1 Department of Medicine, Lund University, SE-221 84 Lund, Sweden; and 2 Institute of Systems Science and Biomedical Engineering-Italian National Research Council, 35127 Padua, Italy
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ABSTRACT |
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This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at 1 wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness (SG) and disposition index (DI), i.e., insulin sensitivity (SI) times early or total insulin secretion. Glucose disappearance (KG) and SI were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced SI, as judged by normal DI50 min. In contrast, early (10 min) insulin secretion was not sufficiently increased; DI10 min was reduced after 1, 3, and 10 mo. SG was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding.
glucose tolerance; glucose intolerance; insulin secretion; high-fat diet
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INTRODUCTION |
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TYPE 2 DIABETES
OCCURS when the -cells fail to adequately compensate a reduced
insulin sensitivity with a sufficient insulin secretion (6, 7,
16, 19, 28). Also, glucose uptake mediated by mechanisms
independent of dynamic insulin, the so-called glucose effectiveness
(SG), importantly contributes to glucose tolerance and is
an independent risk factor for type 2 diabetes (1, 2, 8,
17). The relative impact of reduced
-cell compensation vs.
SG for development of glucose intolerance is, however, not
known. Therefore, we have explored in this study the temporal
relationship between insulin-dependent mechanisms and processes being
independent of dynamic insulin in the standardized experimental model
of mice fed a high-fat diet by use of the frequently sampled
intravenous glucose tolerance test (FSIVTT) recently developed for use
in mice (26). High-fat diet is known to be linked to both
islet dysfunction and poor glucose effectiveness (9, 13, 18, 21,
22, 24, 32). The high-fat diet mouse model has previously been
shown to be associated with insulin resistance together with glucose
intolerance (4, 5, 11, 15). This model is therefore suited
for studies on the temporal relationship between insulin-dependent
mechanisms and mechanisms independent of dynamic insulin for the
glucose intolerance accompanying insulin resistance caused by high-fat diet.
The study also evaluated the relative contribution of early vs. total insulin secretion for development of glucose intolerance in insulin resistance. This is of interest because recent studies have suggested that the initial insulin response more importantly contributes to glucose tolerance than does total insulin secretion. Thus a negative correlation has been reported between the 30-min insulin response to oral glucose as a marker for early insulin secretion and the 120-min glucose value as a marker of glucose tolerance (23). Furthermore, prevention of the early insulin response results in glucose intolerance (3, 33), and a brief administration of a minute amount of insulin during the first 15 min after food intake markedly improves glucose tolerance in subjects with obesity (33) and type 2 diabetes (10).
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MATERIALS AND METHODS |
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Animals. A total of 119 experiments were performed in nonfasted female C57BL/6J mice (Bomholdtgaard Breeding and Research Centre, Ry, Denmark) weighing 20-25 g at the start of the study and kept five per cage on a 12:12-h light-dark schedule (lights on at 0600). Experiments were performed in late morning without food being removed from the cages. Previous experiments in the laboratory have shown that results with this approach are the same as when food is removed from the cage 4 h before experiments. The animals were obtained at 4 wk of age. On day 4 after arrival, mice received a high-fat diet consisting of 58% fat, 25.6% carbohydrate, and 6.4% protein (total energy 23.4 kJ/g; Research Diets, New Brunswick, NJ). Controls were fed with a standard pellet diet (fat 11.4%, carbohydrate 62.8%, protein 25.8%, total energy 12.6 kJ/g; Research Diets). Tap water was given ad libitum. The experimental procedures were approved by the Ethics Committee of Lund University.
