1 Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, SE-182 88 Danderyd; and 2 Department of Medicine, Lund University, SE-221 84 Lund, Sweden
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ABSTRACT |
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Islet
function was examined in 13 severely obese women [body mass index
46.4 ± 5.5 (SD) kg/m2] before and after standardized
15 and 25% weight reduction (WR) instituted by bariatric surgery. The
insulin response to arginine at fasting (AIR1), at 14 mmol/l, and at >25 mmol/l glucose was reduced by 37-50% after 15 and 25% WR (P 0.05). Insulin sensitivity was
determined as the amount of glucose infused to reach 14 mmol/l divided
by the insulin level (M/I), a measure showing a linear correlation with
insulin sensitivity during euglycemic hyperinsulinemic clamps
(r = 0.74, P < 0.001) and a hyperbolic
relation to AIR1 (r =
0.63,
P < 0.001) in 169 healthy subjects. M/I was increased by 318 ± 182% after 15% (P = 0.004) and by
489 ± 276% after 25% WR (P = 0.007). The
reduction in insulin secretion was not as large as anticipated from the
increased insulin sensitivity, which resulted in an increased
disposition index (DI; AIR1 × M/I). Thus DI increased
by 95 ± 24% after 15% (P = 0.018) and by
176 ± 35% after 25% WR (P = 0.011). This
improved
-cell function correlated independently with reduced
glucose, triglycerides, and leptin and increased adiponectin levels and
was associated with a reduced proinsulin-to-insulin ratio. In contrast,
glucagon secretion was not significantly affected by WR. We conclude
that WR results in improved
-cell function when related to insulin sensitivity.
insulin secretion; glucagon secretion; obesity; glucose tolerance
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INTRODUCTION |
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DUE TO THE
CURVILINEAR RELATION between insulin sensitivity and insulin
secretion, insulin resistance, as in obesity, is compensated for by
increased insulin secretion, and, accordingly, the improved insulin
sensitivity that follows weight reduction adaptively reduces insulin
secretion (3, 7, 8, 15, 16). The relation between insulin
sensitivity and insulin secretion has been shown to be hyperbolic in
nature (16) and to be quantified by making a product of
the two variables, named the disposition index (DI; 8, 16). The
relation is of clinical importance for glucose homeostasis because, if
the islet compensation is inadequate in relation to insulin resistance,
impaired glucose tolerance (IGT) or type 2 diabetes develops (3,
7, 15, 20, 21, 23, 45). The usually observed improvement of
glucose homeostasis after weight reduction in obesity (9, 13,
35) therefore suggests that insulin secretion is not reduced as
much as anticipated by the increased insulin sensitivity. However, it
is not known whether insulin secretion is improved during weight
reduction, despite its reduction per se because of the adaptation to
the increased insulin sensitivity. Similarly, it is not clear by which
mechanism -cell function is altered during weight reduction in
regard to signals affecting
-cell function or insulin-secretory
mechanisms (3, 7, 15). In addition to insulin secretion,
glucagon has an important role in glucose tolerance, as has previously been demonstrated in subjects with type 2 diabetes and IGT, who display
increased circulating glucagon in relation to the ambient glucose level
(2, 21, 31, 37, 42). However, the extent to which changes
in glucagon secretion contribute to the improved glucose tolerance
after weight reduction in obese subjects is not known.
In view of these fundamental questions on islet function after weight
reduction in obesity, this study investigated how insulin and glucagon
secretion adapts to improvement in insulin sensitivity after
standardized massive weight reduction in severely obese subjects. To
that end, 13 morbidly obese subjects [all with body mass index (BMI)
>40 kg/m2] undergoing bariatric surgery were studied
before operation and after standardized weight reduction by 15 and
25%. For detailed analyses of islet hormone secretion, we employed the
glucose-dependent arginine stimulation test, which characterizes both
acute insulin and glucagon secretion and the glucose sensitivity of
- and
-cell secretion (3, 22, 44). From this test, a
measure of insulin sensitivity was also calculated, and in initial
studies we observed a significant linear correlation with this
measurement and insulin sensitivity as determined during a euglycemic
hyperinsulinemic clamp test.
