The Insulin Response to Intravenous Fructose in Relation to Blood Glucose Levels M. G. DUNNIGAN AND J. A. FORD Endocrine and Metabolic Unit, Stobhill General Hospital, Glasgow, Scotland ABSTRACT. The insulinotropic action of intravenous fructose was examined in 24 subjects without known metabolic disease. When blood glucose values before the fructose infusion were at or below normal fasting levels, fructose elicited only a small plasma insulin response. In contrast, the insulin response was strikingly augmented when preinfusion blood glucose and plasma insulin levels were moderately elevated. The insulinotropic ac-
tion of fructose appears closely related to the preinfusion blood glucose level. Fructose has little or no insulinotropic action in the absence of glucose but potentiates glucose-mediated insulin release. The insulinotropic potency of other glucose analogues in vivo may show a similar dependence on concomitant blood glucose levels. (J Clin Endocrinol Metab 40: 629, 1975)
T
HE ability of fructose to provoke in- from metabolic disease and all had been on a sulin secretion is the subject of con- normal carbohydrate intake prior to the test. flicting reports. Based on in vitro experi- The patients were divided into three groups. ments in pancreas preparations and in vivo studies in animals and man, fructose has Group I (9 subjects). Samples for blood glucose been stated to produce no insulin secretion and plasma insulin were withdrawn through an indwelling cannula and 31 g of fructose was (1-5), variable secretion (6,7), or consistent thereafter administered intravenously over 5 min. secretion (8-12). The latter has been at- . Blood glucose, plasma insulin and plasma fructributed either to a direct insulinotropic tose were then estimated at 10-min intervals action or to the hepatic conversion of fruc- for 60 min. Blood glucose and plasma insulin tose to glucose. were again measured after a 30-min interval and In a previous study of fructose utilization 31 g of glucose was infused over 5 min. Plasma in normal, diabetic and postmyocardial insulin and blood glucose were thereafter estiinfarction subjects, small but significant mated at 10-min intervals for 60 min. rises in plasma insulin were noted following fructose infusions, with only slight Group II (9 subjects). In this group, the prochanges in blood glucose levels (13). It cedure was reversed, the glucose infusion being given first and the fructose second. Estimations was concluded that fructose had a small of blood glucose, plasma fructose and plasma insulinotropic action in man independent of insulin were made as in Group I. concomitant changes in blood glucose. In the present study, we have examined the Group III (6 subjects). Glucose was infused insulin response to intravenous fructose first; the fructose infusion was given 50 min with particular reference to preinfusion later without an intervening 30-min interval as blood glucose levels. in Groups I and II. Fructose was thus infused while blood glucose levels in each subject remained elevated above fasting. Estimations of Subjects and Methods blood glucose, plasma fructose and plasma Twenty-four male patients aged from 26 to 59 yr insulin were made as in Groups I and II. gave their informed consent to the intravenous Plasma fructose was determined by the method infusion of fructose and glucose following an of Kulka (14) and true blood glucose by a overnight fast. None was acutely ill or suffered glucose oxidase method (15). Plasma insulin was determined by an immunoassay technique (16). Received September 13, 1974. 629
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
DUNNIGAN AND FORD
630
JCE & M • 1975 Vol 40 • No 4
values had returned to normal fasting levels (IIA) or remained elevated above fasting (IIB).
Results Group I (Fig. 1) In the nine subjects in whom fructose was infused first, the sugar provoked a small rise in plasma insulin which preceded the rise in blood glucose, with a maximal mean increment of 15 (JLU of insulin 20 min postinfusion. The insulin response to the subsequent glucose infusion was, as expected, more pronounced with a maximal mean increment of 38 (JLU of insulin 10 min postinfusion. The correlation between blood glucose and plasma insulin levels during both fructose and glucose infusions was highly significant (r = +0.878; P < 0.001). The correlation between plasma fructose and plasma insulin levels was not significant (r = +0.477; NS). Group II In subjects to whom fructose was given second, the insulin response to the sugar fell into two clearly defined groups depending on whether preinfusion blood glucose
IIA (Fig. 2) In this group of four subjects, the insulin response to fructose was similar to that found in Group I. A slight rise 10 min postinfusion, before any perceptible rise in blood glucose levels, was followed by a small peak at 20 min with a maximal mean increment of 22 /uU of insulin. The insulin response to glucose considerably exceeded the fructose response with a maximal mean increment of 43 /JLU of insulin. As in Group I subjects the correlation between blood glucose and plasma insulin levels during both infusions was highly significant (r = +0.875; P < 0.001). The correlation between plasma fructose and plasma insulin levels was not significant (r = +0.630; NS). UB (Fig. 3) In this group of five subjects, the insulin response to fructose was strikingly aug-
300
Blood Glucose mg/100ml
Plasma Fructose mg/K)0ml FIG. 1. Group I. Fructose infusion first: glucose infusion second. Mean levels of plasma fructose, blood glucose and plasma insulin are plotted semilogarithmically in this and subsequent figures (2-4). The insulin response to fructose is small and much less than that to glucose.
