(19)F-heptuloses as tools for the non-invasive imaging of GLUT2-expressing cells.

Suitable analogs of d-mannoheptulose are currently considered as possible tools for the non-invasive imaging of pancreatic islet insulin-producing cells. Here, we examined whether (19)F-heptuloses could be used for non-invasive imaging of GLUT2-expressing cells. After 20 min incubation, the uptake of (19)F-heptuloses (25 mM) by rat hepatocytes, as assessed by (19)F NMR spectroscopy, ranged from 0.50 (1-deoxy-1-fluoro-d-mannoheptulose and 3-deoxy-3-fluoro-d-mannoheptulose) to 0.25 (1,3-dideoxy-1,3-difluoro-d-mannoheptulose) and 0.13 (1-deoxy-1-fluoro-d-glucoheptulose, 3-deoxy-3-fluoro-d-glucoheptulose and 1,3-dideoxy-1,3-difluoro-d-glucoheptulose) µmol per 3×10(6)cells. (19)F MRI experiments also allowed the detection of 1-deoxy-1-fluoro-d-mannoheptulose in rat hepatocytes. All three (19)F-mannoheptuloses cited above, as well as 7-deoxy-7-fluoro-d-mannoheptulose and 1-deoxy-1-fluoro-d-glucoheptulose inhibited insulin release evoked in rat isolated pancreatic islets by 10mM d-glucose to the same extent as that observed with an equivalent concentration (10mM) of d-mannoheptulose, while 3-deoxy-3-fluoro-d-glucoheptulose and 1,3-dideoxy-1,3-difluoro-d-glucoheptulose (also 10mM) were less potent than d-mannoheptulose in inhibiting insulin release. The 1-deoxy-1-fluoro-d-mannoheptulose and 3-deoxy-3-fluoro-d-mannoheptulose only marginally affected INS-1 cell viability. These findings are compatible with the view that selected (19)F-heptuloses may represent suitable tools for the non-invasive imaging of hepatocytes and insulin-producing cells by (19)F MRI.

Effects of D-mannoheptulose and its hexaacetate ester on hormonal secretion from the perfused pancreas.

D-mannoheptulose was recently proposed to be transported into cells by GLUT2, whereas its hexaacetate ester may cross the plasma membrane without requiring the intervention of a specific carrier system. In the light of these proposals, the effects of unesterified D-mannoheptulose and D-mannoheptulose hexaacetate upon hormonal secretion by the perfused rat pancreas were now investigated. Unesterified D-mannoheptulose (1.7 mM) inhibited insulin release and, in most cases, somatostatin output, whereas it augmented glucagon secretion by pancreases exposed to D-glucose (3.3 mM) in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM). The heptose failed, however, to affect hormonal secretion in the sole presence of SAD. D-mannoheptulose hexaacetate (also 1.7 mM) reproduced, within limits, the effects of unesterified D-mannoheptulose in pancreases exposed to both D-glucose and SAD. In addition, however, the ester displayed a positive effect upon the secretion of the three hormones, even in the sole presence of SAD. These findings support the view that monosaccharide esters may affect the secretion of pancreatic hormones in a dual manner, linked to both the metabolic response to their glucidic moiety and a direct effect of the ester itself. Moreover, they reveal that unesterified D-mannoheptulose is able to antagonize the effect of D-glucose upon hormonal secretion even in cells claimed not to contain GLUT2. The modality by which D-mannoheptulose apparently gains access to the cytosol of these cells remains to be elucidated.

Insulinotropic action of the polyacetate esters of two non-nutrient monosaccharides in normal and diabetic rats.

The polyacetate esters of certain non-nutrient monosaccharides, such as L-glucose and 2-deoxy-D-glucose, were recently reported to display positive insulinotropic action and, hence, proposed as possible tools for stimulation of insulin release in non-insulin-dependent diabetes. In the present study, the secretory response to four carbohydrate esters was compared in islets of both normal and hereditary diabetic Goto-Kakizaki rats. Three major findings are documented. First, in islets exposed to the dimethyl ester of succinic acid (10.0 mmol/l), D-mannoheptulose hexaacetate (1.7 mmol/l) was found to stimulate insulin release in both normal and diabetic rats. Second, relative to the control value recorded in the sole presence of the succinic acid ester, the increments in insulin output evoked by D-mannoheptulose hexaacetate, alpha-L-glucose pentaacetate and beta-D-glucose pentaacetate (all 1.7 mmol/l) were not lower and, on occasion, even higher in diabetic rats than in control animals. Last, the sole exception to such a rule was encountered in islets exposed to beta-L-glucose pentaacetate, in which case the hexose moiety of the ester might mimic the inhibitory effect of alpha-D-glucopyranose upon phosphorylase a-catalyzed glycogenolysis in islets from diabetic rats. These findings reinforce the concept that the insulinotropic action of monosaccharide esters is not solely attributable to the catabolism of their carbohydrate moiety but also to a direct effect of the esters themselves upon a yet unidentified receptor system. They also provide further support to the possible use of the esters of non-nutrient monosaccharides as insulinotropic tools in type-2 diabetes.

Comparison between the effects of D-mannoheptulose and its hexaacetate ester upon D-glucose metabolism in rat erythrocytes.

At a 2.0 mM concentration, D-mannoheptulose hexaacetate, but not unesterified D-mannoheptulose, inhibited the generation of radioactive acidic metabolites by rat erythrocytes exposed to D-[U-14C]glucose (8.3 mM). It is proposed that D-mannoheptulose hexaacetate represents a valuable tool to interfere with the phosphorylation of D-glucose in cell types otherwise resistant to the heptose.