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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-C]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-C]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-C]glucose. In STZ rats transplanted with islets and later infused with d-[U-C]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-[F]fluoro- d-glucose or C-labeled d-glucose could conceivably be used to favor the selective labeling of the endocrine, as distinct from exocrine, pancreas. [ABSTRACT FROM AUTHOR]

The role currently ascribed to the accumulation of l-arginine in the pancreatic islet B-cell as a determinant of its insulinotropic action was reevaluated by comparing the uptake and the metabolic, ionic, electric, and secretory effects of the cationic amino acid with those of its more positively charged methyl ester in rat pancreatic islets. The response to l-arginine methyl ester differed from that evoked by the unesterified amino acid by a lower uptake and oxidation, lack of inhibitory action on d-glucose metabolism, more severe inhibition of the catabolism of endogenous l-glutamine, inhibition of Ca net uptake, decrease in both Rb outflow from prelabeled islets perifused at normal extracellular Ca concentration and Ca efflux from prelabeled islets perifused in the absence of extracellular Ca, and delayed and lesser insulinotropic action. These findings reinforce the view that the carrier-meadiated entry of l-arginine into the islet B-cells, with resulting depolarization of the plasma membrane, represents the essential mechanism for stimulation of insulin release by this cationic amino acid. [ABSTRACT FROM AUTHOR]

The fate of 6-deoxy-6-[I[iodo- d-glucose (6-DIG), injected intravenously, was compared in control rats and animals that had received streptozotocin and were then treated with insulin or not. In the control rats, the measurement of plasma radioactivity suggested that, after an initial and rapid (up to min 10) distribution phenomenon ( K value: 12.2 × 10 min), the clearance of the iodinated hexose occurred mainly by glomerular filtration ( K value: 0.2 × 10 min). Three minutes after the injection of 6-DIG, the radioactive content of muscle, liver, and pancreas, relative to the paired value in blood, was lower in untreated diabetic rats than in control animals. In the case of muscle and liver, such a difference was no longer observed when the treatment of the diabetic rats by insulin resulted in restoration of normoglycemia. In the pancreas, however, the radioactive content, whether expressed relative to the paired blood or liver value, remained significantly lower in the insulin-treated diabetic rats than in the control animals. No significant difference between control and diabetic rats, in terms of pancreatic radioactivity, was observed 10 min after the injection of 6-DIG. These findings indicate that advantage can be taken from the vastly different time course for 6-DIG uptake by pancreatic acinar and islet cells, as recently documented in vitro, to label preferentially the endocrine moiety of the pancreatic gland shortly after 6-DIG injection. [ABSTRACT FROM AUTHOR]

The apparent distribution space of 6-[I]iodi- 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 HOH volume in pancreatic islets within 5 min, it slowly increased in pieces of pancreas and, even after 60-min incubation, remained lower than the HOH volume. Moreover, the net uptake of 6-deoxy-6-[I]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-[I]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-[I]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. [ABSTRACT FROM AUTHOR]

Tritiated glibenclamide binds to specific receptors and is internalized in pancreatic insulin-producing B-cells. We investigated, therefore, whether tritiated glibenclamide could be used to preferentially label the endocrine, as distinct from exocrine, pancreas. In isolated rat pancreatic islets, the net uptake of H-glibenclamide reached within 30 min of incubation a near-equilibrium value, corresponding to an apparent distribution space close to three to four times the islet volume. In pieces of pancreas exposed up to 1 h to H-glibenclamide, however, its apparent distribution space progressively increased and, even at the min 60 of incubation, did not exceed a third of the wet weight of the pieces. Yet, no significant difference could be detected between the time course for H-glibenclamide uptake by pancreatic pieces from either control animals or rats injected with streptozotocin a few days before the experiments. Likewise, no significant difference in the paired ratio between the radioactive content of the pancreas and plasma could be found between the control and diabetic rats when examined 1, 5, or 24 h after the IV administration of H-glibenclamide. These findings indicate that the sulfonylurea does not represent a suitable tool for preferential labeling of the endocrine pancreas in the perspective of its imaging by a noninvasive procedure. [ABSTRACT FROM AUTHOR]