Plasma Insulin ^J units/ml
20" 10 20 30 40 50 60
10 20 30 40 5060'
Time poet-lnfuston
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
INSULIN RESPONSE TO INTRAVENOUS FRUCTOSE
Blood Glucose mg/ttOmt
631
Plasma Fructc mg/100ml
FIG. 2. Group IIA. Glucose infusion first: fructose infusion second (90 min postgluoose). In subjects whose prefructose infusion blood glucose values have returned to normal fasting levels the mean insulin response to fructose is much smaller than to glucose, as in Group I. Plasma InsuMn fj units/ml
10' 20T30 40 50" 60
10 20" 30 40 50 60
Time poet-Infusion
mented. With moderately elevated preinfusion levels of blood glucose and plasma insulin, an immediate and striking rise in plasma insulin occurred 10 min postinfusion
with a maximal mean increment of 77 of insulin 20 min postinfusion. This rise in plasma insulin levels was twice that of the maximal mean increment of 38 /u.U of insulin
30O 20O Blood Glucose mg/100ml
Plasma Fructose mg/iOOml
FIG. 3. Group IIB. Glucose infusion first: fructose infusion second (90 min postglucose). In subjects whose prefructose infusion blood glucose values have remained above fasting, the mean insulin response to fructose is augmented, considerably exceeding the response to glu-
« * 20*30 40'50" 60*
10 2a 30 40 50 60
Time poet-Infusion
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
JCE & M • 1975
DUNNIGAN AND FORD
632
provoked by the preceding glucose infusion. The marked rise in plasma insulin occurred when blood glucose levels were simultaneously falling from preinfusion levels. Because the plasma insulin peak following fructose was accompanied by falling blood glucose levels, the correlation between blood glucose and plasma insulin levels during both infusions was insignificant (r = +0.047; NS). In contrast the correlation between plasma fructose and plasma insulin levels was highly significant (r = +0.954; P < 0.001). Group III (Fig. 4) In this group of six subjects fructose was infused while blood glucose levels prior to the fructose infusion were in all cases elevated above fasting. As in Group IIB, the plasma insulin response to fructose was greatly augmented. From above basal values, plasma insulin levels rose promptly to a peak 10 min postinfusion with a maximal mean increment of 70 /uU of insulin
Vol 40 • iNo 4
and thereafter showed a progressive, monoexponential decline. The rise in insulin levels following fructose considerably exceeded the maximal mean increment of 47 fxXJ of insulin produced by the preceding glucose infusion and occurred while blood glucose levels were falling. Because of this rise in plasma insulin, unaccompanied by corresponding changes in blood glucose, the correlation between blood glucose and plasma insulin levels during both infusions was not statistically significant (r = +0.362; NS). In contrast, the correlation between plasma fructose and plasma insulin levels was highly significant (r = +0.966; P < 0.001). Discussion The results of the present study indicate that the insulin response to intravenous fructose depends closely on preinfusion blood glucose levels. When these were at or below fasting (Groups I and IIA; Table 1) fructose provoked only a small rise in plasma -100
30a Gtucose Infusion
-50
200-
Plasma Fructose mg/100 ml
Blood Glucose mg^ 100ml
100-
30 -10
FIG. 4. Group III. Glucose infusion first: Fructose infusion second (50 min postglucose). Prefructose infusion blood glucose values are above normal fasting levels and the mean insulin response to fructose is augmented as in Group IIB, exceeding the response to glucose.
