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Journal of the American College of Nutrition, Vol. 23, No. 5, 414-419 (2004)
Published by the American College of Nutrition

Plasma D-Glucose, D-Fructose and Insulin Responses after Oral Administration of D-Glucose, D-Fructose and Sucrose to Normal Rats

Pablo G. Prieto, MSc, Jesus Cancelas, PhD, Maria L. Villanueva-Peñacarrillo, PhD, Isabel Valverde, MD, PhD and Willy J. Malaisse, MD, PhD, FACN

Fundacíon Jiménez Díaz, Madrid, Spain (J.C., P.G.P., M.L.V., I.V.)
Laboratory of Experimental Hormonology, Brussels Free University, Brussels, Belgium (W.J.M.)

Address reprint requests to: W.J. Malaisse, MD, PhD, FACN, Laboratory of Experimental Hormonology, Brussels Free University (CP 626), 808 Route de Lennik, B-1070 Brussels, BELGIUM. E-mail: malaisse{at}ulb.ac.be


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: To assess whether oral D-fructose modifies the plasma D-glucose and insulin responses to oral D-glucose administration in normal rats.

Design: Oral D-glucose (1.7, 3.5, 6.9 or 13.9 µmol/g body weight), D-fructose (6.9 µmol/g), both D-glucose and D-fructose (1.7 or 3.5 µmol/g of each hexose) or sucrose (3.7 µmol/g) were administered intragastrically to overnight fasted rats and the plasma concentration of D-glucose, D-fructose and insulin measured over the ensuing 120 minutes. Control experiments were conducted after oral administration of H2O or saline.

Results: The administration of D-fructose, given as the free hexose or as sucrose, instead of augmenting the plasma D-glucose concentration evoked by the concomitant administration of D-glucose, tended both to improve the insulin response of the pancreatic B-cell and to minimize hyperglycemia, when compared to the results of experiments including the administration of equimolar amounts of D-glucose alone. For instance, the area under the plasma D-glucose curve was comparable in the rats receiving both D-glucose and D-fructose (3.5 µmol/g of each hexose) and the rats receiving only D-glucose (3.5 µmol/g), averaging respectively 836 ± 32 and 850 ± 34 mM · min each. Likewise, the paired ratio between the areas under the plasma insulin and D-glucose curves, when corrected for the threshold concentration for the insulinotropic action of the hexose (2.05 ± 0.10 mM), averaged 44.3 ± 3.0 nmol/mol in the 16 rats receiving D-fructose alone, sucrose alone or both D-glucose and D-fructose, as compared to 37.7 ± 2.9 nmol/mol in the 22 rats receiving increasing amounts of D-glucose alone.

Conclusions: The intake of D-fructose, as the free hexose or as sucrose, favours D-glucose homeostasis. This is likely to be attributable to the reciprocal effects of the aldose and ketose upon their respective phosphorylation by glucokinase in both hepatocytes and insulin-producing pancreatic islet cells.

Key words: D-glucose, D-fructose, sucrose, plasma insulin, normal rats


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Two novel modalities for the metabolic interaction between D-glucose and D-fructose in both hepatocytes and insulin-producing cells were recently identified. They consist in the capacity of D-fructose 1-phosphate generated in the fructokinase reaction to relieve glucokinase from the inhibitory action of D-fructose 6-phosphate, as mediated at the intervention of the glucokinase regulatory protein [1,2], and in the enhancing action of D-glucose upon the phosphorylation of D-fructose, as catalyzed by glucokinase [3,4]. The major aim of the present study was to investigate whether such metabolic interactions may improve D-glucose homeostasis after oral intake of D-glucose and/or D-fructose, as well as sucrose, to normal rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Overnight fasted male Wistar rats (237 ± 4 g body wt.; n = 38), that had been previously given free access to food (UAR; Panlab, Barcelona, Spain) and tap water, were obtained from a colony maintained at the Fundacíon Jiménez Díaz (Madrid, Spain).

