Gestational Diabetes During and After Pregnancy

8. What Causes Gestational Diabetes?

Thomas A. Buchanan  and Anny H. Xiang

(1)

Departments of Medicine, Obstetrics and Gynecology, and Physiology and Biophysics, Keck School of Medicine, University of Southern California, 1500 San Pablo Street, Los Angeles, CA 90033, USA

Thomas A. Buchanan

Email: buchanan@usc.edu

Abstract

This plasticity of β-cell function in the face of progressive insulin resistance is the hallmark of normal glucose regulation during pregnancy. Like other forms of hyperglycemia, GDM is characterized by an insulin supply that is insufficient to meet the body’s insulin needs. The causes of an insufficient insulin supply reflect the causes of hyperglycemia in general, including autoimmune disease, monogenic causes, and insulin resistance. GDM represents detection of chronic β-cell dysfunction, rather than development of relative insulin deficiency, as insulin resistance increases during pregnancy. The abnormalities are frequently progressive, leading to rising glucose levels and, eventually, to diabetes mellitus. Thus, GDM can be viewed largely as diabetes in evolution that is detected during pregnancy.

8.1 Introduction

Gestational diabetes mellitus (GDM) is hyperglycemia that is first detected during pregnancy. Like other forms of hyperglycemia, GDM is characterized by an insulin supply that is insufficient to meet the body’s insulin needs. The causes of an insufficient insulin supply reflect the causes of hyperglycemia in general, including autoimmune disease, monogenic causes, and insulin resistance. The hyperglycemia that characterizes GDM is often, although not always less severe than the hyperglycemia that defines diabetes outside of pregnancy. Thus, GDM often represents an early manifestation of diabetes in evolution. As such, GDM provides an opportunity to study diabetes in evolution to develop and test strategies for diabetes prevention.

8.2 Detection: Population Screening for Glucose Intolerance

The clinical detection of GDM is generally accomplished by applying one or more of the following procedures: (a) clinical risk assessment, (b) glucose tolerance screening, and (c) formal glucose tolerance testing. The procedures are applied to pregnant women not already known to have diabetes. Criteria used to make the diagnosis vary from region to region, but may soon be standardized as a result of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study,1 a chapter on which appears in this book. Importantly, GDM screening is one of the very few times when glucose intolerance is assessed in a large number of otherwise healthy individuals. Screening identifies relatively young individuals whose glucose levels are in the upper end of the population distribution during pregnancy. A few of those women have glucose levels that would be diagnostic of diabetes outside of pregnancy. The remainder have lower glucose levels, but are nonetheless at high risk for developing worsening hyperglycemia and diabetes after pregnancy.

8.3 Glucose Regulation in Pregnancy and GDM

Pregnancy is normally attended by progressive insulin resistance. It begins near mid-pregnancy and progresses through the third trimester to levels that approximate the insulin resistance seen in type 2 diabetes. The insulin resistance of pregnancy may result from a combination of increased maternal adiposity and the insulin-desensitizing effects of placental products such as human placental lactogen,2placental growth hormone,34 and tumor necrosis factor alpha.5 Studies by Friedman et al6 indicate that, at the cellular level in skeletal muscle, the insulin resistance of pregnancy results from multiple changes in the insulin signaling pathway starting with impaired activation of the insulin receptor by insulin. Women with GDM have additional changes (e.g., serine phosphorylation of insulin receptor substrate-1) that downregulate insulin signaling in a manner typically seen in obesity.

Pancreatic β-cells normally increase their insulin secretion to compensate for the insulin resistance of pregnancy. As a result, changes in circulating glucose levels over the course of pregnancy are quite small compared to the large changes in insulin sensitivity. This plasticity of β-cell function in the face of progressive insulin resistance is the hallmark of normal glucose regulation during pregnancy.

GDM results from an endogenous insulin supply that is inadequate to meet tissue insulin demands. It has long been thought and taught that GDM occurs in women who are not able to increase their insulin supply as demands rise during pregnancy. Serial studies of insulin sensitivity and secretion during and after pregnancy in normal women, and in women with GDM (Fig. 8.1) now reveal this assumption to be false. The curved lines in Fig. 8.1 represent reciprocal relationships between insulin sensitivity and insulin secretion, reflecting β-cell compensation for insulin resistance as described by Bergman.7 In normal women, insulin secretion moves along one curve as insulin sensitivity changes. Women with GDM move as well, but along a curve that reflects lower secretion for any degree of insulin sensitivity.

