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1.
The apparent distribution space of 6-deoxy-6-[125I]iodo-D-glucose, recently proposed as a tracer of D-glucose transport, was measured in rat isolated islets, acinar tissue, and pieces of pancreas. While such a space reached a steady-state value corresponding to the 3HOH volume in pancreatic islets within 5 min, it slowly increased in pieces of pancreas and, even after 60-min incubation, remained lower than the 3HOH volume. Moreover, the net uptake of 6-deoxy-6-[125I]iodo-D-glucose by pancreatic pieces was inhibited by unlabeled 6-deoxy-6-iodo-D-glucose, D-glucose, and cytochalasin B, while being less or not affected by these agents in isolated islets. A preferential labeling of the endocrine, relative to exocrine, moiety of the pancreas was documented both by comparing, after 2 min incubation, the uptake of 6-deoxy-6-[125I]iodo-D-glucose by pieces of pancreas from normal vs streptozotocin-injected rats and by comparing the radioactive content of pancreatic islets and acinar tissue obtained from normal rats injected intravenously 3 min before sacrifice with 6-deoxy-6-[125I]iodo-D-glucose. It is proposed, therefore, that advantage could conceivably be taken from the vastly different time course for the uptake of selected monosaccharides by pancreatic islets vs acinar cells in the perspective of imaging of the endocrine pancreas by a non invasive method. 相似文献
2.
Laurence Ladrière Karim Louchami Aouatif Laghmich Francine Malaisse-Lagae Willy J. Malaisse 《Endocrine》2001,14(3):383-397
Under conditions of sustained hyperglycemia, glycogen accumulates in pancreatic islets, but not so in acinar pancreatic cells.
We investigated whether advantage could be taken of such a situation in the perspective of the noninvasive imaging of the
endocrine pancreas. Control rats or animals injected with streptozotocin (STZ) were infused with solutions of d-glucose mixed with a tracer amount of d-[U-14C]glucose, and the radio-active glycogen content of both liver and pancreas was then measured. After 48 h of infusion, the
radio-active glycogen content of the pancreas was 30 times lower in STZ rats than in control animals, coinciding with a 50
times lower insulin content. In the control rats, a sizable labeling of pancreatic glycogen was also recorded when d-[U-14C]glucose was infused for only the last 4 h of unlabeled d-glucose infusion; such a labeling was not decreased when the animals were further infused for 1 h with only the unlabeled
hexose. Moreover, a pronounced difference in the pancreatic gland and blood radioactive content of control rats was still
observed when the hyperglycemic animals were killed only 40 min after the iv injection of d-[U-14C]glucose. In STZ rats transplanted with islets and later infused with d-[U-14C]glucose, the total radioactive content and radioactive glycogen content were both much higher in the transplanted islets
than in the pancreatic gland. These results allow one to define the conditions under which the administration of either 2-deoxy-2-[18F]fluoro-d-glucose or 11C-labeled d-glucose could conceivably be used to favor the selective labeling of the endocrine, as distinct from exocrine, pancreas. 相似文献
3.
Under conditions of sustained hyperglycemia, glycogen accumulates in pancreatic islets, but not so in acinar pancreatic cells.
Advantage conceivably could be taken from such a situation in the perspective of the noninvasive imaging of the endocrine
pancreas. The present experiments aim, therefore, at characterizing the time course for glycogen accumulation in pancreatic
islets cultured at a high concentration (30 mM) of d-glucose in the presence of tracer amounts of either d-[U-14C]glucose or 2-deoxy-2 [18F]fluoro-d-glucose. The 14C-labeled glycogen content of the cultured islets increased with time (150 min to 72 h), exceeded that found in acinar tumoral
cells, and did not decrease over 60 min of incubation at 30 mM
d-glucose in the absence of d-[U-14C]glucose. Glycogenolysis was observed, however, when the concentration of d-glucose was decreased to 2.8 mM and, in such a case, was further enhanced by forskolin and theophylline. Such a glycogenolysis concided with the generation
of 14CO2 from radioactive intracellular precursors and alteration of the B-cell secretory response to d-glucose. The radioactive glycogen content was higher in islets exposed to 2-deoxy-2-[18F]fluoro-d-glucose than d-[U-14C]glucose. Prior exposure of the islets to streptozotocin suppressed the accumulation of glycogen during their subsequent
culture at high d-glucose concention. These findings may help to define the experimental conditions optimal for the labeling and accumulation
of islet glycogen in vivo. 相似文献
4.