Experiments. Intravenous glucose tolerance tests (IVGTT) were performed at 1 wk and 1, 3, and 10 mo after the high-fat diet was started. The animals were anesthetized with intraperitoneal midazolam (Dormicum, 0.14 mg/mouse; Hoffman-La Roche, Basel, Switzerland) and a combination of fluanison (0.9 mg/mouse) and fentanyl (Hypnorm, 0.02 mg/mouse; Janssen, Beerse, Belgium). After 30 min, a blood sample (75 µl) was taken from the retrobulbar, intraorbital, capillary plexus in a 100-µl pipette, which had been prerinsed in heparin solution (100 U/ml in 0.9% NaCl; Lövens, Ballerud, Denmark). Thereafter, D-glucose (British Drug Houses, Poole, UK) was injected intravenously over 3 s at the dose of 1 g/kg in a tail vein without flushing of the 27-gauge needle after injection. The volume load was 10 µl/g body wt. New blood samples (75 µl each) were taken at 1, 5, 10, 20, 50, and 75 min. In another series of experiments, an insulin-modified IVGTT was undertaken. Animals then underwent the IVGTT as the regular test, with the difference that human insulin (Actrapid, 1 U/kg; Novo Nordisk, Bagsvaerd, Denmark) was administered intravenously at 10 min after glucose, immediately after taking the 10-min sample.
Data analysis.
Insulin and glucose data from the IVGTT were analyzed with the minimal
model technique, as already reported in detail (26). The
model assumes a first-order, nonlinear insulin- and glucose-controlled glucose kinetics following exogenous glucose injection. This analysis provides parameter SI (insulin sensitivity index), which is
defined as the ability of insulin to enhance net glucose disappearance and to inhibit glucose production, and the parameter SG
(glucose effectiveness), representing net glucose disappearance per se from plasma without any change in dynamic insulin. Both the early and
total insulin responses to intravenous glucose were calculated by the
trapezoid rule as the suprabasal area under the insulin curve
(AUCinsulin) for the first 10 min
(AUC0-10) or the AUCinsulin for the
total 50 min (AUC0-50) after the glucose challenge. We
also determined the unitless index DI (global disposition index) by
multiplying SI times
AUC0-10 or times
AUC0-50 (DI10 min and DI50
min, respectively). These indexes are an extension of the
concept proposed in dogs by Bergman et al. (7) and in humans by Kahn et al. (16) and describe the insulin effect
by including both insulin action and insulin secretion. The net glucose elimination rate after the glucose injection [the glucose tolerance index (KG)] was calculated as the slope for the interval
1-20 min after glucose injection of the logarithmic transformation of the individual plasma glucose values (26). The relative
contribution of the insulin-mediated processes and the processes
independent of dynamic insulin for glucose intolerance was assessed as
previously described in detail (26), considering, as has
been demonstrated (34), that intravenous glucose tolerance
is a linear combination of these two processes. To evaluate the
relative contribution of SG and DI to the changes of
KG, we applied the definition and the calculations of
sensitivity, i.e., the quantification of changes of KG for
a unit change of SI or DI (26), that yield the
value (as percentage) of the two contributions. The detailed
description of the method to calculate these sensitivities and the
relative contributions has been reported in Ref. 26.
Statistics. Data and results are reported as means ± SE unless otherwise designated. Statistical comparisons between any group or subgroup with the relative controls were performed with an unpaired t-test. ANOVA was exploited for multiple comparisons.
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RESULTS |
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Regular IVGTT after high-fat feeding.
The two groups of mice being fed a high-fat diet or a control
diet for 10 mo underwent a regular FSIVGTT at 1 wk and 1, 3, and 10 mo
after introduction of diet. Figure 1
shows the body weight, baseline glucose and insulin levels, and glucose
tolerance as calculated by the glucose elimination rate during
minutes 1-20 after glucose injection (KG).
It was seen that body weight was already significantly higher in
high-fat-fed mice after 1 wk, whereas glucose and insulin levels were
elevated after 1 mo on the high-fat diet. The mice on the high-fat diet
were glucose intolerant throughout the study, as KG was
significantly lower than in control diet-fed mice at all studied time
points. Figure 2 shows the time courses
of the glucose and insulin levels during the regular IVGTT, and Fig.