A160858_1_En_8_Fig1_HTML.gif

Fig. 8.1

Left panel: Relationships between pre-hepatic insulin secretion rates and insulin sensitivity measured during steady-state hyperglycemia (3-h, 180 mg/dL) in women with GDM (n = 7) or normal glucose tolerance during pregnancy (n = 8). Data are from Homko et al.8 Right panel: Relationships between acute insulin response to intravenous glucose (AIRg) and insulin sensitivity (minimal model SI) Hispanic women with GDM (n = 99) or normal glucose tolerance during and after pregnancy (n = 7). Curved lines represent insulin sensitivity-secretion relationships defined by the product of sensitivity and secretion in each study group. Reproduced from Buchanan et al9

As the data described below indicate, the routine glucose screening that is used to detect GDM also detects women with chronic β-cell dysfunction, rather than development of relative insulin deficiency as insulin resistance increases during pregnancy. β-cell compensation for insulin resistance can be quantified as the product of insulin sensitivity and insulin response.7 Compensation is reduced to a similar degree during and after pregnancy (Fig. 8.1, left, reductions of 39 and 47%, during and after pregnancy8; Fig. 8.1, right; reductions of 69 and 62%, respectively9). These findings are consistent with earlier studies.10,11 Together, the available data indicate that GDM represents detection of chronic β-cell dysfunction, rather than development of relative insulin deficiency as insulin resistance increases during pregnancy. Thus, the routine glucose screening that is used to detect GDM also detects women with chronic β-cell dysfunction.

While the full array of causes of β-cell dysfunction in humans remains to be determined, clinical classification of diabetes mellitus outside of pregnancy is based on three general categories of dysfunction: (a) autoimmune, (b) monogenic, and (c) associated with insulin resistance. Each of these categories appears to contribute to β-cell dysfunction in GDM, as discussed in the next section.

8.4 GDM and Autoimmunity to β-cells

A small minority (≤10% in most studies) of women with GDM have circulating antibodies to pancreatic islets or to β-cell antigens such as glutamic acid decarboxylase.1218 Although detailed physiological studies are lacking in these women, they most likely have inadequate insulin secretion resulting from autoimmune damage to β cells. They have evolving type 1 diabetes that comes to clinical attention through routine glucose screening during pregnancy. Whether pregnancy initiates or accelerates islet-directed autoimmunity is unknown. The frequency of islet autoimmunity in GDM tends to parallel ethnic trends in the prevalence of type 1 diabetes outside of pregnancy. Patients are often, but not invariably, lean and of European ancestry. They can have a rapidly progressive course to overt diabetes after pregnancy.14

8.5 GDM and Monogenic Diabetes

Monogenic forms of diabetes follow two general inheritance patterns – autosomal dominant (Maturity Onset Diabetes of the Young or “MODY” with genetic subtypes MODY1, MODY2, etc.) and maternal (maternally inherited diabetes due to mutations in mitochondrial DNA). The age at onset/detection tends to be young relative to other forms of nonimmune diabetes and patients tend not to be obese or insulin resistant. Both features point to abnormalities in β-cell mass and/or function that are severe enough to cause hyperglycemia in the diabetic range. Mutations that cause several subtypes of MODY have been found in women with GDM: glucokinase (MODY 2),131921hepatocyte nuclear factor 1α (MODY 3),13 and insulin promoter factor 1 (MODY 4).13 Mitochondrial gene mutations have also been found in small numbers of patients with GDM.22 These monogenic forms of GDM appear to account for only a small fraction of cases of GDM.13,1922 They likely represent examples of preexisting diabetes that are first detected by routine glucose screening during pregnancy.

8.6 GDM in the Context of Chronic Insulin Resistance

Insulin Resistance: GDM is diagnosed during pregnancy, when insulin sensitivity is quite low in everyone. However, insulin resistance is slightly greater in women with GDM than in normal pregnant women.1523 The additional resistance occurs in glucose uptake (predominantly skeletal muscle),1015 glucose production (primarily liver),1015 and fatty acid levels (adipose tissue).15 After pregnancy, insulin sensitivity rises to a greater extent in normal women than in women who had GDM. In addition, serial measurements of insulin sensitivity starting before pregnancy demonstrate insulin resistance before conception and at the beginning of the second trimester in women with GDM.10,11Thus, most women with GDM have a separate, chronic form of insulin resistance compared with normal women.2430