Malaisse WJ 《Diabetologia》2001,44(4):393-406
Abstract
The imaging and quantification of the endocrine pancreas by a non-invasive procedure remains a challenge. In the prolongation
of prior work on selected succinic acid esters and monosaccharide esters, it is proposed that d-mannoheptulose, which might be transported across the plasma membrane at the intervention of GLUT-2, could be used to label
preferentially the endocrine moiety of the pancreatic gland. This heptose is taken up more efficiently by hepatocytes and
islet cells, than by erythrocytes, parotid cells, acinar pancreatic cells or tumoural islet cells of either the RINm5F or
INS-1 line. Likewise, d-mannoheptulose only inhibits d-glucose metabolism in hepatocytes and isolated islets. Its hexaacetate ester, however, inhibits the catabolism of the hexose
in all cell types. The uptake of d-mannoheptulose represents a carrier-mediated process. Human islets behave like rat islets in terms of D-mannoheptulose uptake
and inhibition by the heptose of both D-glucose metabolism and insulinotropic action. The use of radiolabelled analogs of
D-mannoheptulose suitable for imaging of the endocrine pancreas is discussed. In the same perspective, it is proposed that
advantage could be taken of the much greater accumulation of glycogen in insulin-producing cells, as compared to other pancreatic
cell types, in situations of sustained hyperglycaemia. [Diabetologia (2001) 44: 393–406] 相似文献
5.
A gating of volume-sensitive anion channels may participate in the depolarization of the plasma membrane caused by high concentration
of d-glucose in insulin-producing B-cells of the endocrine pancreas. The efflux of tritiated taurine from prelabeled cells is
currently used to assess changes in the activity of such channels. The handling of [1,2-3H]taurine by isolated rat pancreatic islets was therefore investigated. The net uptake of [1,2-3H]taurine was found to represent a concentration-, time-, and temperature-dependent process. It was progressively increased
in the range of d-glucose concentrations between 2.8 and 8.3 mM, but no further increase was observed at 16.7 mM
d-glucose. Over 15 min incubation, the efflux of radioactivity from prelabeled islets was inhibited by MK571 (1.0 mM). It was increased in response to hypoosmolarity both in the presence and absence of extracellular Na+. Whether in salt-balanced or Na+-deprived media, the efflux of radioactivity from prelabeled islets increased in response to a rise in d-glucose concentration from 2.8 to 5.6 or 8.3 mM, but decreased when the concentration of the hexose was further increased from 8.3 to 16.7 mM. In perifused islets, however, the radioactive efflux from prelabeled islets was inhibited, in a concentration-related manner,
when islets first deprived of d-glucose for 45 min were then exposed to 2.8, 5.6, or 16.7 mM
d-glucose. Likewise, in prelabeled and perifused islets first exposed for 45 min to 4.0 mM
d-glucose, a later rise in hexose concentration to 8.3 mM failed to affect significantly effluent radioactivity, while an increase in hexose concentration from 4.0 to 16.7 mM inhibited the radioactive outflow. In these perifusion experiments, the rise in d-glucose concentration provoked the expected changes in insulin output. The findings obtained in islets examined immediately
after preincubation in the presence of [1,2-3H]taurine are consistent with the presence of volume-sensitive anion channels in islet cells and with a gating of such channels
in response to a rise in d-glucose concentration from 2.8 to 5.6–8.3 mM. However, the radioactive fractional outflow rate from prelabeled islets seems to reach its highest value at about 8.3 mM
d-glucose, being unexpectedly decreased at a higher concentration (16.7 mM) of the hexose. In conclusion, the pleiotropic effects of d-glucose upon tritiated taurine outflow from prelabeled rat islets, which could conceivably be ascribed to differences in
the handling of this amino sulfonic acid by distinct islet cell types, indicates that the present approach is far from optimal
to characterize unambiguously the regulation by the hexose of volume-sensitive anion channel activity in insulin-producing
islet cells. 相似文献
6.
