production and net release of leucine and KIC across the hindlimb fell markedly. These studies indicate that physiologic changes in circulating insulin levels result in a differential dose-dependent effect on total body leucine metabolism in the intact animal. Acute insulin withdrawal exerts no effect on leucine rate of appearance, while at twice basal levels, insulin inhibited leucine rate of appearance and stimulated its rate of disappearance.
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PMID:Role of insulin in the regulation of leucine kinetics in the conscious dog. 612 47

We studied the release of insulin, glucagon, and somatostatin in response to glucose, glyceraldehyde (GA), and alpha-ketoisocaproate (KIC) from rat kidneys containing transplanted insulinomas. Kidneys were perfused about 11 wk after transplantation when the plasma glucose concentration of the fed animals had decreased from 180 +/- 7 to 95.1 +/- 9.9 mg/dl and plasma insulin concentrations had increased from 2.6 +/- 0.5 to 14.2 +/- 2.0 ng/ml. The insulin content of the tumor-containing kidney ranged from 40 to 679 micrograms; the glucagon and somatostatin concentrations ranged from undetectable levels to 3.7 micrograms and 248 ng, respectively. The average response to 30 mM glucose and 10 mM GA was a four- to fivefold increase in insulin secretion, whereas 30 mM KIC caused a 16- to 28-fold increase. In vitro stimulation of the insulinoma with 30 mM glucose primed the beta-cell response to a second stimulus following a short rest period. Cytochalasin B did not enhance this primed glucose response. Diazoxide inhibited glucose, GA, and KIC-stimulated insulin release. Glucose, GA, and KIC stimulated glucagon release in 2 of 17 insulinomas studied here. Somatostatin release was not seen in any of the experiments. These findings show that this islet cell tumor transplanted under the kidney capsule releases insulin in response to physiologic and model fuel substances. Thus, this particular transplantable tumor offers an opportunity to study the biochemistry and biophysics that underlie fuel-stimulated insulin release.
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PMID:Fuel-induced insulin release in vitro from insulinomas transplanted into the rat kidney. 614 Jan 99

The response of insulinoma tissue to glucose, alpha-ketoisocaproate, and the modifiers of insulin release, tolbutamide, isoproterenol, and acetylcholine, was studied. Tumor tissue was transplanted under the kidney capsule of 14 rats, and the tumor-bearing kidneys were perfused in vitro about 8 weeks later. The plasma glucose concentration of these animals was 85.0 +/- 7.0 mg/dl, while the plasma insulin concentration was 13.8 +/- 1.5 ng/ml (normal, 180.5 +/- 7.0 mg/dl and 2.6 +/- 0.5 ng/ml, respectively; n = 26). Glucose (30 mM) evoked a 3- to 5-fold increase in insulin secretion, similar to the increase seen when either 100 micrograms/ml tolbutamide or 0.5 micrograms/ml isoproterenol were added to the perfusion medium containing 5 mM glucose. Propranolol at 50 micrograms/ml, but not at 20 micrograms/ml, inhibited insulin release stimulated by isoproterenol. Acetylcholine (10 or 100 microM) did not stimulate insulin secretion. alpha-Ketoisocaproate caused the highest insulin release of all stimuli studied. Glucagon or somatostatin release was not seen in any of the experiments. These results show that the tumor tissue transplanted under the kidney capsule responds not only to model fuels, but also to the sulfonylurea class of drugs and to adrenergic agents.
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PMID:Pharmacological modifications of insulin release in vitro from fuel-responsive transplantable insulinomas. 614 33

The importance of alpha-keto acid binding to plasma proteins was investigated both in vitro and in vivo using alpha-ketoisocaproate (KIC), the alpha-keto acid of leucine. Gel chromatography indicated that 65% of the radioactivity comigrated with serum albumin. An ultrafiltration assay was developed to estimate the percentage of free and bound KIC. These percentages, along with total plasma KIC concentrations, were used to calculate the circulating concentrations of free and bound KIC. KIC or free fatty acids (FFA) displaced [14C]KIC bound to bovine albumin or whole plasma. KIC was totally displaced from plasma proteins by 10 mM oleate, stearate, and myristate; whereas the alpha-keto acids of isoleucine and value were 50 and 85%, respectively, as effective as KIC. To determine whether increased plasma FFA concentrations alter the binding of KIC to plasma proteins in vivo, five postabsorptive humans were infused with triglyceride and heparin during the simultaneous administration of somatostatin, glucagon, and insulin. During the FFA elevation, plasma leucine decreased by 9% (P less than 0.02). Total plasma KIC remained constant, whereas free KIC increased (P less than 0.02) and bound KIC decreased (P less than 0.001). These results indicate that KIC is bound to plasma albumin in vivo and suggests that FFA, by altering circulating free KIC concentrations, may influence protein metabolism in man.
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PMID:Regulation of alpha-ketoisocaproate binding to albumin in vivo by free fatty acids. 703 54

