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.

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.

Metabolic and secretory interactions between D-glucose and D-fructose in islets from GK rats.

The metabolism of D-glucose and/or D-fructose was investigated in both pancreatic islets and parotid cells of control and hereditarily diabetic Goto-Kakizaki (GK) rats. In the islets from GK rats, a preferential alteration of the oxidative response to D-glucose coincided with an impaired secretory response to the aldohexose. Such a metabolic alteration was not found in the parotid cells of GK rats. Whether in islet or parotid cells, D-fructose little affected the catabolism of glucose in either control or GK rats. The metabolism of D-fructose and the effect of D-glucose thereupon were essentially comparable in control and GK rats in both pancreatic islets and parotid cells. In both cell types, the comparison between the metabolism of D-glucose and D-fructose in cells simultaneously exposed to the two hexoses suggested a far from negligible contribution of fructokinase to the phosphorylation of D-fructose. Although the catabolism of the ketohexose and its modulation by D-glucose were closely comparable in islets from control and GK rats, the insulinotropic action of the ketohexose, relative to that of the aldohexose, was severely impaired in the GK rats. The present work thus emphasizes the specificity of the alteration in D-glucose metabolism in islets, as opposed to extrapancreatic cells, of GK rats. It also reveals in the islets of GK rats a further secretory anomaly apparently not attributable to the impairment of nutrient catabolism in the islet cells of these diabetic animals.

Improved viability and metabolic behavior of hepatocytes after liver storage in the presence of a succinic acid ester.

BACKGROUND: Selected esters of succinic acid were recently proposed as novel nutrients to support ATP generation in cells endangered by an imbalance between the formation and breakdown of this adenine nucleotide. In the present study, a new ester, glycerol-1,2,3-trimethylsuccinate, was examined for its potential beneficial effect in the procedures preceding liver transplantation. METHODS: The viability and metabolic behavior of hepatocytes were examined after perfusion and storage of rat livers for 20 hr at 4 degrees C with a Belzer UW-CSS solution in the absence or presence or 2 mM glycerol-1,2,3-trimethylsuccinate. RESULTS: Although it failed to affect significantly the release of cellular enzymes during storage and the protein or glycogen content of the liver, and was unable to prevent the storage-induced decrease in both biosynthetic activity and D-[U-14C]glucose incorporation into glycogen in isolated hepatocytes, the ester restored to a close-to-normal value the viability of the hepatocytes and opposed the starvation-like effects of liver storage upon both the conversion of D-[U-14C]glucose to 14CO2 and radioactive amino acids and the de novo generation of 14C-labeled D-glucose from [2-14C]pyruvate. CONCLUSIONS: Because succinic acid esters are efficiently metabolized in several cell types, the present results suggest that such esters may have a wide field of application in transplantation procedures.

Stimulation of biosynthetic activity by novel succinate esters in rat pancreatic islets.

Selected esters of succinic acid are currently under investigation as possible insulinotropic agents for the treatment of noninsulin-dependent diabetes mellitus. The aim of the present study was to investigate the effects of ten novel esters of succinic acid upon biosynthetic activity in rat pancreatic islets. In the absence of any other exogenous nutrient, glycerol-3-hydroxy-1,2-dimethyl succinate (0.5 mM), D-arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate (0.5 mM), and 4-tert-butylsuccinate (2.5 mM) exerted little or no effect upon L-[4-3H]phenylalanine incorporation into trichloroacetic acid-precipitable material. A modest but significant increase in biosynthetic activity to approximately 150% of basal value was found in the presence of L-threitol-1,2,4-trimethylsuccinate (2.0 mM) and ethanediol-1,2-diethylsuccinate (2.5 mM). A two- to five-fold increase in protein biosynthesis was observed in islets exposed to propanediol-1,2-dimethylsuccinate, glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate, L-threitol-3-succinoyl-1,2,4-trimethylsuccinate, glycerol-1,2-dimethylsuccinate or ethanediol-1,2-dimethylsuccinate (2.5 mM each), these esters being mentioned in order of increasing biological efficiency. There was a significant correlation between these results and the insulinotropic action of the same esters. The present findings thus reinforce the view that such esters act as nutrients in islet cells and, therefore, offer the advantage over pharmacological agents currently used for the treatment of type-2 diabetes in stimulating both the biosynthetic and secretory activity of insulin-producing B-cells.