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SUBJECTS AND METHODS |
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Subjects.
The core study was performed in 13 morbidly obese women 26-39 yr
of age (mean ± SD: 33.5 ± 4.2 yr) and without
cardiovascular diseases or impaired kidney or liver function. None of
these subjects was taking any drugs known to affect carbohydrate
metabolism; five had a family history of diabetes. All women were
Caucasian except for one with African origin. The patients were
recruited from the Division of Surgery at Danderyd Hospital to undergo
a modified Mason vertical banded gastroplasty (8 patients)
(27) or jejunoileal bypass (5 patients) (5)
with the purpose of reducing weight. The studies were performed before
and after 15 and 25% weight loss. These usually occur after 3-5
mo and ~1 yr, respectively, after bariatric surgery
(35). One patient was lost to follow-up at 25% weight
reduction. The study validating the use of the glucose-dependent
arginine stimulation test vs. the euglycemic hyperinsulinemic clamp
technique was performed in 169 healthy females aged 42-61 yr who
were recruited from a larger cohort of women in the city of Malmo,
Sweden, and who had undergone both a glucose-dependent arginine
stimulation test and a euglycemic hyperinsulinemic clamp test (3,
19, 21, 25). These were healthy subjects without diabetes or any
known history of cardiovascular, liver, or kidney diseases, and they
were not taking any medication known to affect carbohydrate metabolism. Both tests were performed after an overnight fast and with 2 wk in
between. The local ethics committees of the Karolinska Hospital, Stockholm, and Lund University, Lund, Sweden, approved the study. All
subjects gave written, informed consent before entrance in the study.
Anthropometric measurements. Body weight and height were measured with the subjects in light clothing and without shoes for calculation of BMI. Waist circumference was measured at the level of the umbilicus and hip circumference at the level of the greater trochanters. Body composition was determined with near-infrared spectrophotometry using a Futrex 5000 (Futrex, Gaithersburg, MD) (11).
Oral glucose tolerance test. An intravenous catheter was inserted into an antecubital vein, and a 75-g glucose load was given. Blood samples were taken at 0, 15, 30, 60, 90, and 120 min.
Glucose-dependent arginine stimulation test.
Insulin and glucagon secretion was determined with intravenous arginine
stimulation at three glucose levels (fasting, 14 mmol/l, and >25
mmol/l), as previously described (22, 44). Intravenous catheters were inserted into antecubital veins in both arms, and baseline samples were taken at 5 and
2 min. A maximally stimulating dose of arginine hydrochloride (5 g) was then injected intravenously over 45 s. Samples were taken at +2, +3, +4, and +5 min.
Variable-rate 20% glucose infusions were then performed sequentially
to raise and maintain blood glucose at 13-15 mmol/l and >25
mmol/l, respectively. New baseline samples were taken at these blood
glucose levels, whereafter arginine (5 g) was again injected and new
samples taken.
Euglycemic hyperinsulinemic clamp test.
Insulin sensitivity was determined with the euglycemic hyperinsulinemic
clamp, performed according to DeFronzo et al. (12). Intravenous catheters were inserted into antecubital veins in both
arms. After baseline samples were obtained, a primed constant infusion
of insulin (Actrapid 100 U/ml; Novo Nordisk, Bagsvaerd, Denmark) with a
constant infusion rate of 0.28 nmol · m body
surface area2 · min
1
was started. After 4 min, a variable-rate 20% glucose infusion was
added, and its infusion rate was adjusted manually throughout the clamp
procedure to maintain the blood glucose level at 5.0 mmol/l, as
determined bedside every 5 min. Samples for analysis of insulin were
taken at 60 and 120 min.
Analyses.
Blood glucose samples from the oral glucose tolerance test (OGTT) were
chilled at 4°C and analyzed with an automatic glucose oxidase method
at the hospital central laboratory, whereas blood glucose from the
glucose-dependent arginine stimulation test was analyzed with a glucose
analyzer (Yellow Springs Instruments, Yellow Springs, OH). Blood
samples for analysis of insulin and glucagon were immediately
centrifuged at 5°C, and plasma was frozen at 20°C until analysis
in duplicate. Plasma insulin and glucagon concentrations were analyzed
with double-antibody radioimmunoassay techniques (Linco Research, St.
