Departments of Medicine, Stanford University School of Medicine, Stanford, 94305; Shaman Pharmaceuticals, South San Francisco, California 94080; and University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637
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ABSTRACT |
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Plasma glucose, insulin,
and C-peptide concentrations were determined in response to graded
infusions of glucose, and insulin secretion rates were calculated over
each sampling period. Measurements were also made of insulin clearance,
resistance to insulin-mediated glucose, uptake, and the plasma glucose,
insulin, and C-peptide concentrations at hourly intervals from 8:00 AM
to 4:00 PM in response to breakfast and lunch. Plasma glucose, insulin,
and C-peptide concentrations were significantly (P < 0.01)
higher in obese women in response to the graded intravenous glucose
infusion, associated with a 40% (P < 0.005) greater
insulin secretory response. Degree of insulin resistance correlated
positively (P < 0.05) with the increase in insulin
secretion rate in both nonobese (r = 0.52) and obese
(r = 0.58) groups and inversely (P < 0.05) with the decrease in insulin clearance in obese (r = 0.46) and
nonobese (r =
0.39) individuals. Weight loss was
associated with significantly lower plasma glucose, insulin, and
C-peptide concentrations in response to graded glucose infusions and in
day-long insulin concentrations. Neither insulin resistance nor the
insulin secretory response changed after weight loss, whereas there was
a significant increase in the rate of insulin clearance during the
glucose infusion. It is concluded that 1) obesity is associated
with a shift to the left in the glucose-stimulated insulin secretory
dose-response curve as well as a decrease in insulin clearance and
2) changes in insulin secretion and insulin clearance in obese
women are more a function of insulin resistance than obesity.
insulin secretion; weight loss
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INTRODUCTION |
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WE HAVE RECENTLY PUBLISHED evidence that the hyperinsulinemia associated with insulin resistance in nondiabetic women results from an increase in insulin secretion, secondary to a shift to the left of the glucose-stimulated insulin response curve, as well as a decrease in insulin clearance (11). Insulin resistance and hyperinsulinemia are associated with obesity, and both abnormalities improve after weight loss (16). Although the effects of obesity and weight loss on various facets of insulin metabolism have been the focus of several recent reports (10, 13, 17, 18, 20), none of them have examined the dose-response relationships between glucose and insulin secretion (2, 3). Furthermore, the published studies have not attempted to define the relative roles played by obesity, as contrasted to insulin resistance, in the hyperinsulinemia associated with obesity. Consequently, we initiated the current study in which we have used a graded intravenous glucose infusion (2, 3) in nondiabetic women to define the effect of obesity and weight loss on the dose-response relationship between plasma glucose concentration and insulin secretion.
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METHODS |
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The experimental population consisted of 18 obese [body mass index (BMI) >29] nondiabetic healthy women <60 yr of age, recruited from the San Francisco Bay area by advertisements in local newspapers. They were compared with 20 nonobese (BMI <26) women of similar age distribution who had been studied previously (11). All subjects were judged to be in good general health on the basis of history, physical examination, complete blood count, routine biochemical screening, and electrocardiogram and had normal oral glucose tolerance on the basis of National Diabetes Data Group criteria (15). They were normotensive (blood pressure <160/90) and were taking no medication known to affect insulin secretion or sensitivity. This project was approved by the Stanford Human Subjects Committee, and all women gave written informed consent.
At baseline, each subject was admitted to the clinical research center for the tests performed in the following order.
Test 1.
Pancreatic -cell function was quantified by determining the insulin
and C-peptide response to graded intravenous infusions of glucose (2,
3, 11). After an overnight fast, intravenous catheters were placed in
superficial antecubital veins in each arm. One arm was used for
infusion of 20% glucose. This was started at a rate of 1 mg · kg
1 · min
1,
followed by infusions of 2, 3, 4, 6, and 8 mg · kg
1 · min
1.
Each infusion was administered for a period of 40 min. Venous blood
samples for glucose (12), insulin (6), and C-peptide (9) were obtained
from the contralateral arm at fasting and then 10, 20, 30, and 40 min
into each glucose infusion period. The last two values at the end of
each infusion period were averaged and used as the mean for that infusion.
