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Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects



We have studied whether the sucrose-induced reduction of insulin sensitivity and cellular insulin binding in normal man is related to the fructose or the glucose moiety. Seven young healthy subjects were fed their usual diets plus 1000 kcal extra glucose per day and eight young healthy subjects were fed their usual diets with addition of 1000 kcal extra fructose per day. The dietary regimens continued for 1 week. Before change of diet there were no statistically significant differences between body weight and fasting plasma concentrations of glucose, insulin, and ketone bodies in the two groups studied. High-glucose feeding caused no significant changes in insulin binding or insulin sensitivity whereas high-fructose feeding was accompanied by a significant reduction both of insulin binding (P less than 0.05) and insulin sensitivity (P less than 0.05). The changes in insulin binding and insulin sensitivity correlated linearly (r = 0.52, P less than 0.01). We conclude that fructose seems to be responsible for the impaired insulin binding and insulin sensitivity induced by sucrose.
The American Journal of Clinical Nutrition 33: FEBRUARY 1980, pp. 273-278. Printed in U.S.A. 273
Impaired cellular insulin binding and insulin
sensitivity induced by high-fructose feeding
in normal subjects13
H. Beck-Nielsen M.D., 0. Pedersen M.D., and H. 0. Lindskov, M.D.
ABSTRACT We have studied whether the sucrose-induced reduction of insulin sensitivity and
cellular insulin binding in normal man is related to the fructose or the glucose moiety. Seven young
healthy subjects were fed their usual diets plus 1000 kcal extra glucose per day and eight young
healthy subjects were fed their usual diets with addition of 1000 kcal extra fructose per day. The
dietary regimens continued for 1 week. Before change of diet there were no statistically significant
differences between body weight and fasting plasma concentrations of glucose. insulin, and ketone
bodies in the two groups studied. High-glucose feeding caused no significant changes in insulin
binding or insulin sensitivity whereas high-fructose feeding was accompanied by a significant
reduction both of insulin binding (P <0.05) and insulin sensitivity (P <0.05). The changes in
insulin binding and insulin sensitivity correlated linearly (r =0.52, P<0.01). We conclude that
fructose seems to be responsible for the impaired insulin binding and insulin sensitivity induced by
sucrose. Am. J. C/in. Nut,. 33: 273-278, 1980.
Epidemiological and experimental studies
indicate that a high sucrose consumption may
be a diabetogenic factor (1-3). High-sucrose
intake may cause an impairement of the in-
sulin sensitivity. Thus, Vrana and Kazdova
(4) found a reduced lipogenesis in adipose
tissue of rats fed a high-sucrose diet when
compared to adipose tissue of rats fed a high-
starch diet. Comparable studies have been
performed by Bruckdorfer et al. (5). Accord-
ingly we recently found (6) 25% reduction of
the insulin sensitivity (intravenous insulin tol-
erance test (IVITT)) in normal man after
high-sucrose feeding for 14 days. The de-
crease of the insulin sensitivity might be ex-
plained by a parallel decrease of the cellular
insulin binding (6).
Animal studies have shown that the fruc-
tose moiety of sucrose may be responsible for
the effect of sucrose on the insulin sensitivity
(5, 7). The aim of this study has been to test
whether the observed effects of sucrose on
insulin binding and insulin sensitivity in man
are related to the glucose or the fructose
moiety of sucrose.
Materials and methods
Normal volunteers
Seventeen young healthy persons, three males and 14
females, ages 2 1 to 35 years, within 80 to 120% of their
ideal weight were studied. There was no difference of
ideal weight between males and females. All volunteers
were nurses with the same degree of physical activity.
Three subjects received contraceptive pills (one in each
group). No other drugs were used. On days of exami-
nation the volunteers were transported to the hospital by
car preventing exercise before blood sampling.
The volunteers were randomly divided into three
study groups. The subjects of group 1 (n =7) were
instructed to eat their normal food plus 250 g pure
glucose per day giving 1000 kcal. The subjects of group
2(n =8) were fed their normal diet with addition of 250
g fructose per day giving a supplement of 1000 kcal/day.
The study was continued for 7 days. Glucose and fructose
were given four times a day dissolved in water. Before
and during the study period the subjects ate a common
everyday diet containing 44% carbohydrate, 38% fat, and
18% protein. The mean energy supply was 2035 ±190
kcal/day (basal diet). The comparable weight gains in
the two groups during the week with sugar loads indicate
that the volunteers did not reduce their intake of normal
‘From the Medical Department III and Department
of Clinical Chemistry, County Hospital, Tage Hansens-
gade 2, Aarhus, and Nutrition Laboratory, Institute of
Hygiene, University of Aarhus, Denmark.
Supported by grants from the Danish Medical Re-
search Council, NOVO FOND, Nordisk Insulin Fond,
Arhus Universitets Forskningsfond and Landsforenin-
gen for Sukkersyges Fond.
