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Original Studies |
Departments of Obstetrics and Gynecology (C.H., E.S., E.A.R.) and Medicine (G.B.), and General Clinical Research Center (X.C.), Temple University School of Medicine, Philadelphia, Pennsylvania 19140
Address correspondence and requests for reprints to: Guenther Boden, M.D., Temple University Hospital, 3401 North Broad Street, Philadelphia, Pennsylvania 19140.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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8.9 mM with iv glucose (hyperglycemic
clamping), and ISRs were determined by deconvolution of peripheral
C-peptide concentrations using C-peptide kinetic parameters that were
obtained in every patient during late gestation and again postpartum.
Plasma insulin levels were measured by RIA with an antibody with
minimal (<0.2%) cross-reactivity with proinsulin. During late
gestation, women with GDM were more insulin resistant than nondiabetic
controls and had significantly lower ISRs (689 vs. 849
pmol/min, P < 0.05) and glucose uptake rates (30.6
vs. 49.4 µmol/kg·min, P < 0.05)
in response to hyperglycemia. Postpartum, ISRs and insulin resistance
decreased in women with GDM and controls (ISR by 43% and 43%,
respectively, and insulin resistance by 75% and 118%, respectively),
and both groups had similar ISRs (352 vs. 408 pmol/min,
nonsignificant). Women with GDM, however, continued to be more
insulin resistant than controls. In summary, patients with GDM during
late pregnancy not only had severe deficiencies in ISR but, in
addition, were more insulin resistant than controls. Postpartum,
insulin resistance and ISRs (and plasma insulin levels) improved in
both groups, and ISRs (and plasma insulin levels) were no longer
significantly different in patients with GDM and controls. Insulin
resistance, however, remained higher in women with GDM, and their
glucose uptake remained lower. We concluded that the women with GDM had
a major ß-cell defect that made it impossible for them to compensate
for their increased level of insulin resistance, which occurred during
late pregnancy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In comparison with the information on insulin resistance, information
on insulin secretion in GDM remains contradictory. For instance, some
studies have shown reduced serum insulin responses to orally or iv
administered glucose (3, 12), whereas others have reported
comparable or even higher insulin responses in women with GDM than in
nondiabetic pregnant controls (8, 10). The reason for
these discrepant results may have been the lack of reliable methods to
determine insulin secretion. In most older studies, only peripheral
venous insulin responses to a glucose challenge were measured. There
are, however, several reasons why peripheral insulin levels are not a
good reflection of insulin secretion. First, 50% of insulin
secreted by the pancreas is metabolized on first pass through the liver
(13) and insulin, which escapes hepatic degradation, is
diluted in the peripheral circulation. Second, plasma insulin levels
are the result of insulin secretion and clearance. Insulin clearance
has been reported to be different in women with GDM than in normal
pregnant women (10, 14). Hence, changes in plasma insulin
levels may not always accurately reflect insulin secretion. Finally,
most insulin RIAs in the past have used antibodies that cross-reacted
strongly with proinsulin. This may be important because proinsulin
secretion has been reported to be elevated in patients with GDM
(15). Currently, the best method to determine prehepatic
insulin secretion noninvasively is based on deconvolution of peripheral
venous C-peptide concentrations using individually determined C-peptide
kinetic parameters (16, 17, 18). In the current study, we have
used this method to determine insulin secretion prospectively in women
during the third trimester of pregnancy and again postpartum. Blood
glucose was clamped at a moderately elevated level (8.9
mM) in all studies to assure that all women were exposed to
the same glycemic stimulation, and serum insulin was measured with an
antiserum that did not significantly cross-react with proinsulin.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eight healthy pregnant, glucose-tolerant women and seven women
with GDM were studied. The women’s age, weight, height, and body
composition are shown in Table 1
. None of
the women in the control group had a history of gestational diabetes or
a family history of type 2 diabetes or other endocrine problems. All
eight control subjects had a normal 100-g, 3-h oral glucose tolerance
test (OGTT; Fig. 1). GDM was diagnosed in
seven women during the late second or early third trimester of
pregnancy using the criteria of Carpenter and Coustan
(19). All GDM women were reevaluated postpartum when they
had normal oral glucose tolerance (Fig. 1). One of seven women with GDM
took birth control pills during the postpartum period. The studies were
approved by the Temple University Hospital Institutional Review Board,
and informed consent was obtained from each subject before study
participation.