Metabolism of [1,3-13C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-13C]succinate) in rat hepatocytes.

Hepatocytes prepared from overnight-fasted rats were incubated for 120 minutes in the presence of 2.5 mmol/L [1,3-13C]glycerol-1,2,3-tris(methylsuccinate) or glycerol-1,2,3-tris(methyl[2,3-13C]succinate). The identification and quantification of 13C-enriched metabolites by a recently developed method for the deconvolution of nuclear magnetic resonance (NMR) spectra with multiplet structures and constraints documented a virtually complete recovery of [1,3-13C]glycerol-1,2,3-tris(methylsuccinate) in 13C-labeled glycerol, lactic acid, and glucose. In hepatocytes exposed to [1,3-13C]glycerol-1,2,3-tris(methylsuccinate), glucose was symmetrically labeled, with the vast majority of hexose molecules being enriched with 13C on both C1 and C3 and/or C6 and C4. The respective abundance of glucose isotopomers labeled either on both C3 and C4 or on only 1 of these 2 C atoms indicated that the triose phosphates generated from [1,3-13C]glycerol represented 44% +/- 1% of the total amount of triose phosphates incorporated into the hexose. In hepatocytes exposed to glycerol-1,2,3-tris(methyl[2,3-13C]succinate), the recovery of [2,3-13C]succinate, [2,3-13C]fumarate, and either double- or single-labeled malate, lactate, alanine, and glucose accounted for about half the initial 13C content of the ester. The majority of the glucose molecules were now labeled in both C, and C2 or C6 and C5, with a preferential labeling of C6-C5 relative to C1-C2, the paired C6/C1 and C5/C2 ratios averaging 1.33 +/-0.04. These findings show that glycerol-1,2,3-tris(methylsuccinate) is efficiently and extensively metabolized in hepatocytes. They reinforce the concept that the asymmetry of glucose 13C-labeling by triose phosphates generated from Krebs cycle intermediates is modulated by the availability of glycerol-derived triose phosphates. Lastly, the present study indicates that the latter triose esters, under the present experimental conditions which do not aim at duplicating the physiological in vivo situation, are largely directly channelled in the gluconeogenic pathway, with only a limited intrahepatic contribution of the "indirect" pathway involving their back-and-forth interconversion to and from pyruvate.

Effects of starvation and diabetes on the metabolism of [2,3-13C]succinic acid dimethyl ester in rat hepatocytes.

The metabolism of [2,3-13C]succinic acid dimethyl ester ([2,3-13C]-SAD) 10 mmol/L was examined in hepatocytes from overnight-fasted normal rats, 3-day starved rats, and overnight-fasted hereditarily diabetic Goto-Kakizaki (GK) rats. The amount of 13C-labeled succinate, fumarate, malate, lactate, alanine, and aspartate released by the hepatocytes was much higher in fasted normal rats than in starved or diabetic animals. Although the integrated areas of the 13C2 and 13C3 signals assigned to double-labeled malate, lactate, or alanine were not significantly different, the amount of single-labeled malate, lactate, alanine, and aspartate was higher in C3- versus C2-labeled isotopomers. The release of 13C-labeled glucose by the hepatocytes was lower in fasted versus starved or diabetic rats. Virtually all hexose molecules double-labeled in the C1-C2-C3 and/or C6-C5-C4 moieties corresponded to the [1,2-13C] and/or [5,6-13C] isotopomers. However, in the case of the single-labeled species, 13C-labeling of C1 (or C6) exceeded that of C2 (or C5). Both the single- and double-labeled molecules enriched with 13C in the C1-C2-C3 moiety were less abundant than those labeled in the C6-C5-C4 moiety, with such asymmetry being most marked in overnight-fasted normal rats, less pronounced in diabetic animals, and virtually absent in starved rats. These findings document that SAD is efficiently metabolized in hepatocytes, with its use as a gluconeogenic precursor being influenced by the nutritional and hormonal status of the animals. The present experiments also reinforce the view that asymmetrical labeling of glucose by 13C-labeled precursors is modulated by the relative contribution of exogenous and endogenous nutrients to the production of triose phosphates incorporated into the hexose.