Charles, MO), using guinea pig anti-human insulin antibodies, human
insulin standard, 125I-labeled human insulin, guinea pig
antiglucagon antibodies specific for pancreatic glucagon,
125I-labeled glucagon, and glucagon standard. Total
proinsulin was measured using goat antibodies raised against human
proinsulin, human proinsulin standard, and 125I-human
proinsulin as tracer (Linco). The assay detects intact proinsulin
(100%) and des-31,32 proinsulin (95%) but does not cross-react with
insulin, C-peptide, or des-64,65 proinsulin (<0.1%). Leptin was
analyzed with a double-antibody radioimmunoassay using rabbit
anti-human leptin antibodies, 125I-labeled human leptin as
tracer, and human leptin as standard (Linco). Adiponectin was analyzed
with a double-antibody radioimmunoassay using rabbit anti-human
adiponectin antibodies, 125I-labeled human adiponectin as
tracer, and human adiponectin as standard (Linco). Cholesterol and
triglycerides were analyzed using routine, standardized methods (Roche
Diagnostics), and free fatty acids (FFA) were determined
spectrophotometrically (Wako Chemicals, Neuss, Germany).
Calculations.
The acute insulin (AIR), acute proinsulin (APIR), and acute glucagon
responses (AGR) to arginine were calculated as the mean of the +2- to
+5-min samples minus the mean prestimulus hormone concentration at
fasting glucose (AIR1, APIR1, or
AGR1), at 14 mmol/l glucose (AIR2,
APIR2, or AGR2), and at >25 mmol/l glucose (AIR3, APIR3, or AGR3). Also, the
ratio between the acute proinsulin-to-insulin (PI) response after the
first arginine challenge was calculated (PI-secretory ratio). The slope
between AIR1 and AIR2
[slopeAIR = (AIR2 AIR1)/
plasma glucose] was calculated as a measure of glucose potentiation of
-cell secretion (22, 44), and
the plasma glucose level at which half-maximal insulin secretion is achieved (PG50), which is a measure of glucose sensitivity
in the
-cells (44), was calculated from
AIR3 and slopeAIR. Similarly, the slope between
AGR1 and AGR2 [slopeAGR = (AGR2
AGR1)/
glucose] was calculated
as the glucose inhibition of
-cell secretion. For estimation of
insulin sensitivity from the arginine stimulation test, the amount of
glucose infused to raise the glucose level to the target of 14 mmol/l
(M value) was divided by the insulin concentration achieved immediately
before the arginine injection (I value) (=M/I). For calculation of
insulin sensitivity from the hyperinsulinemic euglycemic clamp test,
the glucose infusion rate during the 2nd h of the clamp was divided by
the mean of the measured mean insulin concentrations at 60 and 120 min
(M/Iclamp). Previous studies estimating insulin sensitivity
and insulin secretion with the use of data derived from the minimal
model of results from an intravenous glucose tolerance test (IGTT) have
shown that a hyperbolic function is the best predictor of the relation
(16). To explore whether a hyperbolic function
characterizes the relation between insulin secretion and insulin
sensitivity with the use of data derived from the arginine stimulation
test, we calculated the logarithmic transformation of AIR1
as a function of logarithmically transformed M/I, with the expectation
that this relation is a linear function. We also plotted the residuals
of log AIR1 and AIR1 by use of the hyperbolic
and linear regressions, respectively, vs. log M/I or M/I, with the
expectation that residuals of the best fit would be randomly
distributed around zero. Because we found that the hyperbolic function
predicts the relation, we estimated DI by multiplying AIR1
times M/I.
Statistical analyses. Statistical analyses were performed with the SPSS for Windows system (SPSS, Chicago, IL). Differences in parameters before and after weight reduction were tested with Student's paired t-test. Pearson's product moment correlation coefficients were obtained to estimate linear correlations between variables. Linear stepwise forward multiple regression was used to assess the independent effect of several variables. Means ± SD or SE are shown as specified.
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RESULTS |
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Body composition, baseline values, and glucose tolerance.