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All women were studied in the General Clinical Research Center
of Temple University Hospital. They were studied during the third
trimester of pregnancy and again 3 months postpartum, when none of the
women were lactating. During the studies, the women were reclining in
bed. A short polyethylene catheter was inserted into an antecubital
vein for infusion of test substances. Another catheter was placed into
a contralateral forearm vein for blood sampling. This arm was kept at
70 C with a heating blanket to arterialize the venous blood. At
1800 h, all subjects received their last meal consisting of
55% carbohydrate , 30% fat, and 15% protein. After an
overnight fast (at 0800 h) a 5.5-h hyperglycemic clamp was
performed.
Methods and procedures
Hyperglycemic clamps. Plasma glucose concentrations were
raised to 8.9 mM and maintained at that level for
5.5 h in all subjects by a variable rate glucose infusion with
20% glucose. Blood glucose concentrations were determined every 15–30
min with a Beckman Coulter, Inc. glucose analyzer (Palo
Alto, CA), and the glucose infusion was adjusted accordingly.
C-peptide kinetic studies. On the day preceding the hyperglycemic clamps after an overnight fast, a 50-nmol iv bolus of biosynthetic human C-peptide (Eli Lilly & Co., Indianapolis, IN) was administered to each subject and plasma C-peptide concentrations were measured at frequent intervals for 3 h, as described by Polonsky et al. (16) and Van Cauter et al. (18).
Insulin secretory rates. The C-peptide kinetic parameters were used to calculate the insulin secretion rates (ISRs) for each time interval between successive blood samples during the hyperglycemic period by deconvolution of peripheral C-peptide concentration according to Eaton et al. (17) and Polonsky et al. (16). Plasma volume was assumed to be 50% higher in pregnant than in nonpregnant women (4.1% of ideal body weight plus 1% of excess body weight) (20).
Glucose utilization. Glucose utilization was estimated by using the glucose infusion rates (GIRs) needed to maintain the hyperglycemic clamps.
Analytical procedures. Plasma glucose was measured with a glucose analyzer with the glucose oxidase method, and serum insulin was determined by RIA with a specific antibody that cross-reacts only minimally (<0.2%) with proinsulin (Linco, St. Charles, MO). C-peptide was determined by RIA.
Statistical analysis. All data are expressed as means ± SE. Statistical significance was assessed using ANOVA and the two-tailed Student’s t test, when indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Basal (preclamp) plasma glucose concentrations during pregnancy
and postpartum were 4.7 ± 0.2 and 5.2 ± 0.2 mM
in controls and 5.1 ± 0.2 and 5.7 ± 0.3 mM in
patients with GDM, respectively. The differences were not statistically
significant. In all four studies, plasma glucose concentrations were
clamped at 8.9 ± 0.5 mM (coefficient of variation,
5.8%) (Fig. 2).
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Plasma C-peptide
There were no significant differences in basal plasma C-peptide
levels either between the two study groups or be- tween the two
study periods. During hyperglycemia, C-peptide levels were
significantly higher during late gestation than postpartum in women
with GDM (4.9 ± 0.3 vs. 3.3 ± 0.2
nM, P < 0.05) and in controls
(5.8 ± 0.3 vs. 3.7 ± 0.2
nM, P < 0.05) (Table 2).
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Basal ISRs were similar in patients with GDM and controls
during late pregnancy (133 ± 20 vs. 143 ± 16
pmol/min) and postpartum (76 ± 9 vs. 81 ± 13
pmol/min). In both groups, basal ISR were 75% higher during late
pregnancy than postpartum (Table 2
). During hyperglycemia, the ISR in
late pregnancy was 19% less in patients with GDM than in controls
(689 ± 77 vs. 849 ± 52 pmol/min,
P < 0.05), whereas postpartum, ISRs were similar in
patients with GDM and controls (408 ± 47 vs. 352
± 44 pmol/min, NS) (Table 2 and Fig. 2).