At time zero, they received by intragastric tubing either solutions of D-glucose or a mixture of D-glucose and D-fructose (4 µL/g body wt.) prepared in saline (first series of experiments) or solutions of D-fructose or sucrose (also 4 µL/g body wt.) prepared in H2O (second series of experiments). In the first series of experiments, the rats received either saline alone or saline containing either D-glucose (1.7, 3.5, 6.9 or 13.9 µmol/g body wt.) or both D-glucose and D-fructose (1.7 or 3.5 µmol/g of each hexose). In the second experiments, the animals received either H2O alone or H2O containing either D-fructose (6.9 µmol/g) or sucrose (3.7 µmol/g).

Blood samples (0.5 mL) were collected from the severed tip of the tail for measuring plasma insulin by radioimmunoassay [5], plasma D-glucose by the glucose oxidase method [6] and, in some cases, the total plasma concentration of both D-glucose and D-fructose by the glucose-6-phosphate dehydrogenase procedure [7].

The measurements of the standards of D-glucose (0 to 100 nmol/sample) by the glucose-6-phosphate dehydrogenase procedure yielded results proportional to the amount of the aldohexose with a S.D. representing 3.3% of their mean values (n = 6). Such was also the case for the measurements of the standards of D-fructose or a mixture of D-glucose and D-fructose (Fig. 3, upper panel). Pooling all available data, the confidence interval for the mean value derived from such measurements did not exceed 5.0% (t0.05 · SEM).



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  		Fig. 3. Upper panel: Assay of standard amounts of D-glucose, D-fructose or a mixture of the two hexoses by the glucose-6-phosphate dehydrogenase procedure; mean values (± SEM) are derived from two separate experiments for each hexose or mixture of hexoses and normalized relative to the sum of the optical densities recorded with each of the three standard amounts of hexose(s) in each experiment. Lower panel: Time course for the changes in plasma D-fructose concentration after oral administration of D-fructose (6.9 µmol/g); mean values (± SEM) refer to 4 individual experiments.

 
The area under the plasma insulin, D-glucose and D-fructose curves over the 120 min of the experiments was calculated by planimetry. All results, including those already mentioned, are presented as mean values (± SEM) together with the number of individual measurements (n). The statistical significance of differences between mean values was assessed by use of Student’s t-test. Correlation and regression analyses were conducted according to Snedecor [8]. A geometric mean was used for the ratio between plasma insulin and D-glucose concentrations. In such a case, the SEM cited in the text corresponds to the mean of the upper and lower deviation from such a geometric mean [9].


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Fig. 1 illustrates the results of representative experiments conducted in rats receiving no hexose, only D-glucose (6.9 µmol/g), or both D-glucose and D-fructose (3.5 µmol/g of each hexose) dissolved in saline.



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  		Fig. 1. Time course for the changes in plasma D-glucose (left panel) and insulin (right panel) concentrations after oral administration of D-glucose (6.9 µmol/g; closed circles and dashed line) or both D-glucose and D-fructose (3.5 µmol/g of each hexose; crosses and solid line). Control experiments are shown as open circles and solid line. Mean values (± SEM) refer to 3 (control experiments) or 4 (hexose administration) individual measurements. The incremental area under the plasma D-glucose and insulin curves averaged, after administration of D-glucose alone or together with D-fructose respectively, 413 ± 23 and 185 ± 39 mM · min and 12.31 ± 2.71 and 5.81 ± 1.21 nM · min (n = 4 in all cases).