Leukocyte glycolysis and lactate output in animal sepsis and ex vivo human blood.

Lactate is released in large quantity from sites of sepsis and inflammation. We asked whether the increased lactate production found in sepsis can be explained by the augmented glycolysis of inflammatory cells. The glycolytic metabolism of rat peritoneal leukocytes was measured following cecal ligation and perforation (CLP) or sham laparotomy. CLP augmented glucose uptake, the pentose phosphate pathway, and glucose oxidation. Lactate output increased from 1.03 +/- 0.05 to 1.20 +/- 0.05 fmol x cell(-1) x min(-1) (P < .001). Total lactate output of peritoneal lavage fluid increased from 7.94 +/- 2.59 to 28.12 +/- 5.60 nmol L x min(-1) (P < .005). The effect of lipopolysaccharide (LPS) on the lactate output of whole blood from 31 critically ill patients was measured. Leukocyte lactate production was calculated by multiple linear regression analysis. Following exposure to LPS, human leukocyte lactate output increased from 0.20 +/- 0.09 to 1.22 +/- 0.14 fmol x cell(-1) x min(-1) (P < .001). This rate of production is so high that it suggests that the lactate output of different tissue beds in sepsis may be affected by their different cell populations and state of activation. This study supports the hypothesis that lactate may be more a product of inflammation than a marker of tissue hypoxia in sepsis.

Repaglinide, glibenclamide and glimepiride administration to normal and hereditarily diabetic rats.

Repaglinide (1 microg/g body wt), glibenclamide (10 microg/g) or glimepiride (10 microg/g) were administered orally to either fed or overnight fasted normal rats and hereditarily diabetic animals (GK rats). In both fed and starved normal rats, repaglinide provoked a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than those observed after administration of the hypoglycemic sulfonylureas. Likewise, in fed GK rats, the plasma insulin concentration was already increased by 30.0 +/- 1.6% 15 min after administration of repaglinide, whilst a sizeable insulinotropic action of the sulfonylureas was only recorded at much later times. Except for a lower glycemia at the 240th min of the test, there was little to distinguish, in starved GK rats, between control experiments including the oral administration of the solution of carboxymethylcellulose used as vehicle and the experiments conducted with the antidiabetic agents. Several converging observations indicated that glimepiride stimulated insulin release more promptly than glibenclamide. It is proposed that advantage can be taken from these vastly different time-courses of the hormonal and metabolic response to distinct hypoglycemic agents to optimize the control of glucose homeostasis in non-insulin-dependent diabetic subjects.

Pancreatic islet responsiveness to D-glucose after repeated administration of repaglinide.

The influence of three daily oral doses of repaglinide (1.0 microg/g body wt.) on plasma insulin and glucose concentrations, pancreatic islet insulin content and both protein biosynthesis and insulin release in isolated islets incubated for 90 min in the presence of either 2.8 or 16.7 mM D-glucose was examined in both control and hereditary diabetic Goto-Kakizaki (GK) rats. In the control rats, repaglinide lowered the plasma glucose concentration, whilst failing to affect significantly the plasma insulin concentration or insulin/glucose ratio, 24 h after the last administration of the antidiabetic agent. Despite a severe decrease of islet insulin content, the ratio between insulin release and content was not altered in islets obtained from repaglinide-treated control rats and incubated in the presence of 16.7 mM D-glucose. Also the biosynthesis of islet peptides was increased at both low and high hexose concentrations. In GK rats, repaglinide administration affected neither plasma glucose nor insulin concentration, restored a normal value for the otherwise abnormally high basal insulin output, increased the 16.7 mM/2.8 mM ratio for insulin release, and again augmented protein biosynthesis at both low and high hexose concentrations. In both control and GK rats, the stress induced by bleeding and decapitation augmented plasma glucose concentration. This effect was more pronounced in GK than in control rats and, in the diabetic animals, coincided with a severe lowering of the plasma insulin/glucose ratio, suggesting a higher adrenergic sensitivity of islet cells in the GK than in control rats. The increased secretory responsiveness to glucose and increased biosynthetic activity found in islets from GK rats after repaglinide administration, are considered favourable attributes of this meglitinide analogue in the perspective of its use as an insulinotropic agent in noninsulin-dependent diabetes.