C-peptide clearance
The half-life of disappearance (t1/2) during pregnancy was
40.6 ± 5.8 min in healthy controls and 31.2 ± 2.7 min in
women with GDM (P = 0.18). During the postpartum
period, t1/2 was 37.8 ± 6.7 min for healthy controls and
49.3 ± 11.5 min for women with GDM (P = 0.41)
(Fig. 3).
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Basal serum insulin levels were not significantly higher in patients with GDM than in controls during late pregnancy (36 ± 12 vs. 66 ± 18 pM, NS) and postpartum (42 ± 12 vs. 78 ± 42 pM, NS).
During hyperglycemia, serum insulin concentrations were significantly
lower postpartum than during late gestation in patients with GDM
(318 ± 84 vs. 564 ± 132
pM, P < 0.05) and in controls
(348 ± 60 vs. 672 ± 138
pM, P < 0.05). However, there
were no significant differences in serum insulin levels comparing GDM
and controls either during late gestation or postpartum (Table 2 and
Fig. 2).
Glucose uptake
GIRs, reflecting insulin plus glucose-stimulated glucose uptake,
were significantly higher in controls than in patients with GDM, during
late gestation (49.4 ± 3.3 vs. 30.6 ± 3.9
µmol/kg·min, P < 0.001) and postpartum (50.6
± 8.9 vs. 32.8 ± 6.7 µmol/kg·min,
P < 0.03). Within groups, GIRs were similar during
late gestation and postpartum (Table 2 and Fig. 4).
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The ratio between stimulated glucose uptake (GIR) during the last
hour of the clamp and peripheral venous insulin concentrations (during
the last hour of the clamp) was used as an index of insulin sensitivity
(ISI). The ISI was 27% lower in patients with GDM than in controls
during late pregnancy (0.08 ± 0.02 vs. 0.11 ±
0.03, P < 0.03) and 42% lower postpartum (0.14
± 0.03 vs. 0.24 ± 0.11, P < 0.03).
Postpartum, the ISI increased 2.6-fold in controls and 1.75-fold in
patients with GDM (Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We found that women with GDM during late pregnancy had a rather large
ß-cell defect. Their ISRs in response to moderate hyperglycemia
(8.9 mM) were reduced not only compared with controls
(i.e. in absolute terms) but also relative to their degree
of insulin resistance. In addition, these women were more insulin
resistant than the pregnant nondiabetic controls. To maintain normal
glucose uptake, they would have needed much higher ISRs than controls.
This is so because the relationship between insulin sensitivity and
insulin secretion is hyperbolic (21), and, therefore,
disproportionally more insulin is needed to compensate for decreasing
insulin sensitivity.
Following delivery, ISRs decreased (by 40%) in both groups and
the ISR was no longer significantly different in controls and in women
with GDM (Fig. 2). It needs to be emphasized, however, that postpartum
ISRs in women with GDM did not become normal, because these women
continued to be more insulin resistant than the controls. The reason
why ISRs improved (relative to controls) may have been that the
postpartum decrease in insulin resistance, which decreased ISRs from
700–800 to 350–400 pmol/min, allowed their ß cells to function
better at this reduced level. Thus, our data suggested that women with
GDM had an underlying ß-cell defect that became evident during late
gestation under the stress of high insulin resistance and hyperglycemia
and was less visible postpartum when the stress of insulin resistance
had decreased.
To the best of our knowledge, there are no other published data comparing ISRs (as measured by deconvolution of individually obtained peripheral C-peptide concentrations) in women with GDM and controls during and after pregnancy. Hence, it was not known whether prehepatic insulin secretion was reduced in GDM compared with pregnant controls and, if so, by how much. Several investigators have reported reduced first phase insulin responses to iv or oral glucose or to mixed meals (3, 4, 22, 23) in GDM compared with nondiabetic pregnant controls. Others have found no significant differences (4, 6). The reason for these discrepancies may have been methodological (i.e. modest reductions in ISRs did not result in reduced peripheral serum insulin levels for the reasons outlined before). In fact, in the current study, serum insulin concentrations were also not significantly different in women with GDM compared with controls, although there was a trend for their stimulated insulin levels to be lower.