3Address reprint requests to: Dr. H. Beck-Nielsen,
Medical Department III, County Hospital, Tage Han-
sengade 2, 8000 Aarhus C, Denmark.
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food to allow for a more isocaloric balance. The fasting
plasma concentrations of glucose and insulin were nor-
mal in all subjects. Before the diet was changed (base-
line period) the following variables were measured: Body
weight, fasting plasma concentrations ofglucose, insulin,
and ketone bodies, insulin binding to monocytes and
IVITT. Metabolic characteristics of the groups are given
in Table 1 .All measurements were repeated after 7 days.
Thus, the subjects were their own controls. As a technical
control of the methods (day to day variation etc.) we
studied two persons who ate their usual diet.
Plasma insulin concentration was measured by the
radioimmunoassay of Heding (8).
Plasma glucose concentration was measured using an
O-toluidine method (9).
Ketone bodies
Plasma acetoacetate concentration and plasma 3-hy-
droxybutyrate concentration were measured separately
by an enzymatic micromethod ( 10). Plasma ketone bod-
ies are expressed as the total of 3-hydroxybutyrate and
Cell binding studies
BlOOd, 140 ml, was drawn from an antecubital vein at
8.00 am after an overnight fast and transferred to tubes
containing EDTA (dipotassium salt). Mononuclear leu-
cocytes were isolated by gradient centrifugation (1 1).
The cells were washed twice and incubated in a Hepes
buffer (100 mmole/hiter, pH 7.8 at 15 C, 1% human
serum albumin) at a concentration of about 50 x 10”/ml
for 100 mm at 15 C with i2Shinsulin (Novo Research
Institute, Copenhagen) at a concentration of 34 pmole/
liter (0.2 ng/ml). The specific activity of the tracer was
about 150 iCi/g. There was only one iodine atom per
iodinated insulin molecule.
Specific insulin binding was estimated by adding
increasing amounts of unlabeled insulin to the incuba-
tion medium. At the end of the incubation period 250-
l cell suspension was added to a 1 .5-ml microtube
containing 1.0 ml ice cold buffer and 100 .tl silicone oil
(relative density 1 .04). Cell bound and free insulin were
separated by centrifugation. “Specific cell bound frac-
tion” was defined as total cell bound fraction minus
nonspecific cell bound fraction. Radioactivity that re-
mained bound in the presence of an excess of native
insulin at 10 .tmo1e/liter was considered “nonspecific”.
This fraction averaged 10% of total binding. There was
no significant difference between the nonspecific binding
before and after dieting in the three groups studied. The
monocytes were identified in cytocentrifuged smears
stained with a-napthyl acetate esterase. The specific cell
bound fraction was adjusted to a standard monocyte
concentration of 1.0 X 10’/ml using the formula de-
scribed previously (11). There were no significant
changes of the monocyte concentration in the three
groups studied during the study period (P> 0.1).
Binding analysis
Whether the curvilinearity of the Scatchard plot for
insulin binding to monocytes is due to negative cooper-
ativity among binding sites or the existence of two bind-
ing sites with different affinity and capacity is somewhat
controversial (12, 13). However, the maximal binding
capacity, R0, is the same no matter which of the two
interpretations is preferred. R0 is the extrapolated inter-
cept on the x-axis of the Scatchard plot. In this study the
binding constants were determined in accordance to both
models for interpretation of binding data (12, 13).
Using the model ofnegative cooperativity the limiting
high affinity state of the receptors (Ke) was determined
from the formula Ke (B/F)e/Rv Be where B is the
concentration of bound insulin at the tracer concentra-
tion (lowest insulin concentration) and (B/F)e is the
binding fraction at the same insulin concentration (12).
The dissociation constant for site 1 (Kr,,) of the two
receptor site model is determined from the slope of the
first part of the Scatchard plot. The extrapolation of this
part of the plot to the x-axis gives the amount of insulin
bound to the high affinity sites (R1).
Crystalline insulin, 0.05 units per kilogram body
weight were injected intravenously. Blood samples for
plasma glucose were taken -30, -15, 0, 5, 10, 15, 20, 25,
30, 35, 40, and 45 mm after insulin injection. The insulin
sensitivity was expressed as the rate constant for plasma
glucose disappearance KIvIrr 1n2/T112, in which T112
is half-life time of the exponential decline of the plasma
glucose concentration between 5 and 30 mm after insulin
injection (14).
Statistical methods
Wilcoxon’s test for paired differences was used for
comparison of values before and after change of diet,
while Spearman’s coefficient of rank (R) was applied in
correlation studies. Results in Figures and Tables are
given as mean values ±SEM.
Group 1 (hypercaloric, high-glucose diet)
There were no statistically significant
changes in the insulin binding at any insulin
concentration tested (P >0. 1, Fig. 1) after 7
days with high-glucose intake. Simultane-
ously, we found no changes in the insulin
sensitivity (P >0. 1, Fig. 2). kzvrrr before and
after glucose intake was 5.5 ±0.6 and 4.9 ±
0.6 x l02 min’ (mean ±SEM), respectively.
