1 Department of Psychology and 2 Department of Medicine, University of Washington School of Medicine, Seattle 98195; and Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, and 3 Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267
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ABSTRACT |
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The ability to
increase -cell function in the face of reduced insulin sensitivity
is essential for normal glucose tolerance. Because high-fat feeding
reduces both insulin sensitivity and glucose tolerance, we hypothesized
that it also reduces
-cell compensation. To test this hypothesis, we
used intravenous glucose tolerance testing with minimal model analysis
to measure glucose tolerance
(Kg), insulin
sensitivity (SI), and the acute
insulin response to glucose
(AIRg) in nine dogs fed a chow
diet and again after 7 wk of high-fat feeding. Additionally, we
measured the effect of consuming each diet on 24-h profiles of insulin
and glucose. After high-fat feeding,
SI decreased by 57%
(P = 0.003) but
AIRg was unchanged. This absence
of
-cell compensation to insulin resistance contributed to a 41%
reduction of Kg
(P = 0.003) and abolished the normal
hyperbolic relationship between
AIRg and
SI observed at baseline. High-fat
feeding also elicited a 44% lower 24-h insulin level
(P = 0.004) in association with an 8%
reduction of glucose (P = 0.0003). We
conclude that high-fat feeding causes insulin resistance that is not
compensated for by increased insulin secretion and that this
contributes to the development of glucose intolerance. These effects of
high-fat feeding may be especially deleterious to individuals
predisposed to type 2 diabetes mellitus.
glucose tolerance; glucose effectiveness; insulin secretion; diabetes; obesity
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INTRODUCTION |
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the regulation of blood glucose levels by insulin
depends on insulin sensitivity and the amount of insulin delivered to
target tissues. Because a variety of acute and chronic factors can
substantially alter insulin sensitivity, the ability of the -cell to
respond with compensatory changes of insulin secretion should play an important role in the maintenance of normal glucose tolerance. Thus it
was hypothesized almost two decades ago that insulin sensitivity and
pancreatic
-cell function are coupled so that a change of insulin
sensitivity engenders a proportionate reciprocal change in
glucose-stimulated insulin secretion in healthy individuals (5, 8).
Accordingly, in the face of reduced insulin sensitivity, proportionate
-cell compensation acts to maintain normal glucose homeostasis (29,
30), whereas impaired
-cell compensation contributes to the
pathophysiology of glucose intolerance and type 2 diabetes mellitus (5,
24, 32, 42).
Empirical confirmation of reciprocity between levels of insulin
sensitivity and -cell function derive in large part from cross-sectional studies of subjects with apparently normal glucose tolerance but wide variation in adiposity and insulin sensitivity. As
predicted by Bergman et al. in 1981 (8), the mathematical model best
describing the relationship between insulin sensitivity, SI, quantified by the minimal
model method (7), and
-cell function, measured as the acute insulin
response to glucose (AIRg), was
hyperbolic such that their product,
SI · AIRg
[the disposition index (8)], equals a constant (29).
Consequently, normal glucose tolerance was preserved even among very
obese insulin-resistant individuals as long as
-cell function
remained intact (29).
Although the -cell response to altered insulin sensitivity has been
examined in only a handful of longitudinal investigations involving a
limited number of subjects, their findings are largely consistent with
a dynamic reciprocal relationship between insulin sensitivity and
-cell function. In a study of older adults who responded to
prolonged exercise training with decreased adiposity and improved
insulin sensitivity, the disposition index and intravenous glucose
tolerance both remained unchanged due to a reciprocal decrease of
AIRg (28). Conversely, reduced
SI associated with late pregnancy
is accompanied by a compensatory increase of
AIRg (17), a response that is
required if gestational diabetes mellitus is to be avoided. Similarly,
experimental insulin resistance induced by administration of nicotinic
acid to human subjects for 2 wk was accompanied by an increase of
AIRg. Because the magnitude of
this response was insufficient to fully offset the reduction of insulin
sensitivity, however, glucose tolerance decreased (27). This outcome
underscores the importance of the
-cell response to insulin
resistance in preserving normal glucose tolerance.