Novel information was recently provided concerning the reciprocal effects of d-glucose and d-fructose upon their respective metabolism in rat pancreatic islets. In the light of such findings, this study aims at comparing
the effects of d-glucose and d-fructose on insulin, somatostatin, and glucagon release from the isolated perfused rat pancreas. A rise in d-glucose concentration from 3.3 to 5.0 or 7.3 mM or the administration of d-fructose (17 and 40 mM) in the presence of 3.3 mM
d-glucose stimulated insulin release in a concentration-related manner, but failed to affect somatostatin output. The secretion
of glucagon was decreased in all cases. The secretory response to l-arginine (5 mM), 25 min after restoring the basal concentration of d-glucose, was more markedly affected, in terms of potentiation of insulin and somatostatin release and reduction of glucagon
output, after prior administration of d-fructose than after a prior increase in d-glucose concentration. These findings argue against any major role for a paracrine regulation of hormonal release and, instead,
are consistent with a causal link between metabolic and secretory events in the islet cells. Nevertheless, the present results
emphasize differences in the response of distinct pancreatic endocrine cell types to the same or distinct hexoses. 相似文献
7.
Oguzhan B Zhang Y Louchami K Courtois P Portois L Chardigny JM Malaisse WJ Carpentier YA Sener A 《Endocrine》2006,29(3):457-466
In order to gain information on the determinism of the perturbation of fuel homeostasis in situations characterized by a depletion
in long-chain polyunsaturated ω3 fatty acids (ω3), the metabolic and hormonal status of ω3-depleted rats (second generation)
was examined. When required, these rats were injected intravenously 120 min before sacrifice with a novel medium-chain triglyceride-fish
oil emulsion able to provoke a rapid and sustained increase of the ω3 content in cell phospholipids. The measurement of plasma
glucose, insulin, phospholipid, triglyceride, and unesterified fatty acid concentration indicated modest insulin resistance
in the ω3-depleted rats. The plasma triglyceride and phospholipid concentrations were decreased in the ω3-depleted rats with
abnormally low contribution of ω3 in both circulating and pancreatic islet lipids. The protein, insulin, and lipid content
of the islets, as well as their intracellular and extracellular spaces, were little affected in the ω3-depleted rats. The
metabolism of d-glucose in the islets of ω3-depleted rats was characterized by a lesser increase in d-[5-3H]glucose utilization and d-[U−14C]glucose oxidation in response to a given rise in hexose concentration and an abnormally low ratio between d-glucose oxidation and utilization. These abnormalities could be linked to an increased metabolism of endogenous fatty acids
with resulting alteration of glucokinase kinetics. The release of insulin evoked by d-glucose, at a close-to-physiological concentration (8.3mM), was increased in the ω3-depleted rats, this being considered as consistent with their insulin resistance. Relative to such
a release, that evoked by a further rise in d-glucose concentration or by non-glucidic nutrients was abnormally high in ω3-depleted rats, and restored to a normal level
after of the intravenous injection of the ω3-rich medium-chain triglyceride-fish oil emulsion. Because the latter procedure
failed to correct the perturbation of d-glucose metabolism in the islets of ω3-depleted rats, it is proposed that the anomalies in the secretory behaviour of islets
in terms of their response to an increase in hexose concentration or non-nutrient secretagogues is mainly attributable to
alteration in K+ and Ca2+ handling, as indeed recently documented in separate experiments. 相似文献
8.
Islets from fed and 3-day-starved rats were incubated for 60 min in the presence of either 2.8 or 16.7 mM
d-glucose, mixed with tracer amounts ofd-[5-3H]glucose,d-[3,4-14C]glucose,d-[6-14C]glucose andd-[2-14C]glucose. Starvation decreased the generation of3HOH fromd-[5-3H]glucose and the production of14CO2 from14C-labelledd-glucose, both at low and high hexose concentrations. In islets from starved and fed rats, a rise ind-glucose concentration preferentially stimulated oxidative glycolysis, pyruvate decarboxylation and acetyl residue oxidation, relative tod-glucose utilization. At both low and high hexose concentrations and in both fed and starved rats, the decarboxylation of pyruvate exceeded the oxidation of glucose-derived acetyl residues, the C1 of such residues being more efficiently converted to14CO2 than their C2. Starvation decreased oxidative glycolysis more severely than non-oxidative glycolysis, impaired the preferential stimulation ofd-[3,4-14C]glucose oxidation relative tod-[5-3H]glucose utilization as observed in response to a rise in hexose concentration, and lowered the ratio betweend-[6-14C]glucose oxidation and hexose utilization. It is proposed, therefore, that the short-term regulation of mitochondrial oxidative events byd-glucose is itself modulated in islet cells by the nutritional status. 相似文献
9.
