Pancreatic B-Cell Defects in Gestational Diabetes: Implications for the Pathogenesis and Prevention of Type 2 Diabetes
Thomas A. Buchanan
University of Southern California School of Medicine, Los Angeles,
California 90089
Address correspondence and requests for reprints to: Thomas A. Buchanan, M.D., University of Southern California School of Medicine, 6602 General Hospital, 1200 North State Street, Los Angeles, California 90089. E-mail: buchanan{at}hsc.usc.edu
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Introduction
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Type 2 diabetes mellitus (T2DM) is characterized
by hyperglycemia that results from tissue resistance to the
glucose-lowering effects of insulin and inadequate pancreatic B-cell
compensation for that resistance (1). Longitudinal studies
of people at risk for T2DM reveal that insulin resistance is often
present years before the onset of hyperglycemia (2, 3, 4).
Studies of the evolution of diabetes during a relatively short period
(i.e. 57 yr) before the diagnosis in Mexican Americans and
Pima Indians have revealed that: 1) poor B-cell function and insulin
resistance precede and predict the development of diabetes (4, 6); and 2) the progression from normal glucose tolerance to
diabetes is attended by a decline in B-cell function and an increase in
insulin resistance (6). These findings indicate that
insulin resistance and B-cell dysfunction both occur in people who
develop T2DM. They do not reveal whether declining B-cell function is
an independent event that is simply coincident with insulin resistance
in some members of the population or whether the two abnormalities are
causally linked. Here, I will develop the theme that insulin resistance
causes B-cell dysfunction in susceptible individuals, using information
from women who are at increased risk for T2DM by virtue of a clinical
diagnosis of gestational diabetes.
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Assessing B-cell function in vivo: the importance of insulin
resistance
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B-cell function can be assessed by quantifying insulin responses
to nutrients or by characterizing the composition of the peptide mix
released by B-cells (e.g. proinsulin to insulin ratios)
(7), or temporal patterns of insulin release
(e.g. pulsatility; Refs. 8 and 9).
Relatively little work has been done on the latter two areas in women
with gestational diabetes mellitus (GDM). Some investigators
have reported an increase in the ratio of proinsulin to insulin in the
circulation of women with GDM (10). Others have failed to
find such a difference (11). Here, the focus will be on
B-cell function as assessed by quantitative insulin responses to
nutrients.
In 1981, Bergman et al. (12) proposed that
there is a predictable relationship, in the shape of a rectangular
hyperbola, between the quantity of insulin produced by B cells and the
sensitivity of tissues to the glucose-lowering effects of that insulin.
Kahn et al. (13) demonstrated that such a
relationship is present across a wide range of insulin sensitivity in
people with normal glucose tolerance. We found a hyperbolic
relationship between insulin sensitivity and several measures of B-cell
insulin release in women with impaired glucose tolerance
(14). The amount of insulin released at a given level of
insulin resistance is lower in people with abnormal compared with
normal glucose tolerance (15).
The general concept of hyperbolic relationships between insulin
sensitivity and B-cell insulin release is depicted in the left
panel of Fig. 1
. Each curved
line (hyperbola) represents an isobar of B-cell compensation for
ambient insulin resistance. Individuals whose sensitivity-secretion
relationships lie on the same line have the same level of B-cell
compensation. To the extent that insulin sensitivity and insulin
release are the main determinants of glycemia, individuals on the same
line will also have the same or very similar plasma glucose levels and
glucose tolerance. People whose B-cell function worsens over time
should move from a more favorable to a less favorable
sensitivity-secretion relationshipmovement down and to the left
in Fig. 1
. Longitudinal studies in Pima Indians indicate that such
movement (i.e. increasing insulin resistance with decreasing
B-cell function; Ref. 6) does occur over the course of
years during progression from normal glucose tolerance to T2DM.

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Figure 1. Left, Schematic
representation of hyperbolic relationships between insulin sensitivity
and insulin secretion in groups with different levels of glycemia.
Right, Expected and observed insulin secretion in two
groups of individuals with normal or impaired glucose tolerance.
Differences in insulin sensitivity predict differences in insulin
secretion. Insulin secretion is the same in the two groups, indicating
a large B-cell defect in the group with impaired glucose tolerance.