Existing data suggest that high-fat feeding alters the relationship
between insulin sensitivity and -cell function. High levels of
dietary fat intake are associated with impaired glucose tolerance (14,
16, 34, 35, 45, 53, 54) and insulin resistance (16, 33, 36, 44, 51,
52). Collectively, these data suggest that high-fat feeding may induce
insulin resistance without proportionate
-cell compensation, a
possibility of particular concern to those at risk for the development
of type 2 diabetes. To test this hypothesis, we used
tolbutamide-modified frequently sampled intravenous glucose tolerance
tests (FSIGT) analyzed by the minimal model (7) to quantify insulin
sensitivity and to measure
-cell function as
AIRg in nine dogs before and after 7 wk of ad libitum high-fat feeding. Additionally, 24-h measurements of
glucose and insulin levels were obtained to determine the effect of the
high-fat diet on circulating insulin and glucose levels under free
living conditions in animals with ad libitum access to food.
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MATERIALS AND METHODS |
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Studies were performed in nine adult male mongrel dogs weighing 31-40 kg at baseline. Each dog served as its own control in a repeated-measures design. All studies were approved by the Animal Care Committee at the Puget Sound Veterans Affair Health Care System.
Study protocol. After catheter implantation (see Surgical methods), animals were provided ad libitum access to standard laboratory chow for at least 5 wk and body weight was recorded at 3-day intervals to document weight stability at the time of the baseline study. During this time, dogs were accustomed to the Pavlov sling used during the FSIGT protocol (see FSIGT procedure). Animals underwent body composition testing, 24-h studies for insulin and glucose levels, and the FSIGT protocol at baseline while on the standard chow diet and again after a 7-wk period on a high-fat diet consumed ad libitum.
Surgical methods. Chronic indwelling arterial catheters were placed under general anesthesia. Tygon (Akron, OH) tubing (0.07 in. OD by 0.04 in. ID) was inserted via the omocervical artery and advanced under guidance of fluoroscopy until the catheter tip resided within the aorta at the level of the diaphragm. The proximal end of the catheter was externalized at the back of the neck via an arterial valve connector (Harvard Apparatus, Holliston, MA) to enable blood sampling. Between studies, patency was maintained with heparin. Dogs were allowed to recover for at least 5 wk before being studied.
Diets. The baseline diet consisted of standard dog chow (Harlan Teklad, Madison, WI) providing 17% of calories as fat. The caloric density of this diet is 3.47 kcal/g. The high-fat diet provides 80% of calories as fat and was developed in this laboratory. This diet entailed two feedings per day, morning and afternoon. The afternoon component consisted of a homogeneous mixture of 454 g of lard (Armour Foods, Omaha, NE) and 748 g of canned dog food. Variety was increased by use of two brands of dog food in three flavors (chicken, beef, and turkey; Blue Mountain Special Menu, Lehigh Valley, PA, and Friskies Alpo Prime Cuts, Glendale, CA). Additionally, 71 g of chicken or beef baby food (Heinz, Pittsburgh, PA) were added to each 1,202 g serving of the lard-dog food mixture. This mixture was estimated to contain 4.13 kcal/g. The morning feeding component consisted of peanut butter coated (57 g)-portions of lard (57 g) with oil-based tuna fish centers (19 g). Each portion was estimated to represent 1,150 kcal. Sufficient amounts of both diets were provided to ensure ad libitum access to food at all times. All animals remained healthy througout the study period. Estimates of caloric intake were based on the weight of food consumed.
Quantification of body composition.
Body composition was estimated using the isotope dilution technique
(23). A stock solution of sterile isotonic saline containing 2 µCi/ml
of
3H2O
(24 ml) was administered intravenously as a bolus. The syringe was
weighed before and after injection for precise determination of the
volume administered. Blood samples were collected before and 3 h after
the injection for determination of plasma radioactivity (dpm). For each
body composition determination, a single assay utilizing a
liquid-scintillation counter (Packwood Tri-Carb 1,600 TR, Meriden, CT)
quantified dpm in each of three 0.3-ml samples of baseline and
equilibrium plasma and in three 0.3-ml samples of scintillation fluid
containing 1 µl of radioactive stock. The difference in mean dpm/ml
between pre- and postinjection plasma samples was taken as the
equilibrium concentration of the
3H2O,
from which lean body mass was calculated (23). Based on the study by
Widdowson and Dickerson (56), we assumed that body water represents
74% of the lean body mass, that total body water equals 95.2% of the
distribution volume of
3H2O,
and that plasma equals 94% water. Percent body fat was calculated as
100 · fat
mass1 · total
body mass
1.