Summary In islets from both adult rats injected with streptozotocin during the neonatal period and spontaneously diabetic rats obtained by repeated selective breedings (GK rats), the ratio between d-[3, 4-14C]glucose oxidation and d-[5-3H]glucose conversion to 3HOH was 25% lower than in islets from control rats, indicating an impaired contribution of oxidative to total glycolysis. No primary defect in the Krebs cycle was found in the islets of diabetic rats, as judged from the ratio between either d-[2-14C]glucose or d-[6-14C]glucose and d-[3, 4-14C]glucose oxidation. Therefore, we propose that a preferential alteration of oxidative glycolysis in the pancreatic beta cell may contribute to the impairment of glucose-induced insulin release not only in a cytotoxic but also in a spontaneous model of non-insulin-dependent diabetes mellitus. 相似文献
10.
Didier Blocklet Hassan Jijakli Abdullah Sener André Schoutens Willy J. Malaisse 《Endocrine》1998,9(1):113-117
99mTc-sesta-(2-methoxy-isobutyl-isonitrile) (Tc-MIBI) is currently used for imaging of several organs. In the present study,
its uptake by rat pancreatic islets, rat parotid cells, and human breast adenocarcinoma cells (MCF-7 cells) was found to be
grossly proportional to its concentration (up to 0.1 μM), time-related (with a fractional turnover rate close to 2–3 10−2 · min−1), and stimulated by d-glucose. Comparable values for the fractional turnover rate were found in prelabeled islets and MCF-7 cells, d-glucose failing to affect Tc-MIBI efflux from prelabeled islets. In the islets, the uptake of Tc-MIBI was decreased at low
temperature, in the presence of mitochondrial poisons and at high extracellular K+ concentration, unaffected by the absence of extracellular Ca2+, and increased by nutrient secretagogs, such as 2-ketoisocaproate and the association of l-leucine and l-glutamine. These findings are consistent with the view that Tc-MIBI uptake is ruled by its extracellular concentration, and
the polarization of both plasma and mitochondrial membranes. It is proposed that this lipophilic cation may be useful to detect
alteration of nutrient metabolism in pancreatic islets deprived of any exogenous fuel. 相似文献
11.
The placental transfer ofd- andl-glucose was investigated in anaesthetised non-diabetic and streptozotocin-induced diabetic rats. Maternal to fetal transfer was determined by perfusing the fetal side of one placenta in situ whilst infusing a mixture ofd-[3-3H]glucose andl-[1-14C]glucose into the maternal circulation. Backtransfer from the fetal to maternal circulation was assessed by determining the uptake of the radiolabelled glucoses from the perfusion fluid during a single passage through the placenta on the fetal side. Maternal diabetes resulted in a reduced utero-placental blood flow but an increased bidirectional transfer ofd-glucose. Non-specific maternal to fetal placental transfer ofl-glucose was greater in diabetic rats than in controls, and the loss ofl-glucose during placental perfusion of the fetal side was, again, greater in diabetic than in control rats. This increased bidirectional leak of glucose possibly reflects a functionally compromised placenta, caused by its formation in a diabetic milieu, and may explain the greater fetal-maternal glucose ratios found in diabetic rats relative to controls. 相似文献
12.