Recently Kautzky-Willer et al. (8) have evaluated ß-cell function in patients with GDM and in nondiabetic pregnant controls during iv and oral glucose challenges by estimating insulin secretion and sensitivity using minimal model calculations. They found that during late gestation, patients with GDM were more insulin resistant and secreted more insulin than nondiabetic pregnant controls. The difference between their and our findings (increased vs. reduced prehepatic ISRs) could have been be due to differences in the patients studied (Kautzky et al. studied lean women; we studied obese women with GDM) or they may have been due to the different methods used to determine insulin secretion (minimal model approach vs. deconvolution of C-peptide levels).
Serum insulin concentrations during late pregnancy were slightly (but
nonsignificantly) lower during the last hour of the clamps (564
vs. 672 pM, NS) in women with GDM than
in controls and decreased postpartum by 40–50% in women with GDM and
controls. Thus, ISRs and serum insulin changed proportionally, and,
hence, there was no evidence for significant effects of either
pregnancy or of GDM on insulin clearance (Fig. 3). This is in agreement
with most (24, 25, 26), but not all, previous reports
(10, 14). It should be pointed out, however, that ISRs
(needed to calculate clearance rates) were not available in any of the
previous reports.
Insulin sensitivity was estimated using an ISI (GIR divided by the
ambient serum insulin concentration). The results suggested that women
with GDM during late pregnancy were 30–40% less insulin sensitive
than controls. Postpartum insulin sensitivity improved 2-fold in
both groups, but women with GDM remained 40% more insulin resistant
than controls. These values must be considered approximations because
insulin sensitivity was not measured directly and the GIR, which was
used to calculate the ISI, may have underestimated true glucose uptake
by 10–15%. The reason for this is that endogenous glucose
production was probably not completely suppressed at the prevailing
serum insulin concentrations (600–720 pM). We do believe,
however, that our conclusion (i.e. that women with GDM were
more insulin resistant than controls) was correct because there is good
evidence that insulin-mediated suppression of endogenous glucose
production is normal in patients with mild type 2 diabetes (such as the
women with GDM in this study) (27), and, thus,
underestimation of glucose uptake occurred equally in both groups and
both study periods. The fact that the two groups were not ideally
matched for weight (women with GDM tended to have higher body mass
indices than controls, although the differences were not significant)
may have contributed to their differences in insulin sensitivity. On
the other hand, to the extent that the women with GDM may have excreted
glucose in the urine (which was not measured), we may have
overestimated their GIRs and underestimated their insulin
resistance.
Our results are in agreement with the original report of Ryan et
al. (2). They are also compatible with the concept
that some, and perhaps most, patients with GDM have a component of
insulin resistance that precedes their pregnancy (28, 29).
It seems unlikely that a significant part of the differences in glucose
utilization observed during pregnancy can be attributed to the fetal
component for the following reason. At the end of the third trimester,
the fetal weight was 4% of the weight of the mother (3.6
vs. 93 kg). Even if one assumes that the fetal tissues were
completely unresponsive to insulin, the fetus could have only
contributed a trivial amount (perhaps 5%) to the increase in
insulin resistance observed in late gestation.
GDM is considered a prediabetic state because of its high conversion
rate to type 2 diabetes (30, 31). We have recently
demonstrated abnormal ß-cell function in another group of prediabetic
subjects, namely in first-degree relatives of patients with type 2
diabetes (32). ß-cell abnormality in these individuals
became apparent only after 20 h of hyperglycemia (8.9
mM). The fact that ß-cell failure in women with GDM
became evident much earlier (after 3–4 h of hyperglycemia) suggested
that the ß-cell defect in these women was more severe than that in
the first-degree relatives.
In summary, we found that during late pregnancy women with GDM were insulin resistant and had defective insulin secretion in response to moderate hyperglycemia. This suggested that GDM resulted from a failure of ß cells to compensate for the increase in insulin resistance that occurred during late gestation. Postpartum, insulin resistance and insulin secretion improved and insulin secretion was no longer significantly different in women with GDM and controls. This suggested that the decrease in insulin resistance that occurred postpartum reduced the demand on insulin secretion and allowed ß cells to function more normally despite a persistent ß-cell defect.
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Acknowledgments |
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Footnotes |
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Received April 3, 2000.
Revised August 29, 2000.
Accepted September 12, 2000.
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References |
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,
P < 0.03 comparing third trimester and postpartum.