Measurement of 24-h insulin and glucose levels. Around-the-clock sampling of arterial plasma was performed in the animal's home cage during ad libitum provision of food and water. Dogs were not fasted overnight for these studies, which began at 9:30 AM. A total of 44 blood samples were obtained. Samples were drawn every 30 min for the first 15 h, every hour for the next 4 h, and at 30-min intervals for the final 5 h. Plasma glucose was quantified as the mean of the 44 values obtained. Plasma insulin was quantified as the time-weighted mean of the 44 values by using the trapezoidal rule to compute the area under the 24-h (1,440 min) insulin curve and dividing by 1,440.
FSIGT procedure.
Tolbutamide-modified FSIGT studies were conducted at 10:30 AM following
an overnight fast. At t = 0 min, a glucose bolus (0.3 g/kg of the baseline body weight) was infused
over 40 s into a forelimb vein. At t = 20 min, tolbutamide was administered (3 mg/kg iv of the baseline body
weight) to improve the precision of parameter estimates derived from
minimal model analysis (4). Arterial blood was collected at
t = 20,
10,
1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 35, 40, 52, 60, 70, 80, 90, 100, 120, 140, 160, and 180 min.
Determination of glucose tolerance. The glucose disappearance constant (Kg) was used as a measure of intravenous glucose tolerance. Kg is an estimate of the disappearance rate (%/min) of plasma glucose based on the slope of the line derived from least-squares regression of the natural logarithm of plasma glucose on time from min 10 through 19 during the FSIGT.
Quantification of insulin sensitivity and glucose effectiveness.
The minimal model method (5-7), developed originally in dogs, was
used to analyze FSIGT for quantification of the insulin sensitivity
index (SI) and glucose
effectiveness at basal insulin (Sg).
SI measures the ability of a given
amount of insulin to enhance glucose disappearance and
Sg measures the ability of glucose to enhance its own disposal at basal insulin.
Sg is comprised of an
insulin-dependent component
(SI · basal
insulin) and a noninsulin-dependent component (glucose effectiveness at
zero insulin, GEZI) (30). Thus GEZI is derived from
Sg as GEZI = Sg (SI · basal
insulin). Studies were analyzed by a co-author (R. L. Prigeon) blind to the condition (baseline or high-fat diet) under which the study was done.
Measurement of pancreatic -cell function and
disposition index.
The AIRg was used as a measure of
-cell function in response to a glucose challenge.
AIRg was determined as the mean
incremental plasma insulin level in samples collected at
t = 2, 3, 4, 5, 6, 8, and 10 min
following intravenous glucose administration during the FSIGT. The
product of
SI · AIRg,
the disposition index (8, 9), was computed as an index of
insulin-mediated glucose disposal during a FSIGT.
Quantification of relationship between insulin sensitivity and
-cell function.
The relationship between insulin sensitivity measured as
SI and
-cell function measured
as AIRg was analyzed via the
approach previously used in human subjects for this purpose (29). The concept underlying this analysis is that
AIRg · SI = a constant, which is a rectangular hyperbolic function. After
expressing AIRg as a function of
SI and taking the natural
logarithm (ln) of both sides of the equation,
ln(AIRg) =
1.0 · ln(SI) + a constant (29). The logarithmic model is favorable in terms of the
homoscedasticity of variance assumption of linear regression (2). A
slope of
1.0 implies that
AIRg · SI = a constant, as predicted for a hyperbolic relationship between
insulin sensitivity and
-cell function.
Insulin and glucose assays.
Blood samples were immediately placed on ice in EDTA and later
centrifuged for storage of plasma at 20°C. Plasma
insulin-like immunoreactivity was assayed using a modification of
the double-antibody method (37). Plasma glucose was analyzed by
the Trinder method (3).
Statistical analyses.
Paired t-tests were used to analyze
the change () of body composition, plasma glucose levels, insulin
levels, Kg,
SI,
Sg, GEZI, and
AIRg (computed as value after
high-fat feeding minus value at baseline). Data are summarized as the
means ± SE. If not normally distributed, data were log transformed
before statistical analysis. Classical least-squares linear regression
was used to evaluate the associations between
Kg and the
disposition index, Kg, and GEZI,
Kg and
GEZI, and
Kg and
disposition index. In accordance with the approach taken by Kahn et
al. (29), we regressed both
ln(AIRg) on
ln(SI), and ln(fasting insulin)
on ln(SI), using a method
[orthogonal distance regression (12)] that takes into account error in both the x and
y variables. This method provides an
unbiased estimate of the slope of the relationship between two
variables that are each measured with error, since classical linear
regression (which assumes that x is
measured without error) tends to underestimate the slope of the
relationship between x and
y variables in this setting (2).