Table 1 shows the characteristics of the
13 subjects before bariatric surgery and after 15.9 ± 2.1% (SD)
and 25.6 ± 5.6% weight reduction, which was reached after
4.3 ± 1.2 (SD) and 11.5 ± 2.8 (SD) mo, respectively. Figure
1 shows that glucose tolerance was
gradually improved after bariatric surgery. At baseline, two patients
were classified as having type 2 diabetes and one as having IGT. After
15% weight reduction, all fasting glucose values were normalized while
three patients had IGT, and after 25% weight reduction all patients
had normal 2-h glucose.
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Insulin and glucagon secretion.
Table 2 and Figs.
2 and 3
show the results from the glucose-dependent arginine stimulation tests.
The test identifies insulin secretion at baseline glucose
(AIR1), after rise of glucose to 14 mmol/l
[AIR2; being significantly higher (P < 0.001) than AIR1 at all three study time points], and
after rise of glucose to >25 mmol/l [AIR3; being
significantly higher than AIR2 before surgery
(P = 0.045), after 15% weight reduction
(P = 0.035), and after 25% weight reduction
(P = 0.006)]. AIR1, AIR2,
AIR3, and slopeAIR were significantly reduced
after 15 and 25% weight reduction. These various measures of insulin
secretion were altered in parallel. Thus, at 15% weight reduction,
AIR1 was reduced by 40 ± 33%, AIR2 by
41 ± 36%, AIR3 by 16 ± 26%, and
slopeAIR by 37 ± 27%. The corresponding figures
after 25% weight reduction were 39 ± 30% (AIR1),
50 ± 23% (AIR2), 39 ± 15% (AIR3),
and 42 ± 51% (slopeAIR). The PG50, i.e.,
the glucose level at which half-maximal insulin secretion is achieved,
was not significantly altered by the reduced body weight. Furthermore,
in contrast to the reduced insulin secretion, AGR1,
AGR2, AGR3, and slopeAGR did not
differ significantly after 15 or 25% weight reduction.
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Insulin sensitivity.
The use of variables obtained from the glucose-dependent arginine
stimulation test for the estimation of insulin sensitivity was
validated against the gold standard technique, the euglycemic hyperinsulinemic clamp, by performing the two tests in 169 healthy female subjects aged 42-61 yr. The measure for insulin sensitivity in the glucose-dependent arginine stimulation test was the amount of
glucose infused to reach the target of 14 mmol/l divided by the
achieved insulin concentration (M/I). Figure
4 shows that this value correlated
linearly with the measure of insulin sensitivity during the euglycemic
hyperinsulinemic clamps (r = 0.67, P < 0.001). This shows that the use of the glucose-dependent arginine
stimulation test is possible for determination of insulin sensitivity.
Table 2 shows that M/I as obtained during the glucose-dependent
arginine stimulation test was gradually increased along with the
reduction in body weight in the obese subjects, being increased by
318 ± 182% (SD) after 15% weight reduction (P = 0.004) and by 489 ± 276% after 25% weight reduction
(P = 0.007).
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Changes in insulin sensitivity vs. insulin secretion.
Figure 5 shows the relation between
AIR1 and M/I in the 169 healthy female subjects. Visual
inspection of the relation suggests a nonlinear function, which is also
supported by a hyperbolic function having a higher regression
coefficient (r = 0.63, P < 0.001)
than a linear function (r =
0.42, P < 0.001). When data were logarithmically transformed, a linear
relation between the two variables was evident, and the function was
log AIR1 = 4.05
0.88 log M/I (95% confidence
interval of slope 0.75-1.01). Because the best fit of the slope
for the regression coefficient would be near
1.0, we conclude that a
hyperbolic function results in the best fit of the relation. This was
also evident by plotting the residuals in AIR1 vs. M/I
after logarithmic transformation of the data or without any
transformation (Fig. 5). It is seen that the residuals were randomly
distributed around zero after logarithmic transformation of the data,
whereas increases in residuals in AIR1 were evident at low
and high M/I without any transformation. The hyperbolic relation
between AIR1 and M/I justifies the calculation of DI as
AIR1 times M/I, as previously established
(16). Table 2 shows that DI was significantly increased
after weight reduction. The reason for this is that there was a
disproportionately lower reduction in insulin secretion in relation to
the increased insulin sensitivity. Hence, although insulin secretion
per se was reduced after weight reduction,
-cell function was
improved.