Test 2.
Resistance to insulin-mediated glucose disposal was estimated by a
modification (7) of the original insulin suppression test (5, 21).
After an overnight fast, intravenous catheters were placed in a
superficial antecubital vein in each arm. One arm was used for a
continuous 180-min infusion of glucose (240 mg · m2 · min
1),
sandostatin (octreotide acetate; bolus of 25 µg followed by 0.5 µg · m
2 · min
1),
and insulin (25 mU · m
2 · min
1).
Venous blood samples for glucose and insulin determinations were
obtained from the contralateral arm every 30 min (to 150 min) and then
every 10 min for the last 30 min of the infusion. The mean of these
last four values was used to calculate the steady-state plasma glucose
(SSPG) and insulin (SSPI) concentrations. Under these experimental
conditions, endogenous insulin secretion is suppressed by sandostatin,
and the SSPI concentration achieved is comparable in all individuals.
The SSPG provides a measure of insulin-mediated glucose disposal; the
higher the SSPG, the more insulin resistant the individual. Insulin
resistance as assessed by the insulin suppression test has been shown
to correlate almost perfectly (>0.9) with values of insulin
resistance achieved with the insulin clamp technique (5).
Test 3. In addition, the obese volunteers received an 8-h meal tolerance test consisting of two meals, breakfast served immediately after fasting blood samples were drawn at ~8:00 AM and lunch served 4 h later. Breakfast contained 20% and lunch 40% of the individual's caloric requirements, and the macronutrient content of each meal was 43% carbohydrate, 15% protein, and 42% fat. Blood was drawn at hourly intervals for 8 h, and plasma was frozen for measurement of glucose and insulin concentrations.
Weight loss began the day after the first meal tolerance test. The Harris-Benedict equation (8) was used to determine each volunteer's total caloric requirements. One thousand calories was subtracted from their total caloric requirements to determine daily caloric intake during the weight loss phase of the study. No one received <1,200 kcal/day. A commercial canned liquid nutritional formula, plus two high-fiber muffins per day, provided their diet for 9 wk. Each volunteer came into the research unit two times a week for measurement of body weight and to pick up their liquid formula and muffins. The hypocaloric diet was effective, with an average weight loss of 9.8% of baseline weight. At the end of the weight loss phase, each volunteer followed a weight maintenance diet for 1 wk before admission to the research center for a repeat of the baseline tests (insulin suppression test, graded glucose infusion, and meal tolerance test). To minimize assay variability, samples from before and after weight loss were determined in the same assay. Values for continuous variables are expressed as means ± SE. The SSPG and SSPI values were compared using two-tailed, paired Student's t-tests. Differences between the glucose and insulin profiles after the meal tolerance test and the insulin secretion response to intravenous glucose in the two groups were compared by two-way ANOVA with SAS software. The integrated plasma insulin and insulin secretory responses and plasma insulin clearances were compared using Student's t-test, paired or unpaired as appropriate. ![]() |
RESULTS |
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The obese and nonobese women were matched for age (42 ± 2 vs.
41 ± 2 yr) but differed by BMI (31.9 ± 0.4 vs. 22.5 ± 0.4
kg/m2). The obese women had higher SSPG concentrations
than their nonobese counterparts (9.22 ± 0.99 vs. 5.87 ± 0.71
mmol/l, P < 0.01), but there was considerable overlap
between the two groups. Mean plasma glucose, insulin, and C-peptide
concentrations achieved at each stage of the graded glucose infusion
are illustrated in Fig. 1. These results
show that the obese women had a slightly higher plasma glucose
concentration (averaging ~1.1 mmol/l higher) at any given glucose
infusion rate (P < 0.01 by 2-way ANOVA). Despite this
relatively small difference in plasma glucose concentrations, it is
apparent that the plasma insulin concentrations at the end of each
glucose infusion were much higher in the obese subjects (P < 0.001 by ANOVA). The relative increase in the plasma
C-peptide concentrations was of comparable magnitude in the obese women (P < 0.01 by ANOVA).
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The plasma insulin concentrations and insulin secretion rates at molar
increments of plasma glucose are shown in Fig.