Significance was established at a two-sided
-level of 0.05.
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RESULTS |
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Body composition.
As shown in Table 1, high-fat feeding for 7 wk significantly increased mean values of body weight ( = 6.6 ± 1.9 kg, P = 0.009), percent body fat
(
= 12.4 ± 3.3%fat units, P = 0.005), and fat mass (
= 6.8 ± 1.9 kg,
P = 0.006). Two of the nine dogs, however, did not increase in adiposity and a third had only a slight
increase. Lean body mass was unchanged by the high-fat diet (
=
0.83 ± 1.60 kg, P = 0.60).
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Fasting plasma insulin and glucose levels.
The mean fasting insulin concentration (Fig.
1A)
increased by 50% from 56.00 ± 6.40 to 84.00 ± 7.87 pM
(P = 0.008) after 7 wk on the high-fat
diet. This increase occurred in association with a 6.2% increase in
the mean fasting plasma glucose level (Fig.
1B) from 4.68 ± 0.14 to
4.97 ± 0.16 mM (P = 0.05).
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Insulin and glucose levels during 24-h studies. When measured after 7-wk of high-fat feeding, there was a significant 44% decrease in the mean time-weighted average 24-h insulin levels generated during ad libitum food intake. During the chow and high-fat feeding studies, the mean time-weighted average insulin levels (Fig. 1C) were 253.47 ± 32.64 and 140.28 ± 22.22 pM (P = 0.004), respectively. This decrease in circulating insulin levels occurred in association with a significant (7.8%) decrease in the 24-h mean glucose level (Fig. 1D) from 4.86 ± 0.05 to 4.48 ± 0.08 mM (P = 0.0003).
Caloric intake during 24-h studies. Mean caloric intakes during the 24-h chow and high-fat feeding studies were not significantly different (control 3,798 ± 481 kcal, high-fat 4,260 ± 636 kcal, P = 0.59).
Glucose tolerance.
Mean glucose tolerance, quantified as
Kg, decreased
markedly from 3.61 ± 0.38 to 2.12 ± 0.16%/min
(41.3%, P = 0.003, Fig. 2A)
after 7 wk of high-fat feeding. Decreases in glucose tolerance were not
significantly associated with
body weight
(r = +0.40, P = 0.28),
fat mass
(r = +0.50,
P = 0.17), or
% fat units
(r = +0.46,
P = 0.21).
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Acute insulin response to glucose. The mean AIRg decreased nonsignificantly from 393.2 ± 62.3 to 336.0 ± 27.5 pM (P = 0.37, Fig. 2B).
Insulin sensitivity and glucose effectiveness.
Insulin sensitivity was markedly decreased after high-fat feeding in
all dogs. The mean value of SI
decreased from 13.55 ± 1.74 to 5.87 ± 1.21 · 105 · min
1 · pM
1,
a reduction of 56.6% (P = 0.003, Fig.
2C). Changes in
SI were not significantly
correlated with
fat mass (r =
0.40, P = 0.29),
body weight
(r =
0.44,
P = 0.22), or
% fat units
(r =
0.48, P = 0.19). Similarly, percent changes
in SI were not significantly associated with percent changes in fat mass
(r =
0.44,
P = 0.23) or percent changes in body
weight (r =
0.46,
P = 0.22). The effect of high-fat
feeding to reduce insulin sensitivity therefore was not accounted for
by changes in adiposity.
Relationship between insulin levels and insulin sensitivity.
To determine if AIRg and
SI are reciprocally related in
dogs consuming the chow diet, we modeled the relationship at baseline between ln(AIRg) and
ln(SI) using orthogonal
regression (see MATERIALS AND
METHODS). The resulting model was described by the
equation ln(AIRg) = 1.05 · ln(SI)
3.53 (P = 0.011). Consistent
with the hypothesis that
AIRg · SI = a constant, the slope estimate of this equation is very close to
1.0 (P = 0.88 for comparison with
1.0). Consequently, the model was refitted with a slope of
1.0 to compute an intercept term corresponding to a rectangular hyperbolic relationship between
AIRg and
SI. This resulted in the equation
ln(AIRg) =
1.0 · ln(SI)
3.10, which after exponentiation translates to
SI · AIRg = 4.50 · 10
2 · min
1
(Fig.