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Proinsulin-to-insulin ratio.
Fasting plasma proinsulin levels were reduced by a larger degree than
fasting plasma insulin, resulting in a reduced fasting proinsulin-to-insulin ratio after weight reduction (Table
3). Also, the reduction in the proinsulin
response to arginine after weight reduction was more pronounced than
the reduction in the insulin response to arginine, resulting in a
significantly decreased proinsulin-to-insulin ratio after arginine
challenge after both 15 and 25% weight reduction. Thus, whereas the
insulin response to arginine at fasting glucose was reduced by 40 ± 33% (SD) after 15% weight reduction (P = 0.008)
and by 39 ± 30% after 25% weight reduction (P = 0.006), the proinsulin response to argine was reduced by 72 ± 26% after 15% weight reduction (P = 0.009) and by
85 ± 18% after 25% weight reduction (P = 0.002), which explains the increased PI-secretory ratio
(P < 0.001; Table 3).
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Relation between improved DI and changes in body composition.
There were significant correlations between DI on the one hand and body
weight, body fat mass, and waist circumference on the other hand as
well as between the increase in DI after weight reduction on the one
hand and the reduction in body weight, body fat mass, and waist
circumference after weight reduction on the other hand (all
P < 0.001). Because these measures of body composition are interrelated, a multivariate regression analysis was undertaken in
which the change in DI after 15% weight reduction (DI) was used as
the dependent variable and the corresponding changes in body weight,
waist circumference, and body fat mass were used as independent
variables. The regression showed that changes in waist, but not in the
other variables of body composition, was independently related to
changes in DI (r2 = 0.55, P = 0.008).
Factors mediating improved -cell function.
Several factors might mediate the improved
-cell function during
weight reduction in obesity. Five potential factors were evaluated in
this study: circulating glucose, triglycerides, and FFA and circulating
levels of the adipocyte-derived hormones leptin and adiponectin, which
were all altered by the weight reduction (Table 1). A multivariate
analysis with the change in DI between baseline and after 15% weight
reduction (
DI) as the dependent variable and
fasting glucose,
fasting triglycerides,
fasting FFA,
fasting leptin, and
fasting adiponectin as independent variables showed that fasting
glucose (r =
0.69), triglycerides (r =
0.72), leptin (r =
0.62), and adiponectin
(r = 0.45) all significantly and independently
contributed to
DI (P < 0.05 or less).
R2 for the model was 0.79 (P < 0.001). In contrast, changes in FFA did not correlate with improved
-cell function.
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DISCUSSION |
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Massive weight reduction by bariatric surgery improves glucose intolerance and type 2 diabetes in subjects with severe obesity (9, 13) as a result of the combination of improved insulin resistance that follows weight reduction (30) and improved islet function (7, 15). In this study, we aimed at disclosing the mechanisms underlying the improved islet function in morbidly obese subjects undergoing standardized 15 and 25% weight reduction. Because we aimed at relating the changes in insulin secretion to those in insulin sensitivity, which is required for an accurate understanding of islet function, we initially explored the use of data derived from the glucose-dependent arginine stimulation test for calculating insulin sensitivity. We therefore compared M/I data from the arginine test with the measurement of insulin sensitivity during euglycemic hyperinsulinemic clamps in 169 healthy female subjects. We found that insulin sensitivity determined by these two techniques was linearly related, with an r value of 0.67. This shows that, although a true steady state is not reached during the 20- to 25-min glucose infusion to the target of 14 mmol/l glucose and, furthermore, that although insulin is not kept constant during the test, there is a good relation between the two tests. As expected, weight reduction increased insulin sensitivity in the obese subjects because the M/I value increased by ~300% after 15% weight reduction and by ~500% after 25% weight reduction and, similarly, fasting insulin, which correlates negatively with insulin sensitivity, was reduced from >300 pmol/l before weight reduction to ~80 and 70 pmol/l after weight reduction.