2. The obese subjects had higher plasma
insulin concentrations and insulin secretion rates as the plasma
glucose concentration was increased above 5 mmol/l, and in both cases
the increases were statistically significant (P < 0.01 by
ANOVA). The magnitude of these differences can be evaluated by
comparing the total integrated responses as the plasma glucose
concentration was increased from 5 to 9 mmol/l. In the case
of plasma insulin, there was an ~60% increase in the response of the
obese individuals (insulin area under the curve: obese vs. nonobese,
660 ± 62 vs. 415 ± 43 pM/mM, P < 0.01 by
t-test), whereas the increase in insulin secretion rate was
40% in these subjects (insulin secretion area under the curve: obese
vs. nonobese was 1,612 ± 107 vs. 1,148 ± 104
pmol · min1 · mM,
P < 0.005 by t-test). Finally, the slope of the
relationship between incremental increases in plasma glucose and
insulin secretion was significantly greater (P < 0.05) in
obese compared with nonobese subjects (121 ± 15 vs. 85 ± 10
pmol · min
1 · mM
1).
The observation that the insulin response tended to increase to a
greater extent than did the insulin secretion rate raised the
possibility that insulin clearance rate might be lower in obese
individuals. Although endogenous insulin clearance [endogenous metabolic clearance rate (MCR) adjusted for body surface area] calculated as the ratio of the total secretion of insulin to the area
under the peripheral insulin curve was lower in the obese subjects
(1.41 ± 0.1 vs. 1.61 ± 0.13
l · min
1 · m
2),
this difference was not statistically significant (P = 0.25).
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Figure 3 shows the relationship between
insulin resistance (as measured by SSPG), plasma insulin concentration,
insulin secretion rate, and plasma insulin clearance as the plasma
glucose concentration was increased from 5 to 9 mmol/l. Integrated
plasma insulin concentrations and insulin secretion rates (area under
the dose-response curves) were highly correlated
(P < 0.001) with SSPG concentration (correlation coefficients 0.77 and 0.66, respectively, for the total group of
women). Furthermore, the relationship between SSPG and the integrated
insulin response remained statistically significant (P < 0.005) when nonobese (r = 0.78) and obese
(r = 0.67) subjects were considered separately. Similarly,
the relationship between SSPG and insulin secretion rate was also
statistically significant (P < 0.05) within the two
subgroups, with r values of 0.52 and 0.58 in nonobese and obese
women, respectively. In marked contrast, the relationship between BMI
and insulin response was not significantly correlated in either
nonobese (r = 0.20) or obese (r = 0.22) women,
nor were BMI and insulin secretion rates related (0.18 and
0.24 in
nonobese and obese women).
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Insulin clearance, calculated as defined above, was negatively
correlated with SSPG (r = 0.46, P < 0.05), as
also shown in Fig. 3. The relationship between SSPG and insulin
clearance was present (P < 0.05) in both the nonobese
(r =
0.49) and obese (r =
0.39) groups.
However, as before, there was no relationship between BMI and insulin
clearance in either weight group (r =
0.13 and 0.19).
Fourteen women successfully completed the weight loss phase of the
study, losing an average of 9.8% of initial body weight in 9 wk.
Figure 4 displays the changes in SSPG
concentration before and after weight loss. It can be seen that SSPG
concentrations varied approximately sixfold in these obese women before
weight loss and that a fall was observed in 10 of the 13 women in whom both values were available. However, in three instances, SSPG concentrations were actually higher after weight loss. As a
consequence, the mean decrease in SSPG concentration associated with
weight loss was not significant (8.6 ± 1.1 vs. 9.9 ± 1.1,
mmol/l, P 0.10). On the other hand, SSPI concentrations
were also slightly lower (P < 0.09) after weight loss
(344 ± 19 vs. 380 ± 25 pmol/l), and this may have minimized the
improvement in SSPG associated with weight loss.
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The results of the meal tolerance tests before and after weight loss are also shown in Fig. 4. There was a small nonsignificant decrease in plasma glucose during the 8 h of the test, averaging 0.2 mmol/l. However, the day-long plasma insulin concentrations were significantly lower after weight loss (P < 0.05 by ANOVA).