 
Over the 120 min of the test, the incremental area under the plasma D-glucose curve (after correction for the initial measurement) was not significantly different from zero (p > 0.1) in the control experiments (only saline but no exogenous hexose given) and increased in gross proportion of the amount of D-glucose given per os (Fig. 2). Likewise, over the 120 min of the test, the area under the plasma D-glucose curve progressively increased from a basal value (no exogenous D-glucose given) of 682 ± 34 mM · min (n = 3) to 734 ± 24, 850 ± 34, 992 ± 63 and 1078 ± 16 mM · min (n = 4 in all cases), as the amount of D-glucose given orally was raised to 1.7, 3.5, 6.9 and 13.9 µmol/g. This coincided with a progressive rise in the incremental area under the plasma insulin curve (after correction for the initial measurement) from a basal value of 1.21 ± 1.60 nM · min (n = 3) to a maximal value of 12.03 ± 2.91 nM · min (n = 4) after administration of 13.9 µmol/g of D-glucose. The area under the plasma insulin curve also increased between the extreme values of 13.87 ± 4.65 nM · min (basal value) and 32.03 ± 4.47 nM · min (after administration of 13.9 µmol/g of D-glucose).



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  		Fig. 2. Incremental area under the plasma D-glucose curve, after correction for the initial measurement, in rats receiving increasing amounts of D-glucose (µmol/g body wt.). Mean values (± SEM) refer to 3–4 individual measurements.

 
The area under the plasma D-glucose curve was comparable in the rats receiving both D-glucose and D-fructose (3.5 µmol/g of each hexose) and the rats receiving only D-glucose (3.5 µmol/g) with mean respective values of 836 ± 32 and 850 ± 34 mM · min (n = 4 in both cases).

Prior to either D-fructose or sucrose administration, the total concentration of D-glucose and D-fructose in plasma, as measured by the glucose-6-phosphate dehydrogenase method, was not significantly different from that of D-glucose, as measured by the glucose oxidase method, with a paired ratio between the latter and former measurements of 94.5 ± 5.6% (n = 8; p > 0.3). After oral D-fructose administration (6.9 µmol/g), the plasma D-fructose concentration increased (p < 0.05) to 0.48 ± 0.13 mM (n = 4) at min 15, reached its peak value at min 60 and declined to 0.55 ± 0.25 mM (n = 4) at min 120 (Fig. 3, lower panel). The area under the D-fructose curve and above basal value (0.05 ± 0.30 mM; n = 4) averaged, over the 120 min of the experiment, 180.7 ± 22.7 mM · min (n = 4; p < 0.005).

After administration of sucrose (3.7 µmol/g), the area under the D-fructose curve and above paired basal value averaged 92.7 ± 39.9 mM · min (n = 4) and, as such, was virtually identical to that recorded after administration of D-fructose, if expressed relative to the molar amount of D-fructose given orally. Indeed, according to such a mode of calculation, the area under the plasma D-fructose curve and above paired basal value averaged 26.02 ± 3.27 and 27.37 ± 10.90 mM · min · g · µmol–1 (n = 4 in both cases) after oral administration of D-fructose and sucrose, respectively, with an overall mean value of 25.69 ± 5.27 mM · min · g · µmol–1 (n = 8).

Two series of observations suggest that D-fructose, when given orally together with D-glucose, participated in the insulin secretory response of the endocrine pancreas.

First, the area under the plasma insulin curve was equally high when half of the exogenous hexoses was given as D-fructose and when only D-glucose was administered. Thus, in the rats receiving both D-glucose and D-fructose (1.7 µmol or 3.5 µmol/g of each hexose), it averaged 27.92 ± 2.57 nM · min (n = 8), as compared to 27.88 ± 1.77 nM · min (n = 8) in the rats receiving only D-glucose (3.5 µmol or 6.9 µmol/g).

Second, relative to the area under the plasma D-glucose curve, that under the plasma insulin curve appeared higher in the rats receiving both oral D-glucose and D-fructose than in those receiving only D-glucose, as documented by the following considerations.