The increased insulin sensitivity after weight reduction was
accompanied by reduced insulin secretion. This reduced insulin secretion is an adaptation to the improved insulin sensitivity, because
insulin secretion is inversely related to insulin sensitivity (3,
7, 8, 15, 16). However, the main finding in the study is that
the reduction in insulin secretion was quantitatively lower than was
the increase in insulin sensitivity, resulting in an increased DI. We
calculated the DI by multiplying AIR1 times M/I as obtained
from the arginine test. Such a calculation of DI has been justified by
the evidence that insulin secretion and insulin sensitivity display a
hyperbolic function, which results in a constant value when the two
parameters are multiplied. This has previously been demonstrated for
insulin secretion and insulin sensitivity as derived from minimal-model
analysis of data obtained in the IGTT (16). We show here
that AIR1 and M/I are also related to each other in a
nonlinear manner and that the relation is consistent with a hyperbolic
function. By using this approach, we found that DI was significantly
increased after both 15 and 25% weight reduction. This is equivalent
to improved -cell function, which resulted in improved glucose
tolerance. Hence, weight reduction was accompanied by a reduced insulin
secretion per se, as adjustment for the increased insulin sensitivity,
in combination with improved islet function. The improved
-cell
function was also verified by reduced proinsulin-to-insulin ratios
after weight reduction. Both baseline proinsulin and
arginine-stimulated proinsulin secretions were reduced by a larger
degree than baseline insulin and the insulin response to arginine. This
may be explained by more efficient proinsulin conversion in the
-cells, perhaps due to normalization of a pathogenic defect. An
increased proinsulin-to-insulin ratio is a sign of a defective
proinsulin conversion, which is associated with
-cell dysfunction
(24, 36, 40).
Insulin is secreted from the -cells by a glucose recognition
mechanism followed by an exocytotic mechanism releasing insulin-storing granules. The glucose-dependent arginine stimulation test discloses both of these mechanisms, because AIR1, AIR2,
and AIR3 reflect the exocytosis due to arginine
depolarizing the plasma membranes, resulting in massive inflow of
calcium (41), whereas slopeAIR reflects the
glucose potentiation of the
-cells (22). We found that
the improved insulin sensitivity after weight reduction was accompanied
by a parallel reduction in the two mechanisms. This suggests that the
signals mediating the link between insulin sensitivity and insulin
secretion target both the exocytotic and the glucose potentiation
phases. This finding in our prospective study is similar to
recent cross-sectional studies in obese women, in pregnant women, or in
subjects with polycystic ovary, where differences between subjects
exhibiting different insulin sensitivity rely on differences of both
exocytotic mechanisms and
-cell glucose potentiation (3, 4, 7,
15). In contrast, we found that the glucose sensitivity of the
-cells, i.e., the glucose level at which a half-maximal insulin
secretion is achieved, was not altered by the weight reduction. The
measure representing glucose sensitivity, PG50, is
dependent on both AIR3 and slopeAIR. Therefore, the finding that PG50 was not altered along with the
improved
-cell function after weight reduction is probably explained
by the parallel improvement in insulin-secretory capacity and glucose potentiation. However, because AIR2 and AIR3
were significantly different, we cannot be certain that
AIR3 represents maximal insulin-secretory capacity. If
AIR3 is not maximal, then it is also possible that PG50 is underestimated. Therefore, we cannot be entirely
certain that PG50 may not also have changed with weight reduction.
Several factors might explain the improved -cell function after
weight reduction. One possibility is a reduction in circulating glucose, because hyperglycemia is known to affect
-cell function deleteriously (34). In the present study, the fasting
glucose levels were reduced by ~0.8 mmol/l after 15% weight
reduction. Thus reducing the glucose load, i.e., reducing glucotoxicity
(34), may be one mechanism underlying improved
-cell
function. In addition, substrate-specific factors might contribute,
such as circulating lipids. The subjects had high circulating
triglycerides and FFA before surgery, and these levels were reduced by
weight reduction, and, furthermore, the reduction of triglycerides
correlated with increased DI. High lipids are toxic for the
-cells
(28, 29); therefore, reducing the circulating lipids may
be a second important factor underlying the improved
-cell function.