3 shows the calculated parameters from
the minimal-model analyses of glucose and insulin data obtained from
the FSIVGTT. SI increased slightly by time in control mice over the first 3 mo, being higher at 3 mo than at 1 wk
(P = 0.015), whereafter it fell. Throughout the study
period, however, SI was significantly lower in high-fat-fed
mice than in mice fed a control diet, i.e., already after 1 wk. The
lowered SI was paralleled by an increased insulin secretion
in high-fat-fed mice, when calculated as the total 50-min
AUCinsulin, which was significantly higher in high-fat-fed
mice than in mice fed a control diet at all time points (Fig. 3).
AUC0-50 and SI displayed a hyperbolic
relationship to each other (Fig. 4). The
increase in AUC0-50 induced by high-fat feeding
matched the reduction in SI; hence, the DI50, i.e., the product of insulin secretion times insulin sensitivity, was
not significantly different between the two groups of animals. In
contrast, the first 10-min insulin response to glucose
(AUC0-10) was significantly increased only after 3 and 10 mo on a high-fat diet and was therefore not elevated in
high-fat-fed mice compared with mice fed a control diet at 1 wk and 1 mo. Hence, the 10-min insulin response was not compensatorily increased
in relation to the low SI after 1 wk or 1 mo on high-fat
diet. When calculated for this early 10-min insulin response
(DI10), the DI was therefore lower in high-fat-fed mice
than in mice fed a control diet at all time points, being significant
at 1 mo (P = 0.012), 3 mo (P = 0.013),
and 10 mo (P = 0.017). SG did not change
significantly over time in control mice and was significantly lower in
high-fat-fed mice than in mice fed a control diet at all time points.
In Table 1, a summary of the parameters
calculated after 10 mo of high-fat diet is reported.
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Contribution of metabolic parameters to glucose tolerance.
Across all animals, KG correlated to both DI
(DI10 r = 0.51, P < 0.001;
DI50 r = 0.42, P < 0.001)
and SG (r = 0.56, P < 0.001; Fig. 5). To calculate the relative
contribution of the two DIs vs. SG for the development of
glucose intolerance, multiple regression analysis was performed, with
KG as the independent variable and these parameters as
dependent variables. It was found that, after 1 wk on high-fat diet,
SG (r = 0.85, P < 0.001)
but not DI (either one) correlated independently with KG.
In contrast, after 1 mo on high-fat diet, only DI10
(r = 0.75; P = 0.001), but not
SG or DI50, correlated with KG, and
after 3 mo, both DIs (r = 0.87, P < 0.001), but not SG, correlated with KG.
Finally, after 10 mo, all three parameters correlated independently
with KG (r = 0.78; P < 0.001). When the relative contribution of DI50 vs.
SG to KG was calculated, all control and
high-fat-fed mice, respectively, were included in the analysis. It was
found that, in controls, SG contributed by 72%, whereas
DI50 contributed by 28% to KG. In contrast, in
high-fat-fed mice, the contribution by DI50 was considerably increased, being 54.3%, vs. only 45.7% for
SG.
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Insulin-modified IVGTT after high-fat feeding.
Also at 10 mo, a modified IVGTT was performed in which insulin was
injected 10 min after glucose, which resulted in very high insulin
levels at minute 20 (Fig. 6).
The aim of this set of experiments was to evaluate whether reduced
glucose tolerance in animals under high-fat diet was reversed with very
high levels of ambient insulin. The total insulin levels
(AUC0-50) were very high in this test, whereas the
early insulin response (AUC0-10) was not
significantly different from the values obtained in the regular IVGTT.
We confirmed the reduction of SI, DI (both DIs), and
SG in mice fed a high-fat diet (Table 1). Also with the
insulin-modified IVGTT, despite a very high ambient insulin, the
high-fat-fed animals displayed a lower KG
(P = 0.002). It is worth noting that KG in the insulin-modified IVGTT in high-fat-fed mice was higher than in
control mice during the regular IVGTT, being calculated at two
different ambient insulin levels. Finally, it is also
interesting to observe that the value of SI in both tests
in the control animals was virtually the same (Table 1), supporting the
robustness of this parameter in situations characterized by different
insulin concentrations.