As illustrated in Fig. 4, there was a significant correlation (p < 0.05) between the individual values for the area under the plasma insulin curve and the area under the plasma glucose curve over the 120 min of the test in the 19 animals receiving increasing amounts of oral D-glucose (zero to 13.9 µmol/g). When corrected for the intercept of the regression line with the abscissa (plasma D-glucose concentration), the paired ratio between these two variables averaged (geometric mean) 26.36 ± 2.15 nmol/mol (n = 19). When the same analysis was conducted in the 8 animals receiving increasing amounts of both D-glucose and D-fructose (1.7 to 3.5 µmol/g of each hexose), such a paired ratio averaged (geometric mean) 45.91 ± 5.21 nmol/mol (n = 8), a value significantly higher (p < 0.001) than that found in the rats receiving increasing amounts of oral D-glucose (1.4 to 13.9 µmol/g), i.e. 28.51 ± 1.73 nmol/mol (n = 16). It should be underlined, however, that the intercept of the regression line with the abscissa (area under the plasma D-glucose curve) was lower in the 19 rats receiving increasing amounts of oral D-glucose (zero to 13.9 µmol/g) than in the 11 rats receiving increasing amounts of both D-glucose and D-fructose (zero to 3.5 µmol/g of each hexose). When only the first of these two intercepts was taken into account in both groups of rats, the mean paired ratio between the area under the plasma insulin and glucose curves remained higher, albeit no more significantly so, in the 8 rats receiving the two sugars (31.84 ± 2.67 nmol/mol) than in the 16 rats receiving only D-glucose (see above).



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  		Fig. 4. Regression lines for the changes in the area under the plasma insulin curve as a function of the changes in the area under the plasma D-glucose curve in rats receiving either increasing amounts of D-glucose (nil : open circles; 1.4 µmol/g : closed circles; 3.5 µmol/g : crosses; 6.9 µmol/g : open triangles; 13.9 µmol/L = closed triangles; left panel) or increasing amounts of both D-glucose and D-fructose (nil : open circles; 1.7 µmol/g of each hexose : open triangles; 3.5 µmol/g of each hexose : closed triangles; right panel).

 
In the light of these findings, further experiments aimed at comparing the effect of oral D-fructose (6.9 µmol/g) and sucrose (3.7 µmol/g) both solubilized in H2O, suitable control experiments being conducted in rats receiving only H2O. The administration of oral D-fructose alone (6.9 µmol/g) increased the plasma D-glucose concentration by 349 ± 30 mM · min (n = 4), as compared (p < 0.01) to 141 ± 35 mM · min (n = 3) in the corresponding control experiments including the sole administration of water (Fig. 5). The latter value was not significantly different from zero. After administration of oral D-fructose alone, both the incremental area under the plasma D-glucose curve and total area under such a curve (894 ± 24 mM · min; n = 4) were slightly, but not significantly, lower than those recorded in the first series of experiments after oral administration of the same molar amount (6.9 µmol/g) of D-glucose. Thus, relative to the latter values, they averaged 84.5 ± 7.4% (incremental area) and 90.2 ± 2.4% (total area). For the purpose of comparison, oral sucrose (3.7 µmol/g) was given to four rats. Despite the somewhat greater amount of hexose-equivalent given in these experiments (7.3 µmol/g) than in those conducted after oral administration of D-fructose alone (6.9 µmol/g) and despite the fact that half of such an amount consisted of D-glucose in the sucrose experiments, the incremental area under the plasma D-glucose curve after administration of sucrose was not greater than that recorded after D-fructose intake, averaging no more than 293 ± 13 mM · min (n = 4) or 70.9 ± 3.2% of that observed after oral administration of D-glucose alone (6.9 µmol/g).



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  		Fig. 5. Time course for the changes in plasma D-glucose (left panel) and insulin (right panel) concentrations after oral administration of D-fructose (6.9 µmol/g; closed circles and dashed line) or sucrose (3.7 µmol/g; crosses and solid line). Control experiments are shown as open circles and solid line. Mean values (± SEM) refer to 3 (control experiments) or 4 (D-fructose or sucrose administration) individual measurements.