Mean plasma glucose, insulin, and C-peptide concentrations achieved at
each stage of the graded glucose infusion before and after weight loss
are shown in Fig. 5. These results show
that weight loss led to a modest but significant decrease in plasma glucose of ~0.42 mmol/l at any given glucose infusion rate
(P < 0.05 by ANOVA). The plasma insulin concentrations at
the end of each glucose infusion rate were 38% lower and the plasma
C-peptide concentrations 18% lower after weight loss
(P < 0.01 by ANOVA).
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The effect of weight loss on the plasma insulin concentrations and
insulin secretion rates at molar increments of plasma glucose are shown
in Fig. 6. Although the plasma insulin
concentrations were clearly decreased after weight loss, the insulin
secretion rate was only minimally and nonsignificantly lower. The
magnitude of these differences can be evaluated by comparing the total
integrated responses as the plasma glucose concentration was increased
from 5 to 9 mmol/l. In the case of plasma insulin, there was an ~30% decrease after weight loss (insulin area under the curve: before vs.
after 700 ± 73 vs. 481 ± 46 pM/mM,
P < 0.005 by paired t-test), whereas there was
little change in insulin secretion rate (insulin secretion area under
the curve: before vs. after 1,560 ± 129 vs. 1,464 ± 132
pmol · min1 · mM; not
significant).
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The observation that there was a decrease in plasma insulin
concentration after weight loss without a corresponding decrease in
insulin secretion rate strongly suggested that there was an increase in
the rate of insulin clearance, a possibility supported by the fact that
there was a decrease in SSPI concentrations after weight loss.
Calculating insulin clearance as the ratio of the total production of
insulin to the area under the peripheral insulin curve confirmed this
(endogenous MCR adjusted for body surface area: before vs. after weight
loss 1.23 ± 0.07 vs. 1.75 ± 0.09 l · min1/m
2,
P < 0.001 by paired t-test). To further evaluate
the effect of weight loss on insulin clearance, we calculated the
exogenous MCR by using the SSPI concentrations obtained during the
insulin suppression test. In this case, the increase with weight loss was of lesser magnitude (0.48 ± 0.18 vs. 0.37 ± 0.15
l · min
1 · m
2,
P < 0.05).
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DISCUSSION |
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These studies were designed to explore the dose-response relationships
between plasma glucose concentration and insulin secretion rates in
response to intravenous glucose and were initiated for two reasons. In
the first place, we wished to quantify the effect of obesity on the
insulin secretory response to a graded intravenous glucose infusion in
healthy normal glucose-tolerant females. The results presented have
shown that the plasma insulin and C-peptide responses were
significantly higher in response to the glucose infusion in obese
compared with nonobese women studied previously (11), and the increment
in the two variables was comparable. In addition, obesity was
associated with an ~40% increase in the insulin secretory response.
The evidence that the glucose-stimulated insulin dose-response curve
was shifted to the left in obese women is consistent with the
conclusions from earlier studies (10, 13, 17, 18, 20), using a variety
of different experimental approaches, that the hyperinsulinemia
associated with obesity is primarily due to increased insulin
secretion. However, it should be emphasized that the increases in
plasma insulin and C-peptide concentrations, as well as insulin
secretion rates, seen in the obese women were markedly accentuated
compared with the much more modest increase in plasma glucose
concentration during the infusion study. In other words, the stimulus
to the pancreatic -cells to secrete more insulin in these obese
women cannot be a simple function of the coexisting plasma glucose
concentration. Rather, it appears that there is an increase in the
sensitivity of the pancreatic
-cells to a given increment in plasma
glucose concentration in obese women, a phenomenon quite similar to
that we recently described in nonobese, insulin-resistant women (11).