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The right panel of Fig. 1
demonstrates the pitfalls that may
be encountered when comparing quantitative aspects of B-cell function
between individuals or groups with different levels of insulin
sensitivity. Two groups that differ in their degree of insulin
resistance should also differ in quantitative B-cell responses to
glucose or other nutrients. If they fail to do so, as is true for the
groups depicted in the right panel of Fig. 1
, then they have
different B-cell function (i.e. different compensation for
ambient insulin resistance). The best way to compare B-cell function
between such groups in a quantitative fashion is to determine whether
their sensitivity-secretion relationships are on the same or different
hyperbolic lines. Taking advantage of the mathematical formula of a
rectangular hyperbola (y = x * k, where y = insulin release,
x = insulin sensitivity and k = constant), Bergman (12, 16) proposed the product of insulin sensitivity and insulin
secretion (the "disposition index") as a measure of B-cell
compensation for insulin resistance, perhaps the most important
quantitative measure of B-cell function in vivo. Note that
the disposition index will be the same for individuals whose
sensitivity-secretion relationships lie on the same hyperbola, but
different for individuals or groups whose relationships lie on
different hyperbolae. The "take home" message is that valid
cross-sectional comparisons of B-cell function can be obtained only
when individuals or groups are matched for their degree of insulin
resistance or when the expected impact of any differences in insulin
resistance on B-cell function are taken into account.
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Insulin resistance in women with GDM
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Cross-sectional studies. Pregnancy induces progressive insulin
resistance (17, 18, 19) that is quite severe by the third
trimester, approaching the degree of resistance seen in nonpregnant
people with type 2 diabetes (16). If this acquired
resistance were to be the same in all individuals, it would create a
background on which B-cell function could be compared between women
with and without GDM simply by quantifying their circulating insulin
responses to nutrients. Whether women with and without GDM truly have
the same degree of insulin resistance in late pregnancy has been the
subject of several studies that have come to different conclusions. The
different conclusions can be explained, in large part, by differences
in subject selection, methodology, and sample size. Ryan et
al. (17) demonstrated that women with GDM and overt
fasting hyperglycemia had lower insulin sensitivity in the third
trimester compared with pregnant women with normal glucose tolerance.
They used hyperinsulinemic, euglycemic clamps to measure insulin
sensitivity and studied only five women in each group. The marked
hyperglycemia in their patients and the accuracy of the clamp
methodology likely accounted for their finding of greater insulin
resistance in women with GDM despite the small sample size. Our group
(18), using an early version of the frequently sampled iv
glucose tolerance test (FSIGT)-minimal model approach, and Catalano
et al. (19), using euglycemic clamps, failed to
find significant differences in insulin sensitivity between relatively
small groups of women with and without mild GDM in the third trimester.
The FSIGT protocol that we used was not sensitive enough find small
differences in insulin sensitivity. The sample sizes in both studies
were too small to provide good statistical power. Indeed, insulin
sensitivity in the study of Catalano et al.
(19) was 22% lower in the women with GDM, but the
difference was not statistically significant. We (15)
subsequently used a more sensitive FSIGT protocol and glucose clamps to
demonstrate small but significant reductions in insulin sensitivity in
150 Hispanic women with GDM compared with a smaller number of
well-matched pregnant controls in the third trimester. Kautzky-Willer
et al. (20) and Homko et al.
(21) have also reported greater insulin resistance in late
pregnancy in women with mild gestational diabetes compared with normal
pregnant women. Taken together, these studies indicate that women with
GDM have greater insulin resistance during late pregnancy than women
without the disease, but that the difference is small unless the women
with GDM have marked hyperglycemia.
Several studies conducted in nonpregnant women with a history of GDM
have revealed greater insulin resistance compared with nondiabetic
women with no such history (20, 21, 22, 23, 24, 25). Likewise, one study
of women with and without GDM early in the second trimester, before the
acquired insulin resistance of pregnancy becomes severe, revealed
greater insulin resistance in women with GDM (20). The
magnitude of these differences in insulin action have generally been
greater than the small differences reported in the third trimester.
This concept is best demonstrated by studies of the same patients
during the third trimester and either before (19) or after
(21) pregnancy (Fig. 2
).
Insulin sensitivity is consistently higher outside of pregnancy than in
the third trimester, whether subjects are normal or have GDM. However,
the difference between late pregnancy and the nonpregnant condition is
greater in the women who did not have GDM. This pattern indicates that
women who develop GDM have chronic insulin resistance compared with
normal women. The difference between groups is relatively large and
easy to detect outside of pregnancy. It is masked partially, but not
completely when both groups acquire a high degree of insulin resistance
in late pregnancy.