The metabolism of α-D-glucose pentaacetate and its positive insulinotropic action in isolated rat pancreatic islets are both unexpectedly resistant
toD-mannoheptulose, as judged from experiments conducted over 90–120 min incubation. In the present study, the possible effects
of the heptose upon the immediate cationic and secretory response to the ester were investigated in perifused islets prelabeled
with either86Rb or45Ca. At a 10 mM concentration, sufficient to abolish the inhibitory action of unesterifiedD-glucose upon86Rb outflow,d-mannoheptulose failed to suppress the decrease in86Rb outflow and increase in45Ca efflux caused by α-D-glucose pentaacetate at normal extracellular Ca2+ concentration and also failed to prevent the decrease in both45Ca and insulin release provoked by the ester in the absence of extracellular Ca2+. The sole obvious effect of the heptose was to change the early peak-shaped positive secretory response to α-D-glucose pentaacetate to a transient inhibition of insulin release. This change was observed in islets either deprived of
any other exogenous nutrient or exposed toL-leucine throughout the experiments. These findings support the view that the islet functional response to α-D-glucose pentaacetate is largely resistant toD-mannoheptulose. They also reinforce the concept that the insulinotropic action of this and other monosaccharide esters involves
a dual modality of B-cell activation, linked to both the catabolism of their carbohydrate moieties and a direct effect of
the esters themselves upon a specific receptor system. 相似文献
13.
Abdellatif Bakkali-Nadi Marcel M. Kadiata Willy J. Malaisse 《Journal of gastrointestinal cancer》2000,27(1):59-63
Background. The tetra-acetate ester of 2-deoxy-d-glucose was recently found to either inhibit or augment insulin secretion, depending on the concentration of the ester. Both the positive and negative insulinotropic actions of the ester display anomeric specificity. Methods. The effects of the α- and β-anomer of 2-deoxy-d-glucose tetra-acetate (5.0 mM) on the metabolism of d-[5-3H]glucose and d-[U-14C]glucose (8.3 mM) were investigated in isolated rat pancreatic islets. 相似文献
14.
Karim Louchami Marcel M. Kadiata Hassan Jijakli Willy J. Malaisse 《Journal of gastrointestinal cancer》1998,24(2):103-109
Summary
Conclusion
The polyacetate esters of selected nonnutrient monosaccharides represent potential tools for either stimulation of insulin
release in noninsulin-dependent diabetes or inhibition of insulin secretion in hyperinsulinemic syndromes.
Background The polyacetate esters of several monosaccharides were recently shown to display greater nutritional value or biological efficiency
than the corresponding unesterified carbohydrates.
Methods The effects of seven polyacetate esters of monosaccharides, all tested at a 1.7-mM concentration on both45Ca efflux and insulin release were investigated in prelabeled rat pancreatic islets perifused in the presence of 10.0 mM succinic acid dimethyl ester.
Results Both α-D-glucose penta-acetate and, to a lesser extent, β-L-glucose penta-acetate stimulated insulin release. Inversely, α-D-galactose penta-acetate, but not β-D-galactose penta-acetate inhibited insulin secretion evoked by succinic acid dimethyl ester. Esters of carbohydrates which
are inhibitors ofD-glucose metabolism, such asD-mannoheptulose hexa-acetate and the two anomers of 2-deoxy-D-glucose tetra-acetate. Only also enhanced insulin output, with a preference for the α-anomer of 2-deoxy-D-glucose tetra-acetate. Only those esters with positive insulinotropic action augmented45Ca efflux from the prelabeled islets. 相似文献
15.
Ying Zhang Raphael Crutzen Karim Louchami Yvon A. Carpentier Abdullah Sener Willy J. Malaisse 《Endocrine》2009,35(3):438-448
The long-term metabolic and functional effects of a dietary deprivation of long-chain polyunsaturated ω3 fatty acids were
recently investigated in second-generation ω3-depleted rats. This study represents the first attempt to explore the direct,
but not immediate, effects of ω3 fatty acids on insulin-producing cells. For this purpose, BRIN-BD11 cells were cultured for
24 h in the absence or presence of both C20:5ω3 and C22:6ω3 (50 μM each) and, thereafter, examined for their phospholipid
and triglyceride fatty acid pattern, and their metabolic, ionic, and secretory responses to d-glucose and/or non-nutrient insulinotropic agents. The prior culture in the presence of the two ω3 fatty acids provoked an
enrichment of cell lipids in such ω3 fatty acids, changes in the phospholipid fatty acid pattern of long-chain polyunsaturated
ω6 fatty acids as well as saturated and monodesaturated fatty acids, and cell steatosis. It minimized the relative increase
in d-[5-3H]glucose utilization and d-[U-14C]glucose oxidation otherwise resulting from an increase in the concentration of the hexose from 1.1 to 11.1 mM. It also minimized
the changes in 86Rb+ net uptake otherwise provoked by rises in d-glucose concentration and decreased the absolute values for insulin output. It is concluded that the major changes in metabolic,
cationic, and secretory behavior of the ω3-enriched BRIN-BD11 cells are paradoxically similar to those encountered in pancreatic
islets from ω3-depleted rats and, in both cases, possibly attributable to a phenomenon of lipotoxicity. 相似文献
16.
