Causes and cures for endoplasmic reticulum stress in lipotoxic ß-cell dysfunction.

Pancreatic ß-cell dysfunction is central to the pathogenesis of type 2 diabetes, and the loss of functional ß-cell mass in type 2 diabetes is at least in part secondary to increased ß-cell apoptosis. Accumulating evidence suggests that endoplasmic reticulum (ER) stress is present in ß-cells in type 2 diabetes. Free fatty acids (FFAs) cause ER stress and are putative mediators of ß-cell dysfunction and death. In this review, we discuss the molecular mechanisms underlying ER stress induced by saturated and unsaturated FFAs. Oleate and palmitate trigger ER stress through ER Ca(2+) depletion and build-up of unfolded proteins in the secretory pathway. Saturated and unsaturated FFAs elicit a differential signal transduction in the three branches of the ER stress response, resulting in different survival/apoptosis outcomes. The protection of ß-cells against FFAs through the interference with ER stress signalling has opened novel therapeutic perspectives for type 2 diabetes. Chemical chaperones, salubrinal and glucagon-like peptide-1 (GLP-1) analogues have been used to protect ß-cells from lipotoxic ER stress. Importantly, the pro- and antiapoptotic effects of these compounds are cell and context dependent.

Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes.

AIMS/HYPOTHESIS: Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate. METHODS: Chemokine and cytokine expression was studied by microarray analysis of laser-capture microdissected islets from pancreases obtained from ten non-diabetic and ten type 2 diabetic donors, and by real-time PCR of human islets exposed to oleate or palmitate at 6 or 28 mmol/l glucose. The cellular source of the chemokines was analysed by immunofluorescence of pancreatic sections from individuals without diabetes and with type 2 diabetes. RESULTS: Microarray analysis of laser-capture microdissected beta cells showed increased chemokine and cytokine expression in type 2 diabetes compared with non-diabetic controls. The inflammatory response in type 2 diabetes was mimicked by exposure of non-diabetic human islets to palmitate, but not to oleate or high glucose, leading to the induction of IL-1beta, TNF-alpha, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL2). Interference with IL-1beta signalling abolished palmitate-induced cytokine and chemokine expression but failed to prevent lipotoxic human islet cell death. Palmitate activated nuclear factor kappaB (NF-kappaB) in human pancreatic beta and non-beta cells, and chemically induced endoplasmic reticulum stress caused cytokine expression and NF-kappaB activation similar to that occurring with palmitate. CONCLUSIONS/INTERPRETATION: Saturated-fatty-acid-induced NF-kappaB activation and endoplasmic reticulum stress may contribute to IL-1beta production and mild islet inflammation in type 2 diabetes. This inflammatory process does not contribute to lipotoxicity ex vivo, but may lead to local chemokine release.

Effects of D-glucose upon D-fructose metabolism in rat hepatocytes: A 13C NMR study.

Isolated hepatocytes from fed rats were exposed for 120 min to D-glucose (10 mM) and either D-[1-13C]fructose, D-[2-13C]fructose or D-[6-13C]fructose (also 10 mM) in the presence of D2O. The identification and quantification of 13C-enriched D-fructose and its metabolites (D-glucose, L-lactate, L-alanine) in the incubation medium and the measurement of their deuterated isotopomers indicated, by comparison with a prior study conducted in the absence of exogenous D-glucose, that the major effects of the aldohexose were to increase the recovery of 13C-enriched D-fructose, decrease the production of 13C-enriched D-glucose, restrict the deuteration of the 13C-enriched isotopomers of D-glucose to those generated by cells exposed to D-[2-13C]fructose, and to accentuate the lesser deuteration of the C, (as compared to C5) of 13C-enriched D-glucose derived from D-[2-13C]fructose. The ratio between C2-deuterated and C2-hydrogenated L-lactate, as well as the relative amounts of the CH3-, CH2D-, CHD, and CD3- isotopomers of 13C-enriched L-lactate were not significantly different, however, in the absence or presence of exogenous D-glucose. These findings indicate that exogenous D-glucose suppressed the deuteration of the C1 of D-[I-13C]glucose generated by hepatocytes exposed to D-[1-13C]fructose or D-[6-13C]fructose, as otherwise attributable, in part at least, to gluconeogenesis from fructose-derived [3-13C]pyruvate, and apparently favoured the phosphorylation of D-fructose by hexokinase isoenzymes, probably through stimulation of D-fructose phosphorylation by glucokinase.