P l a s m a Insulin p units/ml
2010 20 30 40 50 K> 2030 40 5060 Time post-Infusion
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
633
INSULIN RESPONSE TO INTRAVENOUS FRUCTOSE
T A B L E 1. Effect of preinfusion blood glucose levels on the plasma insulin response to intravenous fructose
Time postinfusion min Preinfusion 10
20 30 40 50 60
A 78 77 99 105 101 95 92
dt 4.3 < 0.001 Ht 4.5 < 0.001 dt 5 . 0 dt 5.4 dt 5.9 dt 6.3 dt 6.5
Plasma insulin Units per 10C) m l Mean ± SEM
Plasma fructose nig per 100 ml Mean ± SEM
Plasma glucose mg per 100 ml Mean ± SEM
B 131 ± 8.6 113 ± 6.4
118 ± 8.1 112 ± 104 ± 98 ± 92 ±
]B
A
6.8 7.3 8.6 7.4
80 ± 42 ± 28 ± 18 ± 14 ± 11 ±
4.7 < 0.05 3.4 2.1 1.8 1.2 0.7
95 51 33 22 16 12
dt 4.4 dt3.3 dr 2.2 d: 1.5 d: 1.2 dt 1.3
B
A
13 22 29 26 22 20 18
dt 2.6 dt 2.8 dt 4.6 dt 4.3 dt 4.0 dt 3 dt 3.4
< < < < < <
tion of fructose appears closely related to the preinfusion blood glucose level. Fructose has little or no insulinotropic action in the absence of glucose but potentiates glucose-mediated insulin release. The insulinotropic potency of other glucose analogues in vivo may show a similar dependence on concomitant blood glucose levels. (J Clin Endocrinol Metab 40: 629, 1975)
T
HE ability of fructose to provoke in- from metabolic disease and all had been on a sulin secretion is the subject of con- normal carbohydrate intake prior to the test. flicting reports. Based on in vitro experi- The patients were divided into three groups. ments in pancreas preparations and in vivo studies in animals and man, fructose has Group I (9 subjects). Samples for blood glucose been stated to produce no insulin secretion and plasma insulin were withdrawn through an indwelling cannula and 31 g of fructose was (1-5), variable secretion (6,7), or consistent thereafter administered intravenously over 5 min. secretion (8-12). The latter has been at- . Blood glucose, plasma insulin and plasma fructributed either to a direct insulinotropic tose were then estimated at 10-min intervals action or to the hepatic conversion of fruc- for 60 min. Blood glucose and plasma insulin tose to glucose. were again measured after a 30-min interval and In a previous study of fructose utilization 31 g of glucose was infused over 5 min. Plasma in normal, diabetic and postmyocardial insulin and blood glucose were thereafter estiinfarction subjects, small but significant mated at 10-min intervals for 60 min. rises in plasma insulin were noted following fructose infusions, with only slight Group II (9 subjects). In this group, the prochanges in blood glucose levels (13). It cedure was reversed, the glucose infusion being given first and the fructose second. Estimations was concluded that fructose had a small of blood glucose, plasma fructose and plasma insulinotropic action in man independent of insulin were made as in Group I. concomitant changes in blood glucose. In the present study, we have examined the Group III (6 subjects). Glucose was infused insulin response to intravenous fructose first; the fructose infusion was given 50 min with particular reference to preinfusion later without an intervening 30-min interval as blood glucose levels. in Groups I and II. Fructose was thus infused while blood glucose levels in each subject remained elevated above fasting. Estimations of Subjects and Methods blood glucose, plasma fructose and plasma Twenty-four male patients aged from 26 to 59 yr insulin were made as in Groups I and II. gave their informed consent to the intravenous Plasma fructose was determined by the method infusion of fructose and glucose following an of Kulka (14) and true blood glucose by a overnight fast. None was acutely ill or suffered glucose oxidase method (15). Plasma insulin was determined by an immunoassay technique (16). Received September 13, 1974. 629
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
DUNNIGAN AND FORD
630
JCE & M • 1975 Vol 40 • No 4
values had returned to normal fasting levels (IIA) or remained elevated above fasting (IIB).
Results Group I (Fig. 1) In the nine subjects in whom fructose was infused first, the sugar provoked a small rise in plasma insulin which preceded the rise in blood glucose, with a maximal mean increment of 15 (JLU of insulin 20 min postinfusion. The insulin response to the subsequent glucose infusion was, as expected, more pronounced with a maximal mean increment of 38 (JLU of insulin 10 min postinfusion. The correlation between blood glucose and plasma insulin levels during both fructose and glucose infusions was highly significant (r = +0.878; P < 0.001). The correlation between plasma fructose and plasma insulin levels was not significant (r = +0.477; NS). Group II In subjects to whom fructose was given second, the insulin response to the sugar fell into two clearly defined groups depending on whether preinfusion blood glucose
IIA (Fig. 2) In this group of four subjects, the insulin response to fructose was similar to that found in Group I. A slight rise 10 min postinfusion, before any perceptible rise in blood glucose levels, was followed by a small peak at 20 min with a maximal mean increment of 22 /uU of insulin. The insulin response to glucose considerably exceeded the fructose response with a maximal mean increment of 43 /JLU of insulin. As in Group I subjects the correlation between blood glucose and plasma insulin levels during both infusions was highly significant (r = +0.875; P < 0.001). The correlation between plasma fructose and plasma insulin levels was not significant (r = +0.630; NS). UB (Fig. 3) In this group of five subjects, the insulin response to fructose was strikingly aug-
300
Blood Glucose mg/100ml
Plasma Fructose mg/K)0ml FIG. 1. Group I. Fructose infusion first: glucose infusion second. Mean levels of plasma fructose, blood glucose and plasma insulin are plotted semilogarithmically in this and subsequent figures (2-4). The insulin response to fructose is small and much less than that to glucose.