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Figure 2. Insulin sensitivity in women studied in the
third trimester and when not pregnant. Left, Insulin
sensitivity assessed as steady-state glucose requirements during
physiologic hyperinsulinemia (mg/min per kg fat-free mass; Ref.
19 ) Right, Insulin sensitivity assessed as
the ratio of glucose disposal rate to plasma insulin during
steady-state hyperglycemia (21 ).
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B-cell function in women with GDM
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Studies of B-cell function in pregnant women with GDM were
conducted using various methodologies long before direct measures of
insulin sensitivity were performed during pregnancy
(26, 27, 28, 29). All of those early studies revealed lower
insulin responses to glucose compared with pregnant women without GDM.
The B-cell defects were relatively easy to detect, presumably because
normal and gestational diabetic women did not differ very much in their
degree of insulin resistance (see above). In other words, pregnancy
comes close to matching insulin resistance between those two groups,
making the B-cell defect in women with GDM very easy to detect by
direct comparisons of insulin responses to nutrients. However, to the
extent that women with GDM are slightly more insulin resistant than
normal pregnant women, the magnitude of the B-cell defects in GDM may
be underestimated by such comparisons. Indeed, we found that insulin
responses to oral and iv glucose were 34% and 27% lower in Hispanic
women with GDM than in a matched group of normal pregnant women. When
the insulin responses were corrected for small differences in insulin
sensitivity using the disposition index (vide supra) the defects proved
to be larger, 63% and 70%, respectively (15).
When the acquired insulin resistance of pregnancy abates after
delivery, underlying differences in B-cell function become more
difficult to detect by direct comparisons of insulin levels or
responses to nutrients. Although this observation has been interpreted
by some (21) to mean that the B-cell defect in women with
GDM is only present during pregnancy, such is not the case. Instead,
the defect is easily detectable in both settings when insulin
sensitivity-secretion relationships are considered, as shown in Fig. 3
using data from Homko et al.
(21). It can be seen that normal and gestational diabetic
women regulate insulin secretion on two distinct hyperbolae. Women with
GDM consistently manifest lower insulin responses for their degree of
insulin resistance. During pregnancy, when insulin resistance is nearly
matched in the two groups, insulin responses to fixed hyperglycemia
(i.e. during a hyperglycemic clamp) were clearly lower in
the women with GDM. After pregnancy, when the abatement of acquired
insulin resistance unmasked the larger difference in chronic insulin
resistance between the two groups, insulin responses to fixed
hyperglycemia were of similar magnitude. However, the responses
remained inappropriately low for the degree of insulin resistance in
women with prior GDM. In fact, when B-cell function was assessed using
the product of insulin sensitivity and secretion, the B-cell defect in
women with GDM was of approximately the same magnitude during and after
pregnancy (41% and 50%, respectively). These findings highlight the
importance of assessing B-cell function in relation to ambient insulin
sensitivity.

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Figure 3. Insulin sensitivity-secretion relationships
in normal women and women with GDM. The insulin sensitivity index is
shown in Fig. 2 , right. Prehepatic insulin secretion was
assessed during steady-state hyperglycemia using plasma insulin and
C-peptide concentrations and C-peptide kinetics in individual patients
(21 ).
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The results in Fig. 3
demonstrate another important characteristic of
B-cell function in women with GDMthe ability to adapt to changes in
insulin sensitivity. Within each of the GDM and control groups, B cells
altered their responses to insulin resistance to maintain a constant
degree of compensation, albeit at different levels in the two groups.
Because B-cell function was assessed as prehepatic insulin secretion
rates under conditions of matched hyperglycemia, the B-cell
"autoregulation" cannot be explained by changes in hepatic insulin
clearance or glycemic signals to B cells. We have observed an analogous
phenomenon in nonpregnant women with impaired glucose tolerance and a
history of GDM (14). When treated for 3 months with the
insulin-sensitizing drug troglitazone, the women reduced
early insulin responses to oral glucose and total insulin responses to
iv glucose nearly proportionally to the amount of increase in insulin
sensitivity. As a result, insulin levels fell while oral and iv glucose
tolerance did not change significantly. Thus, in response to relatively
short-term changes in insulin sensitivity, B cells of women with GDM
can reduce or increase their insulin output to maintain nearly constant
compensation for insulin resistance at a level that is reduced
(i.e. a lower disposition index) compared with normal
women.