Oxidation of D-[U-(14)C] glucose and [1,12-(14)C] dodecanedioic acid by pancreatic islets from Goto-Kakizaki rats.

In pancreatic islets from hereditarily diabetic GK rats, [1,12 -(14)C] dodecanedioic acid (5.0 mM) was oxidized at a rate representing about 5 % of that of D-[U - (14)C] glucose (8.3 mM). Dioic acid and hexose failed to exert any significant reciprocal effects on their respective oxidation. The production of (14)CO(2) from [1,12 -(14)C] dodecanedioic acid was proportional to its concentration in the 0.2 - 5.0 mM range. These results were essentially comparable to those obtained in islets from control rats. They extend, therefore, to GK rats the knowledge that dodecanedioic acid acts as a nutrient in pancreatic islet cells.

Pancreatic fate of D-[3H] mannoheptulose.

D-Mannoheptulose was recently postulated to be transported into cells by GLUT2. The validity of such an hypothesis was assessed by comparing the uptake of tritiated D-mannoheptulose by pancreatic islets versus pieces of pancreas and, in the latter case, by comparing results obtained in control rats versus animals injected with streptozotocin (STZ). The uptake of D-[3H] mannoheptulose by islets represents a time-related and temperature-sensitive process, inhibited by cytochalasin B and enhanced by D-glucose. The uptake of the tritiated heptose was much lower in pieces of pancreatic tissue and inhibited by D-glucose, at least in the STZ rats. Whether in pieces of pancreas exposed in vitro to D-[3H] mannoheptulose or after intravenous injection of the tritiated heptose, the radioactive content of the pancreatic tissue was lower in STZ rats than in control animals. This contrasted with an unaltered radioactive content of liver and muscle in the STZ rats, at least when treated with insulin. Suitably radiolabelled D-mannoheptulose or an analogue of the heptose could thus conceivably be used for quantification of the endocrine pancreatic mass.

Labeling of pancreatic glycogen by D-[U-14c]glucose in hyperglycemic rats.

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 radioactive glycogen content of both liver and pancreas was then measured. After 48 h of infusion, the radioactive 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 i.v. 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.

Assessment of islet beta-cell mass in isolated rat pancreases perfused with D-[(3)H]mannoheptulose.

D-mannoheptulose is apparently transported into cells mainly at the intervention of GLUT-2 and hence was recently proposed as a tool to label preferentially insulin-producing beta-cells in the pancreatic gland. The validity of such a proposal was investigated in the present study conducted in isolated perfused pancreatic glands from control and streptozotocin-induced diabetic rats. After a 30-min equilibration period, D-[(3)H]mannoheptulose (0.1 mM) and [U-(14)C]sucrose (0.5 mM) were infused for 15 min in the presence of 30 mM D-glucose. The pancreatic glands were then perfused for 10 min with a nonradioactive medium during and after administration of cytochalasin B (0.02 mM). Under these experimental conditions, the intracellular distribution space of D-[(3)H]mannoheptulose averaged 5.42 +/- 0.75 nl/mg in control animals, whereas it failed to be significantly different from zero in the streptozotocin rats. The present procedure may thus allow the assessment of the relative contribution of islet beta-cells to the total mass of the pancreatic gland.

Assessment by D-[(3)H]mannoheptulose uptake of B-cell density in isolated pancreatic islets from Goto-Kakizaki rats.

The uptake of D-[3H]mannoheptulose by isolated pancreatic islets was recently proposed as a tool to assess the relative contribution of insulin-producing cells to the total mass of the islets. In the present study, the uptake of the tritiated heptose over 60 min incubation at 37 degrees C was about 21% lower in islets from hereditarily diabetic rats (GK rats) than in islets from control animals, this decrease being virtually identical to that documented previously by morphometric analysis of islets from the same type of rats. The intracellular 3HOH space and extracellular [U-14C]sucrose space were not significantly different in control and diabetic rats, at least when the comparison was restricted to animals of the same sex. There was a trend, however, towards a somewhat lower D-[5-3H]-glucose intracellular distribution space in islets from GK rats, as compared to control animals. These findings provide further support to the validity of D-[3H]mannoheptulose uptake as a tool to assess the density of insulin-producing cells in isolated islets.