This is also supported by a previous study showing that improved
glucose metabolism after weight reduction in obese diabetic subjects is
related to reduced lipids (30).
The multivariate regression analyses including various measures of body composition showed that reduced waist circumference was the best predictor for increased DI after weight reduction. This could indicate a role of the fatty acids released from intra-abdominal fat for improvement of insulin sensitivity and insulin secretion, because it has been reported that, in dogs, insulin resistance is associated with fatty acids derived from intra-abdominal fat (38, 39). However, the reduction in FFA did not correlate with improved DI. Instead, the association between reduction in waist circumference and improvement of insulin sensitivity and insulin secretion may be dependent on hormones produced and secreted by the abdominally located adipocytes. Two of these hormones were analyzed in the present study, leptin and adiponectin. We confirm that, whereas leptin levels are reduced after weight reduction, adiponectin levels increase, as has recently been reviewed (14). We also found that leptin levels were reduced after change in body adiposity was controlled for; i.e., leptin per unit fat mass was reduced, suggesting altered regulation of its secretion rate. Leptin has previously been shown to improve insulin resistance in rats (6), and recently an inrease in insulin sensitivity has been reported after leptin administration to humans with lipodystrophy (32, 33). Furthermore, adiponectin has been shown to increase insulin sensitivity in mice (46), and in the present study we found a linear correlation between the increase in circulating adiponectin and insulin sensitivity after 15% weight reduction (r = 0.46, P = 0.012). Moreover, adiponectin-deficient mice have been shown to exhibit insulin resistance (18, 26). Regarding effects on insulin secretion, leptin in most studies inhibits insulin secretion (1, 10, 14, 17), whereas the influence of adiponectin has not yet been established. We found that changes in both of these hormones contributed independently to the improved DI after weight reduction. In fact, the multivariate regression analyses showed that reduction in fasting glucose, in fasting triglycerides, and in fasting leptin, together with the increase in fasting adiponectin, independently contributed to almost 80% of the increase in DI. This suggests that both circulating glucose and lipids as well as adipocyte-derived hormones are important for improved islet function. However, interventional studies are required to establish more direct relations between these variables and insulin secretion after weight reduction.
The glucose-dependent arginine stimulation test determines glucagon secretion (22). In subjects with diabetes, hyperglucagonemia is often prevalent, and this may underlie the hyperglycemia caused by increased hepatic glucose production (2, 21, 31, 37, 42). We found, however, that neither baseline glucagon levels nor the glucagon responses to arginine were significantly altered after 15 or 25% weight reduction. This suggests that, under these conditions, changes in glucagon secretion do not contribute to the improved glucose homeostasis.
In conclusion, this study revealed a reduced insulin secretion along
with the increased insulin sensitivity after both 15 and 25% weight
reduction but that insulin secretion was not reduced by as large a
degree as would be expected from the increased insulin sensitivity. Consequently, DI was increased along with an improved glucose tolerance. Weight reduction also reduced the
proinsulin-to-insulin ratio. The findings show that, although insulin
secretion is adaptively reduced when insulin sensitivity is increased
after weight reduction, -cell function improves.
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ACKNOWLEDGEMENTS |
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We are grateful to Prof. Lars Backman for help in recruiting the patients. We thank Lena Gabrielsson, Margaretha Persson, and Kerstin Nilsson for nursing assistance during the study, and Lilian Bengtsson for expert technical assistance in the analyses of samples.
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FOOTNOTES |
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This work was supported by grants from the Swedish Research Council (Grant nos. 6589 and 6834), the Bert von Kantzow Foundation, the Albert Påhlsson Foundation, the Novo Nordisk Foundation, the Swedish Diabetes Association, the Swedish Society for Medical Research, Lund University Hospital Research Funds, and the Faculty of Medicine, Lund University.
Address for reprint requests and other correspondence: B. Ahrén, Dept. of Medicine, Lund Univ., 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.
10.1152/ajpendo.00325.2002
Received 18 July 2002; accepted in final form 16 October 2002.
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