Comparison between the insulinotropic potential of ten new esters of succinic acid.

Selected esters of succinic acid are currently under investigation as insulinotropic tools for the treatment of non-insulin-dependent diabetes mellitus. The aim of the present study was to investigate, in isolated rat pancreatic islets, the insulin secretory response to ten novel esters of succinic acid. According to six different methods of comparison, the following hierarchy in insulinotropic potential was established: 4-tert-butyl-succinate < or = glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate < or = threitol-3-succinoyl-1,2,4-trimethylsuccinate < or = ethanediol-1,2-diethylsuccinate < or = glycerol-1,2-dimethylsuccinate < or = glycerol-3-hydroxy-1,2-dimethylsuccinate < or = arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate < or = threitol-1,2,4-trimethylsuccinate < or = ethanediol-1,2-dimethylsuccinate < propanediol-1,2-dimethylsuccinate. There was a close correlation (r = 0.823) between the insulinotropic potential and the minimal effective concentration, which ranged between the extreme values of 10 microM and 2.5 mM. In the presence of the esters, the concentration-response relationship for glucose-stimulated insulin release was changed from its typically sigmoidal shape to a hyperbolic pattern, with most agents enhancing insulin output at a low hexose concentration (2.8 mM) but failing to do so at a high glucose level (16.7 mM). Highly potent insulinotropic esters have several advantages over other antidiabetic agents in clinical use.

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.

Effects of succinate dimethyl ester on the metabolic and hormonal response to exercise in fed and starved rats.

This study aims at investigating the possible beneficial effect of succinic acid dimethyl ester (SAD), injected intraperitoneally (5.0 micromol/g body wt.), upon the metabolic and hormonal response to a 60 min exercise in both fed and overnight starved rats. In fed rats, the injection of SAD minimized the fall in plasma D-glucose concentration, and the increase in plasma lactate, beta-hydroxybutyrate, free fatty acid and glycerol concentrations, otherwise provoked by exercise. SAD, however, failed to prevent the decrease in plasma insulin concentration and liver glycogen content caused by exercise. Starved rats displayed lower plasma D-glucose and insulin concentrations and higher plasma beta-hydroxybutyrate and free fatty acid concentrations than fed rats. The body weight, liver weight and paraovarian fat weight, as well as the glycogen content of both liver and heart were also decreased in the starved rats. In the latter animals, the injection of SAD again opposed the exercise-induced increase in plasma beta-hydroxybutyrate, free fatty acid and glycerol concentrations, and again failed to prevent the more modest decreases in plasma insulin concentration and liver glycogen content caused by exercise in the starved, as distinct from fed rats. These findings suggest that, independently of any obvious change in plasma insulin concentration, SAD minimizes the exercise-induced mobilization and enhanced utilization of endogenous nutrients, especially fatty acids and glycerol produced by hydrolysis of triglycerides in adipose tissue, presumably through its capacity to act as an oxidizable nutrient in various cell types and as a gluconeogenic precursor in hepatocytes.

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.

Stimulation of insulin release in hereditarily diabetic rats by mixed molecules formed of nateglinide and a succinic acid ester.