Uptake of D-mannoheptulose by rat erythrocytes, hepatocytes and parotid cells.

D-[3H]mannoheptulose (or D-[1-14C] mannoheptulose) net uptake was measured in rat erythrocytes, parotid cells and hepatocytes. In the erythrocytes and parotid cells, the intracellular distribution space of the heptose (0.1 mM) represented only about 1 and 13%, respectively, of the intracellular 3HOH space. In hepatocytes, however, it amounted to approximately 45% of the intracellular 3HOH space. In all cases, the apparent distribution space of D-[3H]mannoheptulose hexaacetate largely exceeded that of unesterified D-[3H]mannoheptulose. Relative to the intracellular water space, the generation of acidic metabolites (expressed as an apparent distribution space) from radioactive D-mannoheptulose was one order of magnitude lower in parotid cells (< or = 3%) than in hepatocytes (> or = 20%). These findings are compatible with the hypothesis that D-mannoheptulose is transported into cells mainly, if not exclusively, at the intervention of GLUT2.

Pancreatic and hepatic glycogen content in normoglycemic and hyperglycemic rats.

As judged from morphological criteria, glycogen accumulates to a larger extent in insulin-producing B-cells than in acinar cells of the pancreas in situations of sustained hyperglycemia. In the present study, the glycogen content of the pancreatic gland and liver was measured in either euglycemic or glucose-infused hyperglycemic control rats, as well as in streptozotocin-induced diabetic rats. Whilst the glycogen content of the pancreas was significantly higher in STZ rats than in control euglycemic rats, it was further enhanced in glucose-infused control rats, despite the fact that the latter animals were not more severely hyperglycemic and for a shorter time than STZ rats. From these measurements, it was estimated that, relative to wet weight, the glycogen content was, under the present experimental conditions, about 75 times higher in insulin-producing than other pancreatic cells. Moreover, it is proposed that the intravenous administration of glucagon may help in distinguishing between the glycogen present in the endocrine and exocrine moieties of the pancreatic gland, this hormone being apparently unable to provoke glycogenolysis in the exocrine pancreas, at variance with the situation prevailing in isolated pancreatic islets.

Pancreatic fate of a (125)I-labelled mouse monoclonal antibody directed against pancreatic B-cell surface ganglioside(s) in control and diabetic rats.

The possible use of a mouse monoclonal antibody directed against rat pancreatic B-cell surface ganglioside(s) and labelled with radioactive iodine for selective imaging of the endocrine pancreas by a non-invasive procedure was investigated by following its pancreatic fate in experiments conducted either in vitro by incubation of rat isolated pancreatic islets, acinar tissue and pancreatic pieces or in vivo after intravenous injection of the (125)I-labelled antibodies ([(125)I]gamma-G). Although the binding of [(125)I]gamma-G per microg protein was about one order of magnitude higher in isolated islets than in acinar tissue, no significant difference was detected when comparing pancreatic pieces or isolated islets from control animals and rats rendered diabetic by one or two prior administrations of streptozotocin (STZ rats). Likewise, except in one set of experiments, no significant difference was found between control animals and STZ rats, when measuring the radioactive content of the pancreatic gland, relative to that of plasma, 1-4 days after the intravenous injection of [(125)I]gamma-G. These findings indicate that under the present experimental conditions, the mouse monoclonal antibody labelled with radioactive iodine does not appear to be a promising tool for selective imaging of the endocrine pancreas, e.g. by single photon emission computerized tomography.

Uptake of 1-deoxy-1-[125I]iodo-D-mannoheptulose by different cell types: in vitro and in vivo experiments.