Fasting plasma concentrations of glucose, in-
sulin, and ketone bodies were unaltered, too
(P>0.l, Table 1).
Group 2 (hypercaloric, high-fructose diet)
After 7 days with 1000 kcal extra fructose
per day the cellular insulin binding decreased
about 30% at insulin tracer concentration.
The reduction of cellular insulin binding was
significant at the two lowest insulin concen-
trations (P <0.05, Fig. 3A) whereas no sig-
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Specific cell bound Bound/free insulin
x102 x102
0.1 1.0 10 100
Total insulin nmol/l
Plasma glucose
mmol II
Plasma glucose
mmol /l
B100 200
Insulin bound pmol/l
FIG. 1. Insulin binding to monocytes in seven normal subjects: effect of hypercaloric high-glucose feeding. The
subjects were studied on their usual diet and after 7 days. when fed their usual diet with addition of 1000 kcal
glucose per day. Mononuclear leucocytes were incubated with ‘251-insulin (34 pmole/hiter) and native insulin in
increasing concentrations. Radioactivity bound in the presence of 10 mole/hiter unlabeled insulin was called
nonspecific cell binding. Total binding minus nonspecific binding give the specific cell bound fraction. Cell bound
fractions were corrected to a monocyte concentration of lO/ml. A, specific cell bound fraction of ‘25I-insulin as a
function of native insulin: B, Scatchard analysis of the binding data from A.
i‘ ‘ J. ; i i
0 5 10 15 20 0 5 10 15 20
AMinutes B Minutes
FIG. 2. Insulin tolerance tests in the two groups studied before and 7 days after change of diet. A, group I ate
a hypercaloric high-glucose diet: B, group 2 ate a hypercaloric high-fructose diet. The plasma glucose concentration
is plotted as a function of time after iv injection of 0.05 units insulin per kilogram body weight at time zero.
nificant differences were found between
binding fractions at the six highest insulin
concentrations (P> 0.1, Fig. 3A). The insulin
concentration that was necessary to reduce
specific ‘251-insulin binding 50% was signifi-
cantly increased after fructose feeding for 1
week (P> 0.05), suggesting a reduction of
apparent receptor affinity. The total receptor
number (R0) was unaltered (P> 0.1) after
hyperalimentation with fructose (Fig. 3B).
Interpretating the binding data in accordance
with a two receptor sites model we neither
found a decrease in r1 (from 5.2 ±1.0 to 3.8
±1.5 pmole/liter, P<0.1) nor in the affinity
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Body weight and fasting plasma concentration of glucose,
(mean ±SEM)
Group I Group 2 ControLs
Base-line Pc. After 7 days period After diet Base.Line penod After diet
Fasting plasma glucose
Fasting plasma insulin (/LU/ml)
Fasting plasma ketone bodies
Body weight (kg)
±0.0 14
±0.0 13
Group I ate a high-glucose diet and group 2 ate a high-fructose diet.
Specific cell bound Bound/free insulin
x102 X]
A0.01 0.1 1.0 10 100
Total insulin nmol/l
100 150
BInsulin bound pmol/I
of site one receptors (Kd) from 0.20 ±0.04
to 0.24 ±0. 12 nmole/liter, P>0. 1). The
interpretation of the binding data in accord-
ance to the model of negative cooperativity
showed no changes in the binding affinity (P
>0.1, Fig. 4).
At the two lowest insulin concentrations
the insulin binding fractions were signifi-
cantly (P <0.05) lower in the postfructose
binding curve (Fig. 3A) compared to the
postglucose binding curve (Fig. lA).
Adecrease in the same order of magnitude
was found in the insulin sensitivity as Kivrr-r
decreased from 6.0 ±0.2 to 4.6 ±0.3 x 102
min’ (P <0.05, Fig. 2). Figure 5shows a
positive correlation between the changes in
insulin binding and insulin sensitivity (R =
0.52, P < 0.05). In the fructose fed group we
found no changes in the fasting plasma con-
centrations of glucose, ketone bodies, and
insulin (P >0. 1, Table 1).
Group 3 (controls)
No changes in insulin binding (not shown),
insulin sensitivity (kivrrr was 4.7 and 4.9 X
10_2 min’, respectively) and fasting concen-
trations of plasma glucose and insulin (Table
}) were found during the study period.
High-fructose feeding for I week was as-
sociated with 30% reduction of the insulin
binding to monocytes from young normals
whereas high-glucose feeding had no signifi-
insulin, and ketone bodies in the three groups studied
FIG. 3. Insulin binding to monocytes from eight normal subjects: effect of hypercaloric high-fructose feeding.
The subjects were studied on their usual diet and after 7 days when fed their usual diet plus 1000 extra kilocalories
per day arising from fructose. Experimental conditions as described in legend to Figure 1. A, specific cell bound
fraction of ‘251-insulin as a function of native insulin; B, Scatchard analysis of the binding data derived from A.