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

Fibrinogen, an acute-phase protein, and glucagon, a stress hormone, are often elevated in many conditions of physical and metabolic stress, including uncontrolled diabetes. However, the possible mechanisms for this association are poorly known. We have studied the acute effects of selective hyperglucagonemia (raised from -200 to -350 pg/ml for 3 h) on fibrinogen fractional secretion rate (FSR) in eight normal subjects during infusion of somatostatin and replacement doses of insulin, glucagon, and growth hormone. Fibrinogen FSR was evaluated by precursor-product relationships using either Phe (n = 8) or Leu (n = 2) tracers. Hyperglucagonemia did not change either plasma Phe or Tyr specific activity. After hyperglucagonemia, fibrinogen FSR increased by approximately 65% (from 12.9 +/- 3.6 to 21.5 +/- 6.1% per day, P < 0.025) using plasma Phe specific activity as the precursor pool. FSR increased by approximately 80% (from 16.6 +/- 4.8 to 29.4 +/- 8.8% per day, P < 0.025) if plasma Phe specific activity was corrected for the ketoisocaproate/Leu enrichment (or specific activity) ratio to obtain an approximate estimate of intrahepatic Phe specific activity. FSR increased by approximately 60% when using plasma Tyr specific activity as precursor pool (n = 8) (P < 0.05), as well as when using the Leu tracer precursor-product relationship (n = 2). In conclusion, selective hyperglucagonemia for approximately 3 h acutely stimulated fibrinogen FSR using a Phe tracer method. Thus, glucagon may be involved in the increase of fibrinogen concentration and FSR observed under stressed or pathologic conditions.
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PMID:Evidence for acute stimulation of fibrinogen production by glucagon in humans. 923 65

Somatostatin potently inhibits insulin secretion from pancreatic beta-cells. It does so via activation of ATP-sensitive K+-channels (KATP) and G protein-regulated inwardly rectifying K+-channels, which act to decrease voltage-gated Ca2+-influx, a process central to exocytosis. Because KATP channels, and indeed insulin secretion, is controlled by glucose oxidation, we investigated whether somatostatin inhibits insulin secretion by direct effects on glucose metabolism. Oxidative metabolism in beta-cells was monitored by measuring changes in the O2 consumption (DeltaO2) of isolated mouse islets and MIN6 cells, a murine-derived beta-cell line. In both models, glucose-stimulated DeltaO2, an effect closely associated with inhibition of KATP channel activity and induction of electrical activity (r > 0.98). At 100 nm, somatostatin abolished glucose-stimulated DeltaO2 in mouse islets (n = 5, P < 0.05) and inhibited it by 80 +/- 28% (n = 17, P < 0.01) in MIN6 cells. Removal of extracellular Ca2+, 5 mm Co2+, or 20 microm nifedipine, conditions that inhibit voltage-gated Ca2+ influx, did not mimic but either blocked or reduced the effect of the peptide on DeltaO2. The nutrient secretagogues, methylpyruvate (10 mm) and alpha-ketoisocaproate (20 mm), also stimulated DeltaO2, but this was unaffected by somatostatin. Somatostatin also reversed glucose-induced hyperpolarization of the mitochondrial membrane potential monitored using rhodamine-123. Application of somatostatin receptor selective agonists demonstrated that the peptide worked through activation of the type 5 somatostatin receptor. In conclusion, somatostatin inhibits glucose metabolism in murine beta-cells by an unidentified Ca2+-dependent mechanism. This represents a new signaling pathway by which somatostatin can inhibit cellular functions regulated by glucose metabolism.
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PMID:Somatostatin inhibits oxidative respiration in pancreatic beta-cells. 1635 46