D-mannoheptulose was recently proposed as a tool to label preferentially insulin-producing cells in the pancreatic gland in the perspective of the non-invasive imaging of the endocrine pancreas. In such a perspective, we have now synthesized 1-deoxy-1-[125I]iodo-D-mannoheptulose ([125I]MH) and examined its uptake by different rat cell types. No phosphorylation of [125I]MH by bovine heart hexokinase could be detected. The apparent distribution space of [125I]MH largely exceeded that of [U-14C]sucrose, considered as an extracellular marker, in erythrocytes, parotid cells, hepatocytes, pancreatic pieces and isolated pancreatic islets. Relative to the mean intracellular distribution space of 3HOH, that of [125I]MH was not significantly different in pancreatic pieces from either normal rats or streptozotocin-induced diabetic animals (STZ rats). In pancreatic islets, the uptake of [125I]MH was decreased at low temperature, but failed to be significantly affected by cytochalasin B. Sixty min after the intravenous injection of [125I]MH, the radioactive content of selected organs displayed the following hierarchy: muscle

Assessment of B-cell mass in isolated islets exposed to D-[3H]mannoheptulose.

D-mannoheptulose was recently proposed to be transported into cells mainly at the intervention of GLUT2. In the present study, it was investigated whether advantage could be taken from such a situation to assess the contribution of insulin-producing B-cells to the total mass of isolated rat pancreatic islets. After 60 min incubation at 37 degrees C in the presence of 8.3 mM D-glucose, the intracellular distribution space of D-[3H]mannoheptulose (0.1 mM) averaged, in islets from control and streptozotocin-induced diabetic rats, respectively 49.0+/-2.3 and 6.2+/-1.5% of the corresponding intracellular 3HOH space, all values being corrected for extracellular contamination as judged from the distribution space of [U-14C]sucrose (1.0 mM). These findings indicate that the present approach indeed allows to assess the relative contribution of B-cells to total islet mass for purpose of comparison between animals with different metabolic and/or hormonal status.

Pancreatic uptake of [2-(14)C]alloxan.

The uptake of [2-(14)C]alloxan by the pancreatic gland was investigated in control and streptozotocin-induced diabetic (STZ) rats, using both in vitro and in vivo techniques. Whether after 10 to 60 min incubation of pieces of pancreas in the presence of [2-(14)C]alloxan or 60 min to 24 h after intravenous injection of [2-(14)C]alloxan to control and insulin-treated STZ rats, the radioactive content of the pancreas (dpm/mg wet weight) only represented, in the STZ rats, about two thirds of the reference value found in control animals. These findings indicate that insulin-producing islet B-cells participate to a sizeable extent to the overall uptake of [2-(14)C]- alloxan by the whole pancreatic gland, despite the fact that they account for no more than about one percent of the total pancreas mass. Hence, it should be possible to preferentially label the endocrine moiety of the pancreas, in the perspective of its imaging and quantification by a non-invasive procedure, by use of a suitable radiolabelled molecule selectively taken up by islet, as distinct from acinar, pancreatic cells.

Pancreatic glycogen content in Goto-Kakizaki rats.

In situations of sustained hyperglycemia, much larger amounts of glycogen accumulate in islet B-cells than in other pancreatic cells. The labelling of such a glycogen pool could thus conceivably provide a mean for assessing the relative contribution of insulin-producing cells to the total pancreatic mass. In such a perspective, the present study aims at investigating pancreatic glycogen accumulation in hereditarily diabetic Goto-Kakizaki (GK) rats. When cultured at 30 mM D-glucose in the presence of D-[U-14C]glucose, pancreatic islets from GK rats accumulated 14C-labelled glycogen in a manner comparable to that previously documented in islets from normal rats. Likewise, the glycogen content of the pancreatic gland, relative to the plasma D-glucose concentration, was not different in GK and normal rats. The GK rats thus apparently represent a suitable model for further studies on the in vivo labelling of B-cell glycogen in the perspective of the non-invasive imaging and quantification of the endocrine pancreas.

D-mannoheptulose uptake and its metabolic and secretory effects in human pancreatic islets.