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lO8mol -1
FIG. 5. Correlation between k111-1 and the specific
2 cell bound fraction of ‘251-insulin (34 pmole/liter) in
10 100 X 10 group 2 (hypercaloric high-fructose diet). For details see
Vlegend to Figures 1 and 3.
FIG. 4. Average affinity profiles of ‘1-insulin bind-
ing to monocytes before and after high fructose feeding.
The average K is equal to B/F/R,-B. The percentage of
R0 occupied is given by Y (= B/R0).
cant effect on the cellular insulin binding. In
controls no change of insulin binding oc-
curred indicating that the observed altera-
tions are real and not caused by methodolog-
ical errors. The statistically significant right-
ward shift in the competition curve after fruc-
tose intake (Fig. 3) and the insignificant al-
teration in R0 indicate that high-fructoe in-
take reduces the binding affinity rather than
the number of binding sites (R0). When the
binding data were interpretated in accord-
ance to the two receptor site model or the
model of negative cooperativity we found no
statistically significant reduction in the bind-
ing affmity or in the number of binding sites.
Bar et al. (15) and Beck-Nielsen et al. (16)
have shown that in the obese calorie restric-
tion results in an acute increase in the binding
affmity, followed by a secondary increase in
the receptor number (after treatment for 1 to
2 weeks) and simulataneous normalization of
the binding affmity. Similar insulin receptor
events (acute changes in binding affmity fol-
lowed by changes in receptor number) may
have been induced by high fructose feeding.
Therefore, we may conclude that high fruc-
tose feeding for one week in some persons is
associated mainly with a reduction in the
number of high affinity receptor sites whereas
Specific cell bound
o0 0 0
in other persons a reduction in receptor affin-
ity prevails.
High-sucrose feeding for 7days resulted in
36% decrease in specific cell binding fraction
at insulin tracer concentration (6). When the
results ofthe present study are compared with
the findings after high-sucrose feeding (6) in
normal man we fmd comparable changes as
well quantitatively as qualitatively. There-
fore, it is reasonable to conclude that fructose
is responsible for the sucrose-induced
changes in cellular insulin binding.
Both high-sucrose and high-fructose feed-
ing resulted in 25% decrease of insulin sensi-
tivity. Changes in kivi’r’r and specific cell
binding fraction at insulin tracer concentra-
tion were positively correlated in both situa-
tions. Thus, we conclude that altered insulin
sensitivity at least in part may be explained
by altered insulin binding. A significantly
positive correlation between the insulin bind-
ing to monocytes and the insulin sensitivity
has previously been demonstrated in normals
(17), obese (18, 19), and chemical diabetics
Insulin receptor binding may be influenced
by the ambient plasma level of insulin (21)
and ketones (22). None of these receptor
regulatory factors seems responsible for the
decrease of the cellular insulin binding that
was associated with high-fructose feeding:
thus the fasting plasma concentrations of in-
sulin and ketone bodies remained unchanged.
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It is known that high-fructose feeding is as-
sociated with a reduction of the ATP content
of hepatocytes and consequently a reduction
in cellular levels of cyclic AMP and protein
synthesis (23). Thomopoulos et al. (24) found
that the cellular cyclic AMP level has an
insulin receptor regulatory effect in fibro-
blasts and cultured lymphocytes. The fructose
hyperalimentation in this study may have
caused a similar decrease of cyclic AMP and
protein synthesis of monocytes resulting in a
reduced insulin binding.
The authors thank T. Skrumsager, L. Busch, L. Blak
and J. J#{248}rgensen for skillful technical assistance. The
manuscript was carefully prepared by L. Thomsen.
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... RCTs. Three studies investigated the effect of fructose vs. glucose given as beverages on measures of insulin sensitivity, two in steady-state conditions using the euglycaemic hyperinsulinaemic clamp (Aeberli et al., 2013;Johnston et al., 2013) and one in non-steady state conditions using an IVITT (Beck-Nielsen et al., 1980) (Appendix F). The effect of fructose was also investigated in studies providing different amounts of fructose ad libitum (Aeberli et al., 2013), in isocaloric exchange with starch (Sunehag et al., 2008;Schwarz et al., 2015), in hypercaloric conditions (Le et al., 2009) and in isocaloric exchange with sucrose (Aeberli et al., 2013). ...