Yoshioka M Sato T Furuya T Shibata S Andoh H Asanuma Y Hatazawa J Koyama K 《Journal of gastroenterology》2003,38(12):1189-1193
We used positron emission tomography with 2-deoxy-2-[18F]fluoro-d-glucose (FDG-PET) in the diagnosis of two cases of malignant intraductal papillary mucinous tumor (IPMT) of the pancreas. A 56-year-old man and a 72-year-old man, both with tumors in the pancreatic head, were referred to Akita University Medical Center. Computed tomography revealed tumors with multiple cystic components in both patients. FDG-PET images showed markedly high FDG uptake in the area corresponding to a solid component found in one patient and diffuse faint uptake, higher than that of the surrounding tissue, in the other patient, who had no solid component. Histological examination of the resected specimens after pancreatectomy showed invasive carcinoma involving the pancreatic parenchyma in both patients. Although our experience is limited and preliminary, FDG-PET seems to be useful for the detection of malignancy in IPMT, especially in patients not showing any solid component on conventional diagnostic images such as computed tomography. 相似文献
17.
d-Glucose and other nutrient insulin secretagogues have long been known to induce a transient increase in inorganic phosphate
release from pancreatic islets, a phenomenon currently referred to as a “phosphate flush”. The objective of this study was
to explore the possible participation of volume-sensitive anion channels in such a process. Rat pancreatic islets were preincubated
for 60 min in the presence of [32P]orthophosphate and then perifused for 90 min to measure 32P fractional outflow rate and insulin secretion. From minutes 46 to 70 inclusive either the concentration of d-glucose was increased from 1.1 to 8.3 mmol L−1 or the extracellular osmolarity was decreased by reducing the NaCl concentration by 50 mmol L−1. The increase in d-glucose concentration induced a typical phosphate flush and biphasic stimulation of insulin release. Extracellular hypoosmolarity
caused a monophasic increase in both effluent radioactivity and␣insulin output. The inhibitor of volume-sensitive anion␣channels
5-nitro-2-(3-phenylpropylamino)benzoate (0.1 mmol L−1) inhibited both stimulation of insulin release and phosphate flush induced by either the increase in d-glucose concentration or extracellular hypoosmolarity. It is proposed that gating of volume-sensitive anion channels accounts
for the occurrence of the phosphate flush and subsequent stimulation of insulin secretion in response to either an increase
in d-glucose concentration or a decrease in extracellular osmolarity. 相似文献
18.
Louchami K Zhang Y Carpentier YA Chardigny JM Malaisse WJ Herchuelz A Sener A 《Endocrine》2007,32(2):148-154
A number of metabolic, ionic and secretory variables were recently found to be affected in pancreatic islets obtained from
second generation rats depleted in long-chain polyunsaturated ω3 fatty acids (ω3 rats). The present study further documents
three sets of anomalies in such islets. First, after 90 min exposure to d-glucose (8.3 mM), the release of insulin from perifused islets, prelabelled with 45Ca, is lower in ω3 rats than in control animals, despite comparable 45Ca fractional outflow rate. Second, over 15 min exposure to carbamylcholine (0.1 mM), in the presence of d-glucose, the cytosolic concentration of Ca2+ is increased to a greater relative extent in dispersed islet cells from ω3 rats, as compared to control animals. This coincides
with a greater relative increase in insulin output from perifused islets during the second phase of the secretory response
to the cholinergic agent. Last, the increase provoked by ouabain (1.0 mM) in cytosolic Ca2+ concentration, 45Ca fractional outflow rate and insulin release are all delayed in the ω3 rats. Taking into account the decreased activity
of Na+, K+-ATPase in the islets of ω3 rats, these findings are interpreted as reflecting an impaired priming of insulin-producing cells
when first exposed for 105 min to a physiological postprandial concentration of d-glucose. 相似文献
19.