 
Both oral D-fructose (6.9 µmol/g) and oral sucrose (3.7 µmol/g) augmented plasma insulin concentration above basal value, whilst the administration of H2O alone failed to do so (p > 0.8). The area under the plasma insulin curve was indeed significantly higher (p < 0.05) after administration of D-fructose (26.91 ± 2.57 nM · min; n = 4) or sucrose (31.44 ± 4.14 nM · min; n = 4) than in the control experiments (16.79 ± 2.42 nM · min; n = 3). Fig. 6 illustrates the correlation (p < 0.05) between areas below the plasma insulin and D-glucose curves in these experiments. When corrected for the intercept of the regression line with the abscissa (see above), the paired ratio between these two variables was not significantly different (p > 0.4) after administration of either D-fructose alone or sucrose, with an overall mean value of 42.79 ± 3.49 nmol/mol (n = 8). The intercept of the regression line with the abscissa (area under the plasma D-glucose curve) was comparable in the experiments illustrated in the right panel of Fig. 4 (265.8 mM · min) and in Fig. 6 (226.4 mM · min), corresponding to a plasma D-glucose concentration close to 2.05 ± 0.16 mM. After correction for such intercepts, the paired ratio between the areas under the plasma insulin and D-glucose curves was virtually identical (p > 0.95) in the rats receiving only oral D-fructose (6.9 µmol/g) and those receiving both D-glucose and D-fructose (3.5 µmol/g of each hexose), with mean respective values of 39.87 ± 4.65 and 39.59 ± 5.24 nmol/mol (n = 4 in both cases). In the animals receiving oral sucrose, such a ratio averaged 45.92 ± 5.46 nmol/mol (n = 4). For purpose of comparison, in the rats receiving only oral D-glucose (6.9 µmol/g) and using the mean intercept recorded in Fig. 4 (right panel) and Fig. 5 (i.e., 246.1 mM · min), the same paired ratio did not exceed 35.66 ± 2.97 nmol/mol (n = 4).



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  		Fig. 6. Regression line for the changes in the area under the plasma insulin curve as a function of the changes in the area under the plasma D-glucose curve in rats receiving either H2O (open circles), D-fructose (6.9 µmol/g; closed circles) or sucrose (3.7 µmol/g; crosses).

 
Pooling all available data and using comparable intercepts (246.1 ± 11.4 mM · min) in all cases, such a paired ratio averaged 37.74 ± 2.94 nmol/mol in the 22 rats receiving increasing amounts of D-glucose (zero to 13.9 µmol/g) and 44.32 ± 3.02 nmol/mol in the 16 rats receiving either D-fructose alone (6.9 µmol/g), sucrose alone (3.7 µmol/g) or both D-glucose and D-fructose (1.7 to 3.5 µmol/g of each hexose). Thus, to say the least, relative to plasma D-glucose concentration, the secretory response of insulin-producing cells was not lower in animals receiving oral D-fructose (or sucrose) than in those receiving only D-glucose.


   DISCUSSION
 
In the present study, the control experiments conducted after administration of H2O or saline were characterized by a modest increase in plasma D-glucose concentration, with an incremental area under the D-glucose curve averaging 130 ± 25 mM · min (n = 6; p < 0.005) or 1.09 ± 0.21 mM, if expressed as the mean increase in plasma D-glucose concentration during the test. This contrasted with the absence of any significant change in plasma insulin concentration, with an incremental area under the insulin curve averaging 0.33 ± 1.28 nM · min (n = 6; p > 0.8). These findings are compatible with the metabolic and hormonal effects resulting from the moderate stress imposed by the manipulation and bleeding of the rats during these experiments [10,11].

The experiments conducted in rats receiving increasing amounts of D-glucose (1.7, 3.5, 6.9 and 13.9 µmol/g) document that the incremental area under the plasma D-glucose and insulin curves increases as a function of the amount of D-glucose administered per os. Such was also the case for the total area under the plasma D-glucose and insulin concentration curves, with a significant correlation between the latter two variables.

Whenever D-fructose was administered, a significant increase in both the plasma D-glucose and insulin concentrations was also recorded. Such was the case whether D-fructose was administered alone or together with D-glucose and when the two hexoses were given in the form of a disaccharide, i.e. sucrose.