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Following a request from five European Nordic countries, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was tasked to provide scientific advice on a tolerable upper intake level (UL) or a safe level of intake for dietary (total/added/free) sugars based on available data on chronic metabolic diseases, pregnancy-related endpoints and dental caries. Specific sugar types (fructose) and sources of sugars were also addressed. The intake of dietary sugars is a well-established hazard in relation to dental caries in humans. Based on a systematic review of the literature, prospective cohort studies do not support a positive relationship between the intake of dietary sugars, in isocaloric exchange with other macronutrients, and any of the chronic metabolic diseases or pregnancy-related endpoints assessed. Based on randomised control trials on surrogate disease endpoints, there is evidence for a positive and causal relationship between the intake of added/free sugars and risk of some chronic metabolic diseases: The level of certainty is moderate for obesity and dyslipidaemia (> 50-75% probability), low for non-alcoholic fatty liver disease and type 2 diabetes (> 15-50% probability) and very low for hypertension (0-15% probability). Health effects of added vs. free sugars could not be compared. A level of sugars intake at which the risk of dental caries/chronic metabolic diseases is not increased could not be identified over the range of observed intakes, and thus, a UL or a safe level of intake could not be set. Based on available data and related uncertainties, the intake of added and free sugars should be as low as possible in the context of a nutritionally adequate diet. Decreasing the intake of added and free sugars would decrease the intake of total sugars to a similar extent. This opinion can assist EU Member States in setting national goals/recommendations.
... 4 Excess fructose intake downregulated insulin binding and impaired insulin sensitivity in both normal and overweight/obese humans, which subsequently results in insulin resistance. 55,56 It has been shown that fructose exposure plays a significant role in adipocyte differentiation and enhanced adipogenesis with upregulated GLUT5 expression in white adipose tissues. 43,57 Another report revealed that rats supplemented with 10% fructose in drinking water significantly increased the number of adipocyte precursor cells with enhanced adipogenesis. ...
High fructose consumption has been linked to low‐grade inflammation and insulin resistance that results in increased intracellular 11ß‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity. Celastrol, a pentacyclic triterpene, has been demonstrated to exhibit multifaceted targets to attenuate various metabolic diseases associated with inflammation. However, the underlying mechanisms by which celastrol exerts its attributive properties on high fructose diet (HFrD)‐induced metabolic syndrome remain elusive. Herein, the present study was aimed to elucidate the mechanistic targets of celastrol co‐administrations upon HFrD in rats and evaluate its potential to modulate 11β‐HSD1 activity. Celastrol remarkably improved glucose tolerance, lipid profiles, and insulin sensitivity along with suppression of hepatic glucose production. In rat adipose tissues, celastrol attenuated nuclear factor‐kappa B (NF‐κB)‐driven inflammation, reduced c‐Jun N‐terminal kinases (JNK) phosphorylation, and mitigated oxidative stress via upregulated genes expression involved in mitochondrial biogenesis. Furthermore, insulin signaling pathways were significantly improved through the restoration of Akt phosphorylation levels at Ser473 and Thr308 residues. Celastrol exhibited a potent, selective and specific inhibitor of intracellular 11β‐HSD1 towards oxidoreductase activity (IC50 value = 4.3 nM) in comparison to other HSD‐related enzymes. Inhibition of 11β‐HSD1 expression in rat adipose microsomes reduced the availability of its cofactor NADPH and substrate H6PDH in couple to upregulated mRNA and protein expressions of glucocorticoid receptor. In conclusion, our results underscore the most likely conceivable mechanisms exhibited by celastrol against HFrD‐induced metabolic dysregulations mainly through attenuating inflammation and insulin resistance, at least via specific inhibitions on 11β‐HSD1 activity in adipose tissues.
... Fructose is metabolized more rapidly than glucose and converted directly into fatty acids, which can lead to lactic acidosis, lipogenesis, hypertriglyceridemia, fatty liver, high blood pressure, insulin resistance and weight gain (Swarbrick et al. 2008). Fructose utilization is independent of insulin, ATP and citrate controls (Beck-Nielsen et al. 1980). Fructose-induced decrease in ATP causes ischemia and transient pauses in protein synthesis, production of inflammatory proteins, endothelial dysfunction and oxidative stress (Collino 2011). ...
The liver is the primary site for fructose metabolism; therefore, the liver is susceptible to fructose related metabolic disturbances including metabolic insulin dysfunction, dyslipidemia and inflammation. We investigated whether astaxanthin (ASX) can modify hepatic nuclear factor-kappa B (NF-κB)/sirtuin-1 (SIRT-1) expression to alter oxidative stress caused by ingestion of excess fructose in rats. The animals were divided randomly into two x two factorially arranged groups: two regimens were given either water (W) or 30% fructose in drinking water (F). These two groups were divided further into two subgroups each: two treatments, either orally with 0.2 ml olive oil (OO) or 1 mg ASX/kg/day in 0.2 ml olive oil (ASX). Fructose administration increased serum glucose, triglycerides and very low density lipoproteins, and decreased serum concentration of high density lipoproteins; fructose did not alter serum total cholesterol. Excess fructose decreased hepatic superoxide dismutase (SOD) and increased hepatic NF-κB and MDA levels. ASX treatment increased hepatic SIRT-1 and decreased hepatic NF-κB and malondialdehyde (MDA) levels. ASX treatment decreased hepatic NF-κB and increased SOD levels, but did not alter MDA level in rats fed high fructose. ASX administration ameliorated oxidative stress caused by excess fructose by increasing hepatic NF-κB and SIRT-1 expression.