Tritiated glibenclamide binds to specific receptors and is internalized in pancreatic insulin-producing B-cells. We investigated, therefore, whether tritiated glibenclamide could be used to preferentially label the endocrine, as distinct from exocrine, pancreas. In isolated rat pancreatic islets, the net uptake of H-glibenclamide reached within 30 min of incubation a near-equilibrium value, corresponding to an apparent distribution space close to three to four times the islet volume. In pieces of pancreas exposed up to 1 h to H-glibenclamide, however, its apparent distribution space progressively increased and, even at the min 60 of incubation, did not exceed a third of the wet weight of the pieces. Yet, no significant difference could be detected between the time course for H-glibenclamide uptake by pancreatic pieces from either control animals or rats injected with streptozotocin a few days before the experiments. Likewise, no significant difference in the paired ratio between the radioactive content of the pancreas and plasma could be found between the control and diabetic rats when examined 1, 5, or 24 h after the IV administration of H-glibenclamide. These findings indicate that the sulfonylurea does not represent a suitable tool for preferential labeling of the endocrine pancreas in the perspective of its imaging by a noninvasive procedure. [ABSTRACT FROM AUTHOR]

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 μ M) and poly- l-lysine (0.03-0.1 μM) increased insulin output evoked by d-glucose (8.3 m M). This positive effect faded out at higher concentrations of the basic peptides. Likewise, the release of insulin evoked by 8.3 m M d-glucose was significantly lower at high (1.0 m M) than low (0.05-0.1 m M) concentrations of neomycin. The insulinotropic action of Ba in Ca-deprived islets was potentiated in rats pretreated with pertussis toxin. However, Gd 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. Gd (0.3 m M) failed to affect effluent radioactivity from islets prelabeled with myo-[2-H]inositol and cyclic AMP net production in islets incubated in the absence or presence of forskolin. Gd decreased, however, Ca efflux from prelabeled islets perifused in the absence or presence of extracellular Ca. It is speculated that a negative insulinotropic action mediated by the calcium-sensing receptor, and possibly attributable to a fall in cytosolic Ca concentration, may prevent excessive insulin secretion in pathological situations of hypercalcemia. [ABSTRACT FROM AUTHOR]

Selected esters of D-glucose were recently proposed as tools to provide the sugar to cells, whilst bypassing the carrier system for hexose transport across the plasma membrane. In the present study, α-D-glucose pentaacetate, β-D-glucose pentaacetate, α-D-mannose pentaacetate and, to a lesser extent, 6-O-acetyl-D-glucose, all tested at a 1.7 mM concentration, were found to increase lactate production above basal value in rat erythrocytes. Over 90 min incubation, the increment in lactate production ranged from about 1.2 (α-D-glucose pentaacetate) to 0.6 (6-O-acetyl-D-glucose) μmol/μl of erythrocytes. Little or no change in lactate production was observed in cells exposed to β-L-glucose pentaacetate, α-D-glucose pentaethylsuccinate, α-D-galactose pentaacetate or β-D-galactose pentaacetate. The metabolic response to α-D-glucose pentaacetate was resistant to 3-O-methyl-D-glucose (10-80 mM) which suppressed, however, that evoked by D-glucose. D-mannoheptulose (10 mM) virtually failed to affect the response to D-glucose and its pentaacetate ester. On the contrary, 2-deoxy-D-glucose (10.6 mM) inhibited to the same relative extent (55% decrease) lactate production in erythrocytes exposed to either unesterified D-glucose or α-D-glucose pentaacetate. The tetraacetic ester of 2-deoxy-D-glucose was more efficient than unesterified 2-deoxy-D-glucose in inhibiting lactate production from α-D-glucose pentaacetate. It is proposed that selected esters of saccharides represent useful tools to bypass defects in hexose transport, and to increase their nutritional or therapeutic efficiency. [ABSTRACT FROM AUTHOR]

This study investigates the insulin secretory responsiveness of pancreatic islets to repaglinide in an experimental model of B-cell glucose incompetence. Rats were infused for 2 d with a 1.67 M solution of d-glucose administered at a rate close to 2.8 mL/h. This resulted in a modest rise in glycemia, a severe increase in plasma insulin concentration, an increased sensitivity of B-cells to adrenergic stress, an abnormally high insulin output from isolated islets perifused in the presence of 16.7 m M d-glucose, and a paradoxical transient increase in insulin release from the islets in response to a fall in hexose concentration. The early increment in insulin output evoked by repaglinide, in the presence of 16.7 m M d-glucose, was not lower in the islets from glucose-infused rats than in those from control rats. Moreover, when the meglitinide analog was administered concomitantly with the removal of d-glucose from the perifusion medium, the early response to repaglinide was further increased. Even after 24 min of glucose deprivation, the output of insulin by the islets from glucose-infused rats was higher in the presence of repaglinide than in its absence. These findings indicate that, in this model of B-cell dysfunction, the secretory responsiveness to repaglinide, as distinct from that to glucose, is fully preserved. Therefore, when taken into consideration together with prior observations, these findings argue in support of the use of this insulinotropic agent in the treatment of noninsulin-dependent diabetes. [ABSTRACT FROM AUTHOR]