The hyperglycemia tended to be less pronounced when D-fructose was given alone or together with D-glucose than when D-glucose was given alone. For instance, virtually identical area under the plasma D-glucose curve were obtained when D-fructose and D-glucose (3.5 µmol/g of each hexose) were given together and when only D-glucose (also 3.5 µmol/g) was administered. Likewise, after administration of sucrose (3.7 µmol/g), the incremental area under the plasma D-glucose curve averaged no more than 70.9 ± 3.2% of that observed after administration of D-glucose alone (6.9 µmol/g).

These findings indicate that, under the present experimental conditions, oral D-fructose improved the tolerance to oral D-glucose. This could be due, in part at least, to the effect of D-fructose 1-phosphate generated from D-fructose, to relieve liver glucokinase from the inhibitory action otherwise exerted by D-fructose 6-phosphate at the intervention of the glucokinase regulatory protein [1,2].

There was also a trend for D-fructose to improve the secretory response of the B-cell to the hyperglycemia caused by the oral administration of the sugars, although such an effect failed, as a rule, to achieve statistical significance. A higher insulin output in response to a given hyperglycemia in the rats receiving D-fructose (as the ketohexose itself or through the administration of sucrose) could conceivably be attributable to the modulation of islet glucokinase activity by its regulatory protein [1,2]. Moreover, the catabolism of D-fructose 6-phosphate, generated in islet cells in the reaction catalyzed by hexokinase isoenzyme(s), may also favour insulin secretion [12]. In this respect, the fact that D-glucose increases the phosphorylation of D-fructose as catalyzed by islet glucokinase could represent a significant regulatory factor [3,4].

In hepatocytes, D-glucose also favours D-fructose phosphorylation in the reaction catalyzed by liver glucokinase [13,14]. Such a phenomenon is obviously well suited to ensure, in the liver, an efficient conversion of D-fructose to D-glucose, as indeed observed in the present experiments, e.g. after administration of D-fructose alone.

The question could be raised whether the results here recorded in rats may apply to other species. For instance, at variance with the present findings, Sievenpiper et al. [15] recently confirmed prior reports indicating that, in human subjects, the positive incremental area in plasma D-glucose concentration is lower after oral administration of D-fructose alone than after oral administration of sucrose, both given in equal amounts (25 g). The plasma concentration of D-fructose, however, was not assessed in this recent study.

In fair agreement with the present data, recent studies have documented that, in dogs and human subjects, low amounts of D-fructose given orally or intraduodenally reduce postprandial hyperglycemia and hyperinsulinemia [16,17]. Likewise, in humans, intravenous infusion of D-fructose stimulates net hepatic glycogen synthesis during euglycemic hyperinsulinemic conditions [18]. These findings were interpreted to indicate a favourable direct effect of D-fructose upon D-glucose handling by hepatocytes. As indicated above, we also propose that the effect of D-fructose upon D-glucose homeostasis is attributable, in part at least, to the reciprocal effects of the aldose and ketose upon their respective phosphorylation by liver glucokinase.

Nevertheless, a contributive role of the pancreatic islet B-cell secretory response should not be ruled out. Thus, in the experiments conducted by Moore et al., no information was provided to compare the insulin secretory response to the prevailing plasma D-glucose concentration when oral D-fructose was given (or not) together with oral D-glucose [17]. The present work provides such an information, admittedly in a different species.

In conclusion, therefore, the intake of oral D-fructose, as the free hexose or as sucrose, favours D-glucose homeostasis, rather than augmenting the hyperglycaemic response to oral D-glucose intake.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
This work was supported by grants from the Spanish Institute of Health Carlos III (RGDM-G03/212 and FIS-PI020967), and the Belgian Foundation for Scientific Medical Research (3.4567.97 and 3.4517.02). P.G.P. is a Research Fellow of the Fundación Conchita Rábago de Jiménez Díaz. We are grateful to E. Martin-Crispo for technical assistance and to C. Demesmaeker for secretarial help.