Malaisse WJ Louchami K Laghmich A Ladrière L Morales M Villanueva-Peñacarrillo ML Valverde I Rasschaert J 《Endocrine》1999,11(3):293-300
The calcium-sensing receptor gene was recently shown to be expressed in rat pancreatic islets and purified islet B-cells.
In this study, we investigated the possible role of this receptor in the regulation of insulin release from isolated rat pancreatic
islets. Poly-l-arginine (0.2–0.3 μM) and poly-l-lysine (0.03–0.1 μM) increased insulin output evoked by d-glucose (8.3 mM). This positive effect faded out at higher concentrations of the basic peptides. Likewise, the release of insulin evoked
by 8.3 mM
d-glucose was significantly lower at high (1.0 mM) than low (0.05–0.1 mM) concentrations of neomycin. The insulinotropic action of Ba2+ in Ca2+-deprived islets was potentiated in rats pretreated with pertussis toxin. However, Gd3+ inhibited insulin release evoked by dd-glucose in islets prepared from normal rats or animals pretreated with pertussis toxin and incubated in the absence or presence
of either theophylline or forskolin. Gd3+ (0.3 mM) failed to affect effluent radioactivity from islets prelabeled with myo-[2-3H]inositol and cyclic AMP net production in islets incubated in the absence or presence of forskolin. Gd3+ decreased, however, 45Ca efflux from prelabeled islets perifused in the absence or presence of extracellular Ca2+. It is speculated that a negative insulinotropic action mediated by the calcium-sensing receptor, and possibly attributable
to a fall in cytosolic Ca2+ concentration, may prevent excessive insulin secretion in pathological situations of hypercalcemia. 相似文献
20.
David H. Crean Charles Liebow Ming-Ting Lee Angela R. Kamer Andrew V. Schally Thomas S. Mang 《Journal of cancer research and clinical oncology》1995,121(3):141-149
Increased phosphorylation in cancers can stimulate growth and up-regulate certain receptors. To test whether the functional response of phosphatase receptors is up-regulated during carcinogenesis, we examined the effects of ligands on net phosphorylation in isolated membranes derived from hamster cheekpouch tissues undergoing malignant transformation. The buccal mucosa of groups of Syrian golden hamsters was exposed thrice weekly to 0.5% dimethylbenzanthracene (DMBA) in acetone for 2–12 weeks to produce premalignant and malignant tissues. Homogenates of these tissues were then incubated with [32P]ATP in the presence of epidermal growth factor (EGF), agonist of somatostatin analogue RC-160, luteinizing-hormone-releasing hormone (LH-RH) [d-Trp6]LH-RH, or combinations of EGF, RC-160, and [d-Trp6]LH-RH. Changes compared to controls in phosphorylation in response to ligands provided estimates of kinase or phosphatase activity. Phosphorylation increased continuously, from the first application of DMBA in a linear fashion, and independently of EGF stimulation. RC-160 and [d-Trp6]LH-RH reduced phosphorylation in vitro. This response occurred in premalignant (weeks 6–10 after DMBA application) as well as malignant tissues (week 12 after DMBA application), but was not significant in normal tissues. The results show a continuous augmentation in phosphatase activity prior to the appearance of cancers, but with a delay in expression following the primary event of increased kinase activity. Significantly less phosphorylation of substrates was induced by both RC-160 and [d-Trp6]LH-RH after in vitro activation by EGF than in the absence of EGF. This suggests that EGF activates latent systems of hormonal receptors. Collectively, these results support the hypothesis that the enhancement of the hormonally stimulated phosphatase in cancers occurs secondarily to the increased kinase activity.Abbreviations
EGF
epidermal growth factor
-
RC-160
somatostatin analogue
- [d-Trp6]LH-RH
luteinizing-hormone-releasing harmone
-
DMBA
dimethylbenzanthracene
This work was supported, in part, by research grants from the American Cancer Society PDT-307, the Margaret Duffey and Robert Cameron Troupe Memorial Fund of the Buffalo General Hospital, and the National Institute of Dental Research 相似文献