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DISCUSSION |
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This study examined the relative contribution of insulin-dependent mechanisms vs. processes independent of dynamic insulin for impaired glucose tolerance after high-fat feeding in mice. Furthermore, with regard to insulin-dependent mechanisms, the study also evaluated the relative importance of defective early insulin response to the glucose challenge vs. the total insulin secretion over 50 min. A main novel finding is the demonstration that glucose intolerance in the early stages after initiation of insulin resistance is dependent on a reduction of glucose-controlled glucose clearance (SG), whereas after a longer period of time, when obesity has progressed, insufficient islet compensation to insulin resistance contributes to a higher extent. A second main novel finding is the demonstration that defective compensation of the early insulin response to glucose more importantly than total insulin secretion contributes to defective insulin-dependent mechanisms responsible for glucose intolerance. These results are of importance for our understanding of basic mechanisms for glucose intolerance as well as for identifying targets for treatment.
High-fat feeding is known to induce insulin resistance, as reported from studies in mice (4, 5, 11, 15), dogs (18, 24, 29), rats (31), and humans (9, 21, 22, 32). It has been shown that this is associated with impaired insulin signaling and translocation of GLUT4 in skeletal muscle (15). We show here a marked reduction of insulin sensitivity, as is evident by the low SI, in high-fat-fed mice. A lower SI in the high-fat-fed mice compared with the control mice was already evident at 1 wk after introduction of a high-fat diet and persisted throughout the entire study period. This may be caused by the fat loading per se in combination with the increased degree of obesity.
The insulin response to the intravenous glucose was augmented in
mice fed a high-fat diet compared with control mice. This is a
consequence of the reduced insulin sensitivity and illustrates the
islet compensation to insulin resistance as initially shown by Bergman
et al. (7) and later explored in detail by Kahn et al.
(16). We found that total insulin secretion, as judged by
the 50-min AUCinsulin during the regular IVGTT, was
increased by ~40% in mice on a high-fat diet. This increase
perfectly matched the 40% reduction in SI. In contrast,
the compensatory augmentation of the early (10 min) insulin response to
glucose was slow and delayed compared with the augmented total insulin
secretion and took, in fact, 3 mo to evolve. Thus there was no
significant compensatory increase in the early insulin response to
glucose in the high-fat diet after 1 wk or 1 mo despite the reduced
SI. Furthermore, when the compensation in this parameter
appeared, i.e., after 3 mo and 10 mo, it was lower than what was
required for the reduced SI. Because at these time
points glucose tolerance was markedly impaired, the results suggest
that the defective early insulin response to glucose is of major
importance for the development of glucose intolerance. It should be
emphasized that the defective early insulin response was evident
despite a marked increase in insulin secretion, because
AUC0-10 was 156% higher in high-fat diet-fed mice
than in controls, yet DI10 was reduced by almost 40%. To
be sufficient, an ~50% higher insulin secretion would be required in
the mice with low SI to result in a normal DI. At present,
the mechanism of this failure to adequately compensate for the reduced
insulin secretion is not known. It should be emphasized that the study
explored the insulin response to glucose in vivo. Thus the insulin
response to glucose depends both on the function of the
-cells and
on in vivo factors influencing the
-cells, such as the autonomic
nerves, circulating nutrients, and hormones. It has previously been
shown that high-fat feeding in mice is associated with an ~50%
increase in
-cell mass (25). This would suggest that it
is not a defective increase in
-cell mass that explains the poor
compensation. However, further studies have to analyze the exact
mechanism behind the defective adaptation.
The compensatory increase in insulin secretion in insulin
resistance makes it impossible to quantify insulin secretion
independent of the knowledge of insulin sensitivity. Hence, the
demonstration of the defective insulin secretion in high-fat-fed mice
would not be possible without the knowledge that SI is
markedly reduced, which requires an even higher insulin secretion than
was evident. This failure to determine both processes for accurate
determination of their contributions may underlie previous conclusions
that reduced insulin action is a primary defect for the development of
glucose intolerance and type 2 diabetes (20, 30). In fact, it seems to be the defect of insufficient -cell compensation to the
reduced insulin action that is the main event underlying progression to
glucose intolerance and type 2 diabetes (14, 19). This is
supported by the present standardized model, which expresses
insulin resistance as the temporally initial defect, and glucose
tolerance is worsened by inappropriate
-cell compensation in the
early insulin secretion.