D-mannoheptulose was recently proposed to be transported into cells at the intervention of GLUT2. Since GLUT1, rather than GLUT2, represents the major carrier system for the transport of monosaccharides across the islet B-cell plasma membrane in human subjects, the uptake of D-mannoheptulose and its metabolic and secretory effects were investigated in human islets. The uptake of D-glucose reached much more rapidly a close-to-equilibrium value in isolated islets than in pieces of pancreas obtained from the same donor. The distribution space of D-[3H]mannoheptulose in the human islets largely exceeded that of [U-14C]sucrose, considered as an extracellular marker, and did not differ significantly from that of 3HOH. In the human islets, the heptose (10.0 mM) inhibited both D-[5-3H]glucose utilization and D-[U-14C] glucose oxidation, and decreased glucose-stimulated insulin release to the same extent as D-mannoheptulose hexaacetate. These findings indicate that a suitable radioactive analog of D-mannoheptulose could be used, in human like in rat islets, for preferential labelling of the endocrine moiety of the pancreatic gland.

Metabolism of alpha-D-[1,2-13C]glucose pentaacetate and alpha-D-glucose penta[2-13C]acetate in rat hepatocytes.

Hepatocytes from fed rats were incubated for 120 min in the presence of alpha-D-[1,2-13C]glucose pentaacetate (1.7 mM), both D-[1,2-13C]glucose (1.7 mM) and acetate (8.5 mM), alpha-D-glucose penta[2-13C]acetate (1.7 mM), or D-[1,2-13C]glucose (8.3 mM). The amounts of 13C-enriched L-lactate and D-glucose and those of acetate and beta-hydroxybutyrate recovered in the incubation medium were comparable under the first two experimental conditions. The vast majority of D-glucose isotopomers consisted of alpha- and beta-D[1,2-13C]glucose. The less abundant single-labeled isotopomers of D-glucose were equally labeled on each C atom. The output of 13C-labeled L-lactate, mainly L-[2-13C]lactate and L-[3-13C]lactate, was 1 order of magnitude lower than that found in hepatocytes exposed to 8.3 mM D-[1,2-13C]glucose, in which case the total production of the single-labeled species of D-glucose was also increased and that of the C3- or C4-labeled hexose was lower than that of the other 13C-labeled isotopomers. In cells exposed to alpha-D-glucose penta[2-13C]acetate, the large majority of 13C atoms was recovered as [2-13C]acetate and, to a much lesser extent, beta-hydroxybutyrate labeled in position 2 and/or 4. Nevertheless, L-[2-13C]lactate, L-[3-13C]lactate, and single-labeled D-glucose isotopomers were also produced in amounts higher or comparable to those found in cells exposed to alpha-D-[1,2-13C]glucose pentaacetate. However, a modest preferential labelling of the C6-C5-C4 moiety of D-glucose, relative to its C1-C2-C3 moiety, and a lesser isotopic enrichment of the C3 (or C4), relative to that of C1 (or C6) and C2 (or C5), were now observed. These findings indicate that, despite extensive hydrolysis of alpha-D-glucose pentaacetate (1.7 mM) in the hepatocytes, the catabolism of its D-glucose moiety is not more efficient than that of unesterified D-glucose, tested at the same molar concentration (1.7 mM) in the presence of the same molar concentration of unesterified acetate (8.5 mM), and much lower than that found at a physiological concentration of the hexose (8.3 mM). The present results also argue against any significant back-and-forth interconversion of D-glucose 6-phosphate and triose phosphates, under conditions in which sizeable amounts of D-glucose are formed de novo from 13C-enriched Krebs cycle intermediates generated from either D-[1,2-13C]glucose or [2-13C]acetate.

Pancreatic fate of 6-deoxy-6-[125I]iodo-D-glucose: in vitro experiments.

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.

Pancreatic fate of 6-deoxy-6-[125I]iodo-D-glucose: in vivo experiments.

The fate of 6-deoxy-6-[125I]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 (Kvalue: 12.2 x 10(-2) min(-1)), the clearance of the iodinated hexose occurred mainly by glomerular filtration (K value: 0.2 x 10(-2) min(-1)). 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.

Uptake of tritiated glibenclamide by endocrine and exocrine pancreas.

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 3H-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 3H-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 3H-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 3H-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.