3A).
Supporting the validity of this regression-based model, the actual
geometric and arithmetic means for the
SI · AIRg
product (the disposition index) were 4.50 and
4.72 · 10
2 · min
1,
respectively. During chow feeding therefore a significant inverse association existed between a measure of first-phase insulin secretion and insulin sensitivity such that the product of
AIRg · SI
(the disposition index) tended to remain constant across a broad range of insulin sensitivity.
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Interaction of insulin sensitivity and insulin secretion as
determinants of glucose tolerance.
Figure 4A
depicts the associations between
Kg and the
disposition index both at baseline and after high-fat feeding. At
baseline, Kg was
strongly associated with the disposition index
(r = 0.89, P = 0.001), which accounted for 80%
of the variance in
Kg. After high-fat feeding, the association between
Kg and the
disposition index was similar but did not reach statistical
significance (r = 0.63, P = 0.07). Based on a linear
regression analysis of the combined data obtained from the same animals
on both diets, the disposition index accounted for 79.4% of the
variance in Kg
(P = 0.001). Similarly, the
association between
Kg and
disposition index was significant (Fig.
4B, r = 0.68, P = 0.04), indicating that a
significant proportion of the change in
Kg induced by
high-fat feeding could be accounted for by changes in the disposition
index.
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DISCUSSION |
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Several studies (28, 29) support the hypothesis (5, 8) that altered
insulin sensitivity induces a proportionate reciprocal change in
-cell function that serves to minimize changes of glucose tolerance.
In the case of high-fat feeding, however, reduced glucose tolerance
develops (14, 16, 34, 35, 45, 53, 54) in association with insulin
resistance (16, 36, 44, 51, 52) and weight gain (31, 44, 48, 49). We therefore hypothesized that high-fat diets impede the increase of
-cell function that normally accompanies reduced insulin
sensitivity. In direct support of this hypothesis, we found that dogs
consuming a high-fat diet for 7 wk had a 57% decrease of
SI that clearly was not
accompanied by an increase of mean
AIRg and consequently, glucose
tolerance was significantly reduced. Moreover, we demonstrated that the
reciprocal relationship between
-cell function and insulin sensitivity that exists during chow feeding is lost after animals are
switched to a high-fat diet.
The 57% reduction of mean SI
observed in our study is consistent with a recent report that 6 wk of
high-fat feeding in dogs was associated with a 60% reduction in whole
body insulin-mediated glucose uptake as measured by the
hyperinsulinemic euglycemic clamp technique (44). Although the results
of human studies are more variable regarding the effect of high-fat
feeding on insulin sensitivity (reviewed in Ref. 50), they are
generally consistent with data reported here. Using the minimal model
approach, Chen et al. (16) found that
SI was significantly reduced after only 3-5 days of high-fat feeding (55% of kcal) in young,
nonobese subjects, whereas Swinburn et al. (53) reported that 14 days of high-fat feeding (50% of kcal) did not significantly reduce SI in human subjects that were
already obese and insulin resistant. This discrepancy likely reflects
the difficulty inherent in detecting a decrease in
SI among the insulin-resistant
subjects in the latter study (53). In rodents, increased dietary fat
intake is clearly associated with reduced insulin sensitivity (reviewed
in Ref. 50), even when the caloric content of the high-fat diet is
matched to that of the control diet (51). Collectively, these findings indicate that high-fat diets may induce insulin resistance even in the
absence of increased body adiposity. Consistent with this possibility
is our finding that SI was reduced
in each of the three dogs that exhibited little or no change of
adiposity in response to high-fat feeding. Additionally, the
observation that changes of SI
were not strongly associated with changes of body weight
(r = 0.44) or fat mass
(r =
0.40) suggests
that increased body adiposity was not the dominant mechanism by which
the high-fat diet reduced insulin sensitivity. It is possible, however,
that increases of central adiposity, a measure strongly linked to
insulin resistance (18, 19) but not evaluated here, contributed to the
decrease of insulin sensitivity induced by the high-fat diet in our
study, even among animals that did not exhibit a detectable increase of
overall fat mass.