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Implications for the pathogenesis and prevention of type 2 diabetes
after GDM
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At first glance, the presence of insulin resistance and impaired
B-cell compensation for that resistance in women with GDM is not
surprising; similar defects have been reported in other people with
abnormal glucose tolerance. However, unlike those other groups, women
with GDM are first identified as having abnormal glucose tolerance in a
setting where everyone has marked insulin resistancelate pregnancy.
It is easy to understand how this setting could allow the detection of
women with limited B-cell reserve. However, simple unmasking of limited
B-cell reserve by the insulin resistance of pregnancy cannot explain
the presence of chronic insulin resistance in women who have had GDM
unless their B-cell defect and insulin resistance are linked
somehow. The presence of chronic insulin resistance in women whose
B-cell defect is first detected under conditions of acquired insulin
resistance (i.e. pregnancy) led us to postulate that the
B-cell defect is caused by chronic insulin resistance. Women who are
unable to mount a robust B-cell response during pregnancy have
developed that defect as a result of years of exposure to chronic
insulin resistance. Additional insulin resistance should worsen B-cell
function in such women; amelioration of insulin resistance should
stabilize or improve the B-cell defect.
To test our hypothesis, we administered the insulinsensitizing
drug troglitazone to women with prior GDM in the
troglitazone in the Prevention of Diabetes (TRIPOD) study
(30). Women who received the drug had a 56% reduction in
the incidence of T2DM compared with women who received placebo during a
median follow-up period of 30 months. Most importantly, protection from
diabetes during troglitazone treatment was most closely
related to the degree to which an increase in insulin sensitivity in
the first 3 months on trial resulted in a reduction in the amount of
insulin required to maintain stable glucose tolerance (Buchanan, T.,
unpublished observation). In other words, reducing secretory demands
placed on B cells by chronic insulin resistance greatly reduced the
risk of deterioration to diabetes during a 30-month period. This
observation provides strong support for the concept that insulin
resistance causes, or at the very least contributes to, the poor B-cell
function in women with prior GDM. It also provides strong rationale for
focusing on B-cell rest when developing and testing strategies for the
prevention of T2DM.
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Summary and issues for future investigation
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Poor B-cell compensation for insulin resistance has been found in
women with GDM from many ethnic groups, suggesting that B-cell
dysfunction is a common, if not universal, feature of GDM. Chronic
autoimmunity directed at B cells is one mechanism that may contribute
to B-cell failure in GDM, perhaps even in the absence of chronic
insulin resistance. However, evidence for such autoimmunity is present
in only a small minority of patients (31, 32, 33). Mechanisms
that lead to B-cell failure in the majority of women remain to be
identified. The frequent occurrence of chronic insulin resistance in
women who have or had GDM suggests that the propensity for B-cells to
fail in the presence of insulin resistance may be a common feature of
the disease. The same mechanism may be involved in progression from GDM
to T2DM and in the pathogenesis of T2DM in general. Our studies of
women with GDM suggest that amelioration of insulin resistance may be a
critical step in preventing progressive B-cell failure and T2DM in
women with GDM.
Important questions remain to be addressed. T2DM is a heterogeneous
disorder, and methods need to be developed to identify the spectrum of
people who will be protected from diabetes by amelioration of insulin
resistance. Fundamental to this process will be elucidation of the
biochemical and genetic determinants that lead to B-cell failure in
insulin-resistant individuals. Animal studies suggest overproduction of
islet amyloid polypeptide (34, 35) and susceptibility to
toxic effects of glucose (36) and fatty acids
(37) may be involved. Whether these mechanisms account for
B-cell failure in the pathogenesis of human T2DM is unknown.
Identification of the genes that impart susceptibility for B-cell
failure in the face of insulin resistance may be required for full
understanding of the mechanism(s) involved. Precise knowledge of
mechanisms that lead to B-cell failure may also help to identify
optimal interventions to prevent diabetes. It will be important to
learn whether amelioration of insulin resistance is the best way to
"rest" B cells, or whether other methods (38) may work
as well. It will also be important to learn whether there is a
threshold of insulin sensitivity above which the development of
diabetes is very unlikely and whether there is a stage in the
development of T2DM after which it is too late to protect B cells by
reducing insulin resistance. Answers to these questions will require a
multidisciplinary approach that spans basic and clinical investigation.
Women with GDM are an excellent population in which to conduct the
clinical components. Pending accurate answers to these questions, it
seems prudent to promote measures that will lessen insulin resistance
in all women who have had GDM, particularly if they show signs of
increasing glucose levels that herald the development of diabetes
(39).
Received December 19, 2000.
Accepted December 19, 2000.
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