... On the other hand, our finding that indicates a beneficial association of fructose intake with insulin sensitivity was not confirmed by many intervention studies in which high proportions of fructose are consumed. These fructose over-consumption trials almost consistently report that higher intakes of fructose lead to decreases in insulin sensitivity (67)(68)(69)(70). Many of the studies outlining the biological pathways of fructose administer high levels of pure fructose and the observed outcomes are not applicable to the amount of fructose typically consumed by humans, particularly considering that fructose is most often coingested with glucose via sucrose or HFCS in ratios similar to sucrose. ...
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Purpose: To examine the prospective relevance of dietary sugar intake (based on dietary data as well as urinary excretion data) in adolescent years for insulin sensitivity and biomarkers of inflammation in young adulthood. Methods: Overall 254 participants of the DONALD study who had at least two 3-day weighed dietary records for calculating intakes of fructose, glucose, sucrose, total, free, added sugars, total sugars from sugar-sweetened beverages (SSB), juice, and sweets/sugar or at least two complete 24 h urine samples ( n = 221) for calculating sugar excretion (urinary fructose and urinary fructose + sucrose) in adolescence (females: 9–15 years, males: 10–16 years) and a fasting blood sample in adulthood (18–36 years), were included in multivariable linear regression analyses assessing their prospective associations with adult homeostasis model assessment insulin sensitivity (HOMA2-%S) and a pro-inflammatory score (based on CRP, IL-6, IL-18, leptin, chemerin, adiponectin). Results: On the dietary intake level, no prospective associations were observed between adolescent fructose, sucrose, glucose, added, free, total sugar, or total sugar from SSB, juice or sweets/sugar intake and adult HOMA2-%S ( p > 0.01). On the urinary level, however, higher excreted fructose levels were associated with improved adult HOMA2-%S ( p = 0.008) among females only. No associations were observed between dietary or urinary sugars and the adult pro-inflammatory score ( p > 0.01). Conclusion: The present study did not provide support that dietary sugar consumed in adolescence is associated with adult insulin sensitivity. The one potential exception was the moderate dietary consumption of fructose, which showed a beneficial association with adult fasting insulin and insulin sensitivity.
Aims Perinatal maternal hypercaloric diets increase the susceptibility to metabolic disorders in the offspring. We hypothesized that maternal intake of an isocaloric moderate-fat diet (mMFD) would disturb the glucose homeostasis and favor the β-cell failure in response to fructose overload in adult male offspring. Methods Female Wistar rats received an isocaloric diet (3.9 kcal/g) containing 29 % (mMFD) or 9 % as fat (mSTD) prior mating and throughout gestation and lactation. After weaning, male offspring received standard chow and fructose-drinking water (15 %) between 120 and 150 days old. Key findings mMFD offspring had higher body weight, visceral adiposity and, fasting glycemia, with normal insulinemia. Fructose increased glycemia at 15 min from oral glucose administration, but only mMFD had returned to basal glucose levels at 120 min. Fructose increased HOMA-IR index regardless diet, but only mMFD exhibited hyperinsulinemia and a higher HOMA-β index. mMFD pancreatic islets showed increased area and insulin immunostaining density, suggesting β-cell hypertrophy. Fructose induced the expected compensatory hypertrophy in mSTD islets, while the opposite occurred in mMFD islets, associated with reduced insulin immunostaining, suggesting lower insulin storage. Pancreatic islets isolated from mMFD offspring exhibited higher glucose-stimulated insulin release at physiological concentrations. However, at higher glucose concentrations, the islets from fructose-treated mMFD reduced dramatically their insulin release, suggesting exhaustion. Significance Isocaloric mMFD induced adaptive mechanism in the offspring allowing insulin hypersecretion, but under metabolic challenge with fructose, β-cell compensation shifts to exhaustion, favoring dysfunction. Therefore, a maternal MFD may contribute to developing diabetes under fructose overload in the adult offspring.
Over the last decades, the role of the intestinal microbiota in metabolic diseases has come forward. In this regard, both composition and function of our intestinal microbiota is highly variable and influenced by multiple factors, of which diet is one of the major elements. Between 1970 and 1990 diet composition has changed and consumption of dietary sugars has increased, of which fructose intake rose by more than tenfold. This increased intake of sugars and fructose is considered as one of the major risk factors in the developments of obesity and several metabolic disturbances. In this review, we describe the association of dietary fructose intake with insulin resistance, non-alcoholic fatty liver disease (NAFLD) and lipid metabolism. Moreover, we will focus on the potential causality of this altered gut microbiota using fecal transplantation studies in human metabolic disease and whether fecal microbial transplant can reverse this phenotype.
