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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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. 5–7 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.


    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. 1Go. 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 relationship—movement down and to the left in Fig. 1Go. 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.

 
The right panel of Fig. 1Go 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. 1Go, 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.


    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. 2Go). 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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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. 3Go 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. 2Go, 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 ).

 
The results in Fig. 3Go demonstrate another important characteristic of B-cell function in women with GDM—the 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.


    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 resistance—late 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.


    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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