The other goal of this study was to define the relationship between changes in plasma glucose concentration and insulin secretion associated with weight loss. In this instance, the answer may not be as straightforward as it might seem. The simplest answer would be that weight loss had little, if any, effect on insulin secretion. This conclusion can be inferred by the observation that the decrease in the plasma insulin response to the graded glucose infusion was approximately two times as great as the fall in C-peptide. More specifically, there was essentially no change in the insulin secretory response to the graded glucose infusion after weight loss, whereas insulin clearance was significantly increased. On the other hand, in our previous study (11) we emphasized the importance of insulin resistance in determining the insulin secretory response to a graded glucose infusion. As the results in Fig. 4 indicate, a large segment of our obese group was not very insulin resistant. Furthermore, the results in Fig. 4 show that the improvement in insulin resistance associated with a decrease in baseline body weight of ~10% was modest in magnitude. In light of these considerations, the most reasonable conclusion would be that weight loss, per se, primarily affects insulin clearance, whereas a decrease in insulin secretion with weight loss may be more dependent on an associated improvement in insulin resistance.
The conclusion that the change in insulin secretion after weight loss may be primarily related to associated changes in insulin resistance is consistent with the results of both the current study and previous observations (10, 13, 18, 20). The great variability in the SSPG concentration of the obese women in the current study was also seen in the nonobese women. However, irrespective of the degree of obesity, SSPG concentration was highly correlated with both the integrated insulin response to the graded glucose infusion and the glucose-stimulated insulin secretory response. These relationships were seen when the obese and the nonobese groups were considered separately and when the two subgroups were combined. In contrast, we could not detect a significant relationship between BMI, the estimate of degree of obesity, and either insulin response or secretion in either group. As such, these data strongly suggest that it is insulin resistance, rather than obesity, that is primarily responsible for the increased insulin secretion and hyperinsulinemia seen in obese individuals. Because obese individuals, as a group, tend to be insulin resistant (16, 20), it is not surprising that they, as a group, secrete more insulin and are hyperinsulinemic. These data provide further evidence that insulin resistance leads to a leftward shift in the glucose-stimulated insulin dose-response curve and support the view that a rightward shift after weight loss would depend on an improvement in insulin sensitivity.
Although our results may seem somewhat disparate from the results of earlier studies, the differences can be easily reconciled. Thus Jimenez et al. (10) found that insulin secretion did not appear to increase after gastroplasty in six obese subjects who lost an average of 22% of initial body weight. Indeed, it required further weight loss of another 14% of initial body weight before there was any reduction in insulin secretion. Similarly, a mean weight loss of 30 kg after gastroplasty in the study by Letiexhe and associates (13) "slightly reduced insulin secretion but markedly improved insulin clearance." Thus, given the fact that the weight loss in our patients was much less in magnitude than in either of the above studies, it should not be too surprising that we did not see a significant increase in insulin secretory response. Perhaps, the results most similar to the current findings are those of Polonsky et al. (18), who found that both basal and 24-h insulin secretion rates decreased after weight loss in obese subjects with normal oral glucose tolerance or with a diabetic glucose tolerance test. However, in the same study, it was apparent that the insulin secretion rates in the more insulin-resistant group, those with the abnormal glucose tolerance tests, were highest at baseline and fell the most with weight loss. These results lend further support to the importance of insulin resistance in regulation of insulin secretion.
In conclusion, the peripheral hyperinsulinemia associated with obesity
in normal glucose-tolerant individuals is due primarily to an increase
in the glucose-stimulated insulin dose-response curve. However, this
change seems to be primarily a function of the fact that insulin
resistance is common in obese individuals, and the more insulin
resistant an individual, the more sensitive the pancreatic -cell to
increments in plasma glucose concentration. An increase in insulin
clearance appears to occur after weight loss of ~10% of initial body
weight, whereas decreases in insulin secretion seem to require a
greater degree of weight loss and/or an improvement in insulin
sensitivity. Perhaps this difference in the observed effects of weight
loss on insulin clearance and insulin secretion is due to the fact that
weight loss in obese individuals will relatively uniformly lead to an
increase in insulin clearance, but any change in pancreatic
-cell
sensitivity to glucose is dependent on an improvement in insulin
resistance. Finally, the insights gained from this study provide
further support for the utility of the graded glucose infusion approach
to illuminate how glucose-stimulated secretion is regulated.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants DK-30372, DK-31842, and DIC-20595 DRTC.
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FOOTNOTES |
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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: G. M. Reaven, Shaman Pharmaceuticals, Inc., 213 E. Grand Ave., South San Francisco, CA 94080-4812.
Received 13 November 1998; accepted in final form 7 October 1999.
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