Hereditarily diabetic Goto-Kakizaki rats were infused for 5 min with saline, containing as required nateglinide or mixed molecules (HD154 and HD166) with both a nateglinide moiety and a succinic acid ester moiety. The dose of these agents given intravenously amounted to 5.0 nmol/g body weight in all cases. All agents provoked a comparable early increase in plasma insulin concentration. However, HD154 and HD166, but not nateglinide itself, also caused a secondary rise in plasma insulin concentration 30 min after their infusion. It is proposed that mixed molecules formed of both a hypoglycemic sulfonylurea or meglitinide analog and a succinic acid ester may be better able than the antidiabetic agents themselves to evoke a sustained stimulation of insulin release in non-insulin-dependent diabetes.

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.

Effects of D-mannoheptulose and its hexaacetate ester upon D-glucose metabolism in rat hepatocytes.

D-mannoheptulose, which inhibits hexokinase isoenzymes in a predominantly competitive manner, has been found to decrease much more modestly D-glucose metabolism in pancreatic islets exposed to a low, as distinct from high, concentration of the hexose. In the present study, which aimed at investigating the factor(s) possibly responsible for such a phenomenon, a comparable situation was found to prevail in rat hepatocytes. However, when the hexaacetate ester of D-mannoheptulose was used instead of the unesterified heptose, the relative extent of inhibition of D-[5-3H]glucose utilization and D-[U-14C]glucose conversion to 14C-labelled acidic metabolites was comparable in hepatocytes exposed to either 1.7 or 8.3 mM D-glucose. Moreover, at the low D-glucose level, the incorporation of 3-O-methyl-D-glucose (6.6 mM) into the incubation medium increased the inhibitory action of unesterified D-mannoheptulose upon D-glucose metabolism. These findings suggest that an insufficient uptake of the heptose accounts, in part at least, for its poor efficiency as inhibitor of D-glucose catabolism in liver, and presumably islet cells exposed to low concentrations of the hexose.

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.

Fate of 6-deoxy-6-[123I]iodo-D-glucose in normal and diabetic rats.

The D-glucose analog 6-deoxy-6-¿123Iiodo-D-glucose (6-DIG) was recently proposed as a potential tracer for the in vivo characterization of D-glucose transport in distinct cell types. In this study, the validity of such a proposal was investigated in both control and streptozotocin-induced diabetic rats. 6-DIG was injected intravenously in either control or diabetic rats. The fate of 6-DIG was assessed by scintigraphy of the injected animals, blood and urine sampling, and measurement of tissue radioactivity at the time of sacrifice, 140 min after 6-DIG injection. The half-life for 6-DIG in plasma and its accumulation in kidney and urinary bladder indicated that it was mainly eliminated from the body by glomerular filtration. The urinary elimination of 6-DIG was accelerated, however, in the polyuric diabetic rats. Bile formation also apparently contributed to the clearance of 6-DIG. Its uptake by liver, heart and muscles yielded values lower than blood concentration. The usefulness of 6-DIG as a tracer for D-glucose transport in selected organs in the perspective of clinical application, e.g. by single photon emission computed tomography, requires further investigations.

Fate of 2-deoxy-2-[18F]fluoro-D-glucose in hyperglycemic rats.

Sustained hyperglycemia allows the preferential labelling of pancreatic glycogen by D-[U-14C]glucose in control rats, as compared to animals previously injected with streptozotocin (STZ rats). The major aim of the present study was to investigate whether a sizeable difference between control and STZ rats could also be observed in terms of the radioactive content of the pancreatic gland 8 h after the intravenous injection of 2-deoxy-2-[18F]fluoro-D-glucose, both types of animals being examined at the same level of hyperglycemia. Although the radioactive content of muscle, liver and kidney was lower in STZ rats than in control animals, such a difference failed to achieve statistical significance in brain, hypophysis, pancreas and parotid gland. It is proposed, therefore, that 11C-labelled D-glucose, rather than 2-deoxy-2-[18F]fluoro-D-glucose should be used in the perspective of the non-invasive imaging of the endocrine pancreas.