To further evaluate in detail the limits of insulin compensation for reduced insulin sensitivity and to assess whether very high insulin levels could ameliorate glucose tolerance during a high-fat diet, we also exploited the insulin-modified IVGTT, which has never been performed previously in mice. Also, this test showed that SI was markedly lower in high-fat-fed vs. control mice, causing again a sustained reduction of DI. Glucose disposal as judged by the KG was also lower in high-fat diet-fed mice, although glucose elimination was higher than that of the regular IVGTT due to the very high insulin levels. This shows that insulin administration improves glucose elimination in high-fat-fed mice, but the glucose disposal remains lower than in control mice to which the same amount of insulin is administered.
In the present study, we exploited the minimal model of glucose disappearance to calculate insulin sensitivity in mice. This method was recently validated against the gold standard hyperinsulinemic euglycemic glucose clamp technique both in control animals and in mice on a high-fat diet (26), thus yielding confidence in the results obtained here. An additional interesting result of the present study was that SI was not different in control animals when obtained with the insulin-modified test or with the regular test, where much lower levels of insulin are present. This further demonstrates that SI from the minimal model is a robust and consistent parameter in rodents also, this having already been shown in humans (27).
The minimal-model analysis of the data during the IVGTT allowed calculation not only of insulin sensitivity and insulin secretion but also of SG and confirmed that SG largely contributes to glucose disposal in normal mice, because KG was dependent on SG by 72% (26). In high-fat-fed mice, SG contributed instead only by 45% to KG, and this was explained by the significantly lower SG that was already evident after only 1 wk of feeding. This shows that the metabolic derangement due to the high-fat diet involves both mechanisms responsible for glucose disappearance from the beginning. The reduction in SG was largest in the early time points. Thus, after 1 wk on a high-fat diet, SG was reduced by >60%, whereas SG thereafter gradually improved and was reduced by only 25% after 3 mo. Therefore, SG shows a different time pattern after initiation of high-fat feeding from SI, which deteriorated progressively throughout the study period. Although there is no evidence of a synergistic process between SI and SG (8), it can be speculated that this mechanism of increasing SG is in the long run an attempt to counterbalance the elevated insulin resistance. The molecular basis for the reduced SG in high-fat-fed mice remains to be studied, however.
In summary, glucose intolerance in insulin resistance in mice is caused by a combination of reduced glucose effectiveness and insufficient islet compensation to insulin resistance, the latter involving the early 10-min insulin response. Reduced glucose effectiveness and defective early 10-min insulin response are, therefore, in addition to insulin resistance, targets for treatment of high-fat diet-associated glucose intolerance.
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ACKNOWLEDGEMENTS |
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We are grateful to Lilian Bengtsson, Kerstin Knutsson, and Lena Kvist for expert technical assistance.
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FOOTNOTES |
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This work was supported by grants from the Swedish Medical Research Council (Grant no. 6834), Albert Påhlsson, Crafoordska, and Nordic Foundations, the Swedish Diabetes Association, and the Faculty of Medicine, Lund University. A special fund (Assegnazione Straordinaria) was awarded to G. Pacini by the Italian National Research Council (Consiglio Nazionale delle Ricerca) for cooperative projects with the University of Lund.
The results of this study were presented, in part, at the 36th annual meeting of the European Association for the Study of Diabetes in Jerusalem, September 2000, and at the 17th International Diabetes Federation Congress in Mexico City in November 2000.
Address for reprint requests and other correspondence: B. Ahrén, Dept. of Medicine, Lund University, B11 BMC, SE-221 84 LUND, Sweden (E-mail: Bo.Ahren{at}med.lu.se).
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. Section 1734 solely to indicate this fact.
June 11, 2002;10.1152/ajpendo.00199.2002
Received 8 May 2002; accepted in final form 10 June 2002.
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