Plasma Insulin ^J units/ml
20" 10 20 30 40 50 60
10 20 30 40 5060'
Time poet-lnfuston
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
INSULIN RESPONSE TO INTRAVENOUS FRUCTOSE
Blood Glucose mg/ttOmt
631
Plasma Fructc mg/100ml
FIG. 2. Group IIA. Glucose infusion first: fructose infusion second (90 min postgluoose). In subjects whose prefructose infusion blood glucose values have returned to normal fasting levels the mean insulin response to fructose is much smaller than to glucose, as in Group I. Plasma InsuMn fj units/ml
10' 20T30 40 50" 60
10 20" 30 40 50 60
Time poet-Infusion
mented. With moderately elevated preinfusion levels of blood glucose and plasma insulin, an immediate and striking rise in plasma insulin occurred 10 min postinfusion
with a maximal mean increment of 77 of insulin 20 min postinfusion. This rise in plasma insulin levels was twice that of the maximal mean increment of 38 /u.U of insulin
30O 20O Blood Glucose mg/100ml
Plasma Fructose mg/iOOml
FIG. 3. Group IIB. Glucose infusion first: fructose infusion second (90 min postglucose). In subjects whose prefructose infusion blood glucose values have remained above fasting, the mean insulin response to fructose is augmented, considerably exceeding the response to glu-
« * 20*30 40'50" 60*
10 2a 30 40 50 60
Time poet-Infusion
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
JCE & M • 1975
DUNNIGAN AND FORD
632
provoked by the preceding glucose infusion. The marked rise in plasma insulin occurred when blood glucose levels were simultaneously falling from preinfusion levels. Because the plasma insulin peak following fructose was accompanied by falling blood glucose levels, the correlation between blood glucose and plasma insulin levels during both infusions was insignificant (r = +0.047; NS). In contrast the correlation between plasma fructose and plasma insulin levels was highly significant (r = +0.954; P < 0.001). Group III (Fig. 4) In this group of six subjects fructose was infused while blood glucose levels prior to the fructose infusion were in all cases elevated above fasting. As in Group IIB, the plasma insulin response to fructose was greatly augmented. From above basal values, plasma insulin levels rose promptly to a peak 10 min postinfusion with a maximal mean increment of 70 /uU of insulin
Vol 40 • iNo 4
and thereafter showed a progressive, monoexponential decline. The rise in insulin levels following fructose considerably exceeded the maximal mean increment of 47 fxXJ of insulin produced by the preceding glucose infusion and occurred while blood glucose levels were falling. Because of this rise in plasma insulin, unaccompanied by corresponding changes in blood glucose, the correlation between blood glucose and plasma insulin levels during both infusions was not statistically significant (r = +0.362; NS). In contrast, the correlation between plasma fructose and plasma insulin levels was highly significant (r = +0.966; P < 0.001). Discussion The results of the present study indicate that the insulin response to intravenous fructose depends closely on preinfusion blood glucose levels. When these were at or below fasting (Groups I and IIA; Table 1) fructose provoked only a small rise in plasma -100
30a Gtucose Infusion
-50
200-
Plasma Fructose mg/100 ml
Blood Glucose mg^ 100ml
100-
30 -10
FIG. 4. Group III. Glucose infusion first: Fructose infusion second (50 min postglucose). Prefructose infusion blood glucose values are above normal fasting levels and the mean insulin response to fructose is augmented as in Group IIB, exceeding the response to glucose.
P l a s m a Insulin p units/ml
2010 20 30 40 50 K> 2030 40 5060 Time post-Infusion
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 May 2015. at 00:59 For personal use only. No other uses without permission. . All rights reserved.
633
INSULIN RESPONSE TO INTRAVENOUS FRUCTOSE
T A B L E 1. Effect of preinfusion blood glucose levels on the plasma insulin response to intravenous fructose
Time postinfusion min Preinfusion 10
20 30 40 50 60
A 78 77 99 105 101 95 92
dt 4.3 < 0.001 Ht 4.5 < 0.001 dt 5 . 0 dt 5.4 dt 5.9 dt 6.3 dt 6.5
Plasma insulin Units per 10C) m l Mean ± SEM
Plasma fructose nig per 100 ml Mean ± SEM
Plasma glucose mg per 100 ml Mean ± SEM
B 131 ± 8.6 113 ± 6.4
118 ± 8.1 112 ± 104 ± 98 ± 92 ±
]B
A
6.8 7.3 8.6 7.4
80 ± 42 ± 28 ± 18 ± 14 ± 11 ±
4.7 < 0.05 3.4 2.1 1.8 1.2 0.7
95 51 33 22 16 12
dt 4.4 dt3.3 dr 2.2 d: 1.5 d: 1.2 dt 1.3
B
A
13 22 29 26 22 20 18
dt 2.6 dt 2.8 dt 4.6 dt 4.3 dt 4.0 dt 3 dt 3.4
< < < < < <