We conducted a scoping review of sweet beverages (SB) and cancer outcomes to ascertain SB's relationship with cancer by SB type and cancer type. We used the PRISMA Scoping Review Guidelines to review quantitative studies of SB and cancer. Eligible studies included articles reporting a quantitative association between SB intake and a cancer-related health outcome in humans, including adiposity-related versus non-adiposity-related cancers. Studies included analyses not confounded by artificial sweeteners. SB was defined as beverages with added sugars, 100% fruit juices, or fruit drinks that were not 100% fruit juice. We used a data-charting form to extract study characteristics and results.A total of 38 were included. The sample consisted predominately of adults from European countries outside of the United States or predominately White samples in the United States. Across all conceptualizations of SB, a greater proportion of studies examining carbonated drinks reported SB's relationship with poorer cancer outcomes, which was exacerbated in adiposity-related cancers.The composition of different types of SB (e.g., high fructose corn syrup, natural fructose) as they relate to cancer is important. Studies including more diverse populations that bear a disproportionate burden of both SB intake and cancer are needed. Prevention relevance: Different sugars in SB may impact cancer differently. Compared with SB made with other types of sugar, drinks made with man-made fructose (carbonated drinks) had poorer cancer outcomes, especially in cancers impacted by obesity. Understanding how different SB affect cancer would help us target which SB to avoid.
Increased consumption of fructose has been suggested to be a contributing cause of the increased rates of obesity in humans. Rodent studies have shown an increase in de novo lipogenesis and decreased insulin sensitivity in response to feeding high levels of fructose, but it is unclear if these effects occur in the same progression in humans. We aimed to develop a swine model for studying changes in glucose metabolism and insulin resistance resulting from dietary carbohydrate alone or in combination with high dietary fat. Two experiments were conducted to determine if the source of dietary carbohydrate, with or without added fat, had an effect on body weight gain, glucose metabolism, or insulin response in growing pigs. In the first experiment, pigs (24 barrows, initial body weight 28 kg) were fed one of four diets in which the source of carbohydrate was varied: 1) 20% starch; 2) 10% glucose + 10% starch; 3) 10% fructose + 10% starch; and 4) 20% fructose for 9 weeks. There were no differences in growth rate or glucose clearance observed. Experiment 2 was conducted as a 3 × 2 factorial with the main effects of carbohydrate source (20% starch, glucose, or fructose) and added fat level (0 vs 10%). Pigs (24 barrows, initial body weight 71 kg) were fed one of six experimental diets for 9 weeks. Compared to the other dietary treatments, pigs fed fructose with high fat had an elevated glucose area under the curve during the GTT (Carbohydrate x Fat interaction, P < 0.01). This same group had a lower insulin response (Carbohydrate x Fat, P < 0.05). This work demonstrates that pigs can be a viable model to assess the long-term effects of dietary carbohydrates on metabolism and body composition. Studies of longer duration are needed to determine if these changes are indicative of insulin resistance.
The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear. Among 1463 stage I–III CRC patients from the Nurses’ Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars. Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26–0.75 and 0.70, 95% CI: 0.55–0.89, respectively). Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination.
High-fructose syrups are used as sugar substitutes due to their physical and functional properties. High fructose corn syrup (HFCS) is used in bakery products, dairy products, breakfast cereals and beverages, but it has been reported that there might be a direct relationship between high fructose intake and adverse health effects such as obesity and the metabolic syndrome. Thus, fructose has recently received much attention, most of which was negative. Although studies have indicated that there might be a correlation between high fructose-rich diet and several adverse effects, however, the results of these studies cannot be certainly generalised to the effects of HFCS; because they have investigated pure fructose at very high concentrations in measurement of metabolic upsets. This review critically considered the advantages and possible disadvantages of HFCS application and consumption in food industry, as a current challenging issue between nutritionists and food technologists.
Diabetes mellitus developed in selected albino rats fed a high-sucrose diet. The interaction between gentic factor(s) and sucrose feeding in the rat and the application of this interaction to the problem of diabetes in the human population is discussed.
Insulin binding to monocytes and insulin action in vivo was examined in 14 obese subjects during the postabsorptive state and after starvation and refeeding. Tissue sensitivity to insulin was evaluated with the euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained 100 muU/ml above the fasting level, and plasma glucose is held constant by a variable glucose infusion. The amount of glucose infused is a measure of tissue sensitivity to insulin and averaged 285+/-15 mg/m(2) per min in controls compared to 136+/-13 mg/m(2) per min in obese subjects (P <0.001). (125)I-Insulin binding to monocytes averaged 8.3+/-0.4% in controls vs. 4.6+/-0.5% in obese subjects (P < 0.001). Insulin binding and insulin action were highly correlated in both control (r = 0.86, P < 0.001) and obese (r = 0.94, P < 0.001) groups. Studies employing tritiated glucose to measure glucose production indicated hepatic as well as extrahepatic resistance to insulin in obesity. After 3 and 14 days of starvation, insulin sensitivity in obese subjects decreased to 69+/-4 and 71+/-7 mg/m(2) per min, respectively, whereas (125)I-insulin binding increased to 8.8+/-0.7 and 9.0+/-0.4%. In contrast to the basal state, there was no correlation between insulin binding and insulin action. After refeeding, tissue sensitivity increased to 168+/-14 mg/m(2) per min (P < 0.001) whereas insulin binding fell to 5.0+/-0.3%. We conclude that (a) in the postabsorptive state insulin binding to monocytes provides an index of in vivo insulin action in nonobese and obese subjects and, (b) during starvation and refeeding, insulin binding and insulin action changes in opposite directions suggesting that postreceptor events determine in vivo insulin sensitivity.