Although we did not assess the mechanism by which high-fat feeding reduces insulin sensitivity, a large portion of literature (reviewed in Ref. 10) suggests that this effect may involve a glucose-fatty acid cycle in which increased lipid oxidation in insulin-sensitive tissues inhibits the action of insulin to stimulate cellular glucose uptake, a mechanism first proposed by Randle in 1963 (reviewed in Ref. 43). Support for the concept that high-fat diets increase lipid oxidation is provided by the finding that high-fat feeding significantly reduces the 24-h respiratory quotient (1, 22, 55), such that daily fat oxidation is increased as much as twofold (22). This shift in fuel metabolism elevates mitochondrial acetyl-CoA and increases citrate formation, which inhibits key glycolytic enzymes (43) and increases the flux of fructose 6-phosphate into the hexosamine pathway, which is hypothesized to generate a signal that induces insulin resistance (20). Several additional mechanisms by which dietary fat may impair insulin sensitivity have also been proposed, including reduced expression of insulin-sensitive glucose transporters (26), a decrease in the active form of glycogen synthase in skeletal muscle (21), reduced insulin binding to its receptor (38), and impaired activation of receptor tyrosine kinase (38).
Consistent with the results of Swinburn et al. (53), we observed that
high-fat feeding was also associated with a significant 36% reduction
in Sg. This finding reflects a
reduction in the insulin-independent component of glucose effectiveness
(GEZI), because GEZI was diminished by 35%
(P = 0.06) after high-fat feeding. However, our data do not support the conclusion of Swinburn et al. that
the predominant effect of increased fat intake on glucose disposal is
to impair the insulin-independent component of glucose uptake. To the
contrary, our results suggest that glucose intolerance induced by
high-fat feeding is the result of defects in insulin sensitivity and
-cell function, as well as reduced insulin-independent glucose uptake.
In contrast to the reliable decreases observed in insulin sensitivity
and glucose effectiveness, high-fat feeding had mixed effects on the
three different insulin responses measured in this study. Specifically,
the fasting plasma insulin level was increased by 50%, whereas the
24-h plasma insulin profile was reduced by 44% and the measure of
first-phase insulin secretion
(AIRg) was essentially
unchanged. Increased fasting insulin is therefore unreliable as a
surrogate measure of glucose-stimulated and feeding-induced insulin
secretion. Whereas the increase of fasting insulin could reflect a
compensatory response to the decrease of insulin sensitivity, other
factors may also have contributed to this response. Specifically, the
rate of insulin secretion rises sharply with increases of circulating
glucose within the physiological range (15). Elevated fasting glucose
levels during high-fat feeding therefore may have contributed to the
increase of fasting insulin. Decreased insulin clearance (25) is a
second mechanism that could have raised fasting insulin levels
independent of -cell compensation. Hence, the extent to which the
increase of fasting insulin observed after high-fat feeding reflects a
compensatory response of the
-cell to insulin resistance is
uncertain. In contrast, AIRg
provides a more direct measure of
-cell function, because the
glucose stimulus is constant across conditions and because the insulin secretion rate greatly predominates over insulin clearance as a
determinant of the acute-phase insulin level achieved during a glucose challenge.
The substantial (44%) reduction in the 24-h circulating insulin level
during ad libitum intake of the high-fat diet in comparison to chow
feeding was unexpected, given the concomitant reduction of
SI. This observation raises the
possibility that the insulin resistance detected under fasting
conditions was not present during ad libitium consumption of the
high-fat diet. However, we favor the alternative explanation that
-cell stimulation was reduced during consumption of the high-fat
diet, because dietary lipids are weak stimulants of insulin secretion
(47). The significant reduction in 24-h plasma glucose levels reflects
the reduced carbohydrate stimulus to
-cells associated with
consumption of the high-fat diet.
Consistent with data obtained in humans (29), we detected a hyperbolic
relationship between -cell function and insulin sensitivity,
described by the equation
AIRg · SI = a constant, during consumption of the chow diet. This relationship is
a quantitative reflection of the hypothesized mechanism by which
glucose tolerance is preserved under conditions associated with a
decline in insulin sensitivity (5, 27, 29, 42). After high-fat feeding, however, the relationship between insulin response and insulin sensitivity was markedly changed (Fig. 3). Specifically, the observed 57% decrease of SI was actually
accompanied by a small, albeit nonsignificant, decrease of
AIRg. This failure of
AIRg to increase in the face of
reduced SI provides direct
evidence that high-fat feeding interferes with
-cell adaptations
that would normally compensate for insulin resistance, as proposed
previously by Swinburn et al. (53). Chen et al. (16) also provided data
in humans concordant with the possibility of adverse effects of
elevated fat intake on
-cell function. Our data therefore provide
further support for the concept that high-fat feeding reduces the
ability of the
-cell to compensate for insulin resistance.