Received February 5, 2003. Accepted January 20, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Van Schaftingen E: A protein from rat liver confers to glucokinase the property of being regulated by fructose 6-phosphate and fructose 1-phosphate. Eur J Biochem179 :175 –184,1989 .
  2. Malaisse WJ, Malaisse-Lagae F, Davies DR, Vandercammen A, Van Schaftingen E: Regulation of glucokinase by a fructose-1-phosphate-sensitive protein in pancreatic islets. Eur J Biochem190 :539 –545,1990 .[Medline]
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  4. Moukil MA, Van Schaftingen E: Analysis of the cooperativity of human ß-cell glucokinase through the stimulatory effect of glucose on fructose phosphorylation. J Biol Chem276 :3872 –3878,2001 .[Abstract/Free Full Text]
  5. Valverde I, Barreto M, Malaisse WJ: Stimulation by D-glucose of proinsulin biosynthesis in tumoral insulin-producing cells (RINm5F line). Endocrinology122 :1443 –1448,1988 .[Abstract]
  6. Bergmeyer HU, Berndt E: Glucose determination with glucose oxidase and peroxidase. In Bergmeyer HU (ed): "Methods of Enzymatic Analysis." New York: Academic Press, pp1205 –1215,1974 .
  7. Lowry OH, Passonneau JV: "A Flexible System of Enzymatic Analysis." New York: Academic Press,1972 .
  8. Snedecor GW: "Statistical Methods." Iowa: The Iowa State University Press,1962 .
  9. Leclercq-Meyer V, Malaisse-Lagae F, Coulic V, Akkan AG, Malaisse WJ: Preservation of the anomeric specificity of glucose-induced insulin release in partially pancreatectomized rats. Diabetologia35 :505 –509,1992 .[Medline]
  10. Ladrière L, Malaisse-Lagae F, Fuhlendorff J, Malaisse WJ: Repaglinide, glibenclamide and glimepiride administration to normal and hereditarily diabetic rats. Eur J Pharmacol335 :227 –234,1997 .[Medline]
  11. Laghmich A, Ladrière L, Malaisse-Lagae F, Malaisse WJ: Pancreatic islet responsiveness to D-glucose after repeated administration of repaglinide. Eur J Pharmacol348 :265 –270,1998 .[Medline]
  12. Malaisse WJ, Giroix M-H, Courtois P, Jijakli H, Sener A: Metabolic interactions between D-glucose and D-fructose in pancreatic islets. Av Diabetol18 :110 –116,2002 .
  13. Malaisse WJ, Ladrière L, Verbruggen I, Willem R: Metabolism of D-[1-13C]fructose, D-[2-13C]fructose, and D-[6-13C]fructose in rat hepatocytes incubated in the presence of H2O or D2O. Mol Gen Metab75 :162 –167,2002 .[Medline]
  14. Malaisse WJ, Ladrière L, Verbruggen I, Willem R: Effects of D-glucose upon D-fructose metabolism in rat hepatocytes: a 13C NMR study. Mol Cell Biochem241 :103 –106,2002 .[Medline]
  15. Sievenpiper JL, Vuksan V, Wong EYY, Mendelson RA, Bruce-Thompson C: Effect of meal dilution on the postprandial glycemic response. Diabetes Care21 :711 –716,1998 .[Abstract]
  16. Shiota M, Courtney Moore M, Galassetti P, Monohan M, Neal DW, Shulman GI, Cherrington AD: Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog. Diabetes51 :469 –478,2002 .[Abstract/Free Full Text]
  17. Moore MC, Davis SN, Mann SL, Cherrington AD: Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes. Diabetes Care24 :1882 –1887,2001 .[Abstract/Free Full Text]
  18. Petersen KF, Laurent D, Yu C, Cline GW, Shulman GI: Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. Diabetes50 :1263 –1268,2001 .[Abstract/Free Full Text]




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