We have characterized the cellular composition of preparations isolated from peripheral blood by Ficoll-Isopaque gradient centrifugation. 125I-insulin binding to every cell type was measured. A highly significantly positive correlation between specific cell binding fraction and the monocyte concentration of the heterogeneous cell suspension was demonstrated. Depletion of monocytes reduced the insulin binding approximately 80%, which confirms previous findings by other investigators. The granulocytes possessed the second highest binding ability, but only one fourteenth of that of monocytes. Compared to the lymphocyte the monocyte had about 25 times greater insulin binding. Also thrombocytes bound insulin and contamination with these meant that their contribution to the total specific cell binding was not negligible. A reduction in these contaminants is essential. We found that insulin binding to erythrocytes was insignificant. A method of calculating the specific insulin binding to monocytes alone is introduced. The monocyte-insulin-receptor possesses specificity. Only an insignificant degradation of receptor bound insulin could be shown. Evidence of negative cooperativity between receptors was found. Consequently monocytes are considered a useful model for insulin receptor studies in man.
Long-term fructose feeding to the genetically selected albino rat resulted in the development of diabetes mellitus and diffuse glomerulosclerosis. Siblings of these animals that were starch fed did not develop the metabolic impairments nor did they develop diabetic microangiopathy. These results are similar to those observed following sucrose feeding to these genetically selected animals. Hence, fructose feeding is not different than that of sucrose in producing diabetes and diabetic angiopathy.
Insulin binding to isolated circulating monocytes from normal subjects and adult patients with diabetes was studied. The diabetic subjects were nonketotic, and their degree of glucose intolerance varied from an abnormal oral glucose tolerance test (chemical diabetes) to significant fasting hyperglycemia. The results indicated that patients with chemical diabetes had a 45 per cent decrease in insulin binding to monocytes, and this decrease was secondary to a reduction in the number of receptor sites per cell (normals, 15,000 sites per monocyte versus 8,500 sites per monocyte for chemical diabetics). When the individual data from the normal and chemical diabetic subjects were examined, a highly significant inverse correlation was found between the amount of insulin bound and both the fasting plasma insulin level (r = 0.61, P>0.001) and the incremental insulin area during an oral glucose tolerance test (r = 0.49, P>0.001). Furthermore, insulin binding was closely and inversely correlated to the degree of insulin resistance (r = 0.65, P>0.001) among these subjects. Thus, the ability to bind insulin is inversely related to both the plasma insulin level and insulin sensitivity, and chemical diabetics who are insulin-resistant and hyperinsulinemic have a decreased ability to bind insulin. Many patients with fasting hyperglycemia also have decreased insulin binding. However, although as a group these patients have fasting hyperinsulinemia, they are hypoinsulinemic in response to a glucose challenge. Thus, inclusion of their data with that of the normal and chemical-diabetic patients enhances the relationship between insulin binding and fasting insulin level (r = 0.68, P>0.001) but obliterates the relationship between insulin binding and incremental insulin area. Furthermore, in these subjects no significant correlation was found between insulin binding and the degree of insulin resistance (r = 0.19, N.S.), suggesting that all or most of the insulin resistance in these subjects was independent of changes in insulin receptors. In conclusion, if the subjects are taken as a group, in patients with chemical diabetes and in diabetic patients with fasting hyperglycemia, insulin binding to monocytes is decreased; over the entire spectrum of adult, nonketotic diabetes, insulin binding is decreased to monocytes from patients with fasting hyperinsulinemia, while subjects with normal insulin levels have normal insulin binding; the insulin resistance of patients with chemical diabetes may be related to a decrease in insulin receptors, but this does not appear to be the case for patients with fasting hyperglycemia; and plasma insulin levels are inversely related to insulin binding, but it is the basal, not the stimulated levels that are associated with changes in insulin receptors.
An enzymatic micro-method for the determination of acetoacetate and 3-hydroxybutyrate in blood and urine is described. 150 μl blood or urine is needed for the analysis of each ketone body. Interference was not found from lactate, malate, pyruvate, or oxaloacetate with either the acetoacetate or 3-hydroxybutyrate determination. The addition of lactate or malate dehydrogenase is therefore unnecessary. The significance of the pH of the reaction mixture is discussed. The analysis is well-suited for routine use.
Fifteen normal volunteer subjects and one patient with “essential” hypertriglyceridemia were given diets in which bread and sucrose, respectively, were the main sources of carbohydrate. The average glucose tolerance curve was significantly lower during the “bread” diet period than during the control “western” diet and “sucrose” diet periods. The relationship of these differences in response to glucose load to the simultaneous changes observed in the blood cholesterol during these dietary periods is discussed.