The mechanisms underlying these effects on insulin responses may
involve chronic exposure of -cells to elevated free fatty acid (FFA)
levels, although the effect of FFAs on insulin secretion is complex.
Thus long-term, but not short-term (39), elevations of FFAs can impair
glucose-stimulated insulin secretion, as demonstrated by both in vitro
rodent studies (46, 57, 58) and an in vivo human study in which a two-
to threefold increase of FFAs maintained for 24 h induced a 50%
decrease in AIRg (39). Mechanisms
that may explain this effect include glucose-FFA substrate competition within
-cells (58) and depletion of insulin stores caused by an
effect of FFAs to stimulate basal insulin secretion without a matching
increase of insulin synthesis (13).
On the other hand, acute exposure of -cells to FFAs increases
insulin release from cultured islets, and a 48-h experimental increase
of FFAs potentiated the insulin secretion rate in a human study
conducted by Boden et al. (11). Because plasma glucose was clamped at a
high level (~9 mM) in this study, however, both insulin secretion and
insulin synthesis may have been augmented. Thus the effect of elevated
FFAs on glucose-stimulated insulin responses may depend on the ambient
glucose level (40) such that prolonged elevation of FFAs without a
concomitant elevation of glucose favors reduced
-cell function. The
absence of
-cell compensation measured in terms of
AIRg in our study may therefore reflect an effect of the high-fat diet to cause insulin resistance without concomitant hyperglycemia, as suggested by the reduction in
24-h glucose levels observed during consumption of the high-fat diet.
If the lack of increased -cell function observed in our study
stemmed from low carbohydrate ingestion, it could represent an
adaptive, carbohydrate-sparing response analogous to that seen during
starvation rather than a maladaptive impairment of
-cell function.
Low glucose levels in starvation, analogous to our high-fat diet, occur
in conjunction with increased lipid oxidation and insulin resistance
and reduced
-cell sensitivity to glucose (15). However, in previous
work AIRg was halved by a
long-term fatty acid infusion despite a progressive increase of glucose
to almost 7 mM (39). Similarly, reducing circulating fatty acids
potentiated AIRg in normoglycemic
first-degree relatives of people with type 2 diabetes (41). Thus
chronically elevated fatty acid concentrations can suppress
-cell
function under conditions that do not involve decreased circulating
glucose levels. Our finding that
-cell function did not increase in
the face of reduced insulin sensitivity caused by high-fat feeding may
therefore reflect the combined effects of low plasma glucose and high
fatty acid levels, and additional studies are warranted to assess this
interaction and the extent to which it pertains to the consumption of
more typical high-fat diets.
Bergman et al. (8) predicted that development of reduced insulin
sensitivity without a quantitatively equivalent compensatory -cell
response would reduce glucose tolerance. Consistent with this proposal,
mean Kg in our
study was reduced by 41% after high-fat feeding, and regression
analysis indicated that 46% of the variability in the change in
Kg was explained
by the decrease of the disposition index. Whether adaptive or
maladaptive, therefore, this observation attaches pathogenic
significance to the failure to increase
AIRg during high-fat feeding and
suggests that impaired insulin-stimulated glucose disposal is a major
determinant of the decline of glucose tolerance
We conclude that a high-fat diet reduces the ability of the -cell to
compensate for insulin resistance and that this leads to glucose
intolerance. The concept that high-fat diets cause insulin resistance
and oppose the compensatory response of the
-cell has potentially
important implications for the pathogenesis of impaired glucose
tolerance and type 2 diabetes.
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ACKNOWLEDGEMENTS |
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We are grateful for the expert technical assistance provided by Rix Keuster, Hong Nguyen, Ruth Hollingworth, and Vicki Hoagland.
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FOOTNOTES |
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This work was supported by the National Institutes of Health Grants DK-17047, DK-35816, DK-12829, DK-52989, NS-32273, and DE-07132.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. W. Schwartz, Metabolism (151), Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108 (E-mail: mschwart{at}u.washington.edu).
Received 18 December 1998; accepted in final form 26 May 1999.
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