Given that GDM represents a cross section of glucose intolerance in young women, mechanisms that lead to chronic insulin resistance in GDM are likely as varied as they are in the general population. Obesity is a common antecedent of GDM and many of the biochemical mediators of insulin resistance that occur in obesity have been identified in small studies of women with GDM or a history thereof. These mediators include increased circulating levels of leptin31 and the inflammatory markers TNF-α32 and C-reactive protein33; decreased levels of adiponectin34,35; and increased fat in liver36 and muscle.37 In vitro studies of adipose tissue and skeletal muscle from women with GDM or a history thereof have revealed abnormalities in the insulin signaling pathway,6,3841 abnormal subcellular localization of GLUT4 transporters,42 and decreased expression of PPAR-γ,38 over-expression of membrane glycoprotein 1,40 all of which could contribute to the observed reductions in insulin-mediated glucose transport. The abnormalities in insulin signaling are the same ones reported in association with obesity, a common feature of women who develop GDM. Due to the very small sample sizes in these in vitro studies, it is not clear whether any of these abnormalities represent universal or even common abnormalities underlying the chronic insulin resistance that is very frequent in GDM.

β-cell Compensation: There are two time frames in which β-cell compensation for insulin resistance must be considered in GDM. In the short term (months), women with GDM appear to be able to increase insulin secretion reciprocally to changes in insulin sensitivity (Fig. 8.1, references811). They do so along an insulin sensitivity-secretion relationship that are ∼40–70% lower (i.e., 40–70% less insulin for any degree of insulin resistance) than the relationship in normal women. In the long-term (years), a large majority of women with GDM manifest progressive loss of β-cell compensation for insulin resistance (Fig. 8.2, left) that is associated with and most likely causes the progressive hyperglycemia that becomes diabetes (Fig. 8.2, right). Taken together, the short- and long-term characteristics of β-cell compensation in women with GDM are most consistent with chronically falling β-cell function that is identified “mid stream” along the progression to type 2 diabetes because routine glucose screening is applied during pregnancy.

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Fig. 8.2

Left Panel: Coordinate changes in SI and AIRg, as defined in Fig. 8.1, in 71 nonpregnant Hispanic women with prior GDM. IVGTTs were performed at 15-month intervals for up to 5 years after index pregnancies. Symbols are mean (±se) values at initial and final visits. Median follow-up was 44 months in 24 women who developed diabetes and 47 months in 47 women who did not. Adapted from Buchanan et al.9 Right Panel: Coordinate changes in β-cell compensation for insulin resistance (disposition index) and 2-h glucose levels from 75-g oral glucose tolerance tests in the same 71 women. Symbols represent mean data at 15-month intervals, ordered relative to final visits. Arrows denote direction of change over time. Adapted from Xiang et al.61 Reproduced from Buchanan et al9

The etiology of falling β-cell function that occurs against a background of chronic insulin resistance is not known. Two observations that we have made in Hispanic women with prior GDM indicate that insulin resistance may be an important cause of falling β-cell function. First, an additional pregnancy, which represents an additional period of severe insulin resistance, tripled the risk of diabetes after GDM even after adjusting for the impact of pregnancy on weight gain.43 Second, treatment with insulin-sensitizing thiazolidinedione drugs slowed or stopped the loss of β-cell function, thereby delaying or preventing diabetes.4446 β-cell protection and diabetes prevention were closely related to reduced insulin secretory demands that occurred when insulin resistance was ameliorated. These findings suggest that Hispanic women who develop GDM do not tolerate high levels of insulin secretion for prolonged periods of time. Chronic insulin resistance (e.g., from obesity) and short-term resistance (e.g., from pregnancy) increase demands, an effect which may cause loss of β-cell function. The biology underlying poor tolerance of high rates of insulin secretion remains to be defined. Likely candidates include susceptibility to β-cell apoptosis due to endoplasmic reticulum stress and abnormal protein folding,4749 islet-associated amyloid polypeptide, which is co-secreted with insulin and can be β-cell toxic,50,51and/or oxidative stress.52 Of note, we have observed that changes in β-cell compensation have also been linked to weight gain, an effect that is explained by insulin resistance, reductions in the adipose tissue hormone adiponectin, and changes in C-reactive protein, a marker of low-grade inflammation associated with obesity. Thus, there may be many signals that, in combination with individual susceptibilities, promote the loss of β-cell mass and function that lead to type 2 diabetes.

8.7 Implications for Diabetes Prevention

In a minority of women diagnosed with GDM, hyperglycemia is already severe enough to meet criteria for diabetes outside of pregnancy. The rest (i.e., the majority) have a form of glucose intolerance that could be (a) limited to pregnancy, (b) chronic and stable, or (c) a stage in progression to diabetes. As reviewed by Kim et al,53 long-term follow-up studies reveal that most, but probably not all women with GDM go on to develop diabetes outside of pregnancy (Fig. 8.3). Thus, in most women GDM is a stage in the evolution of diabetes mellitus, leading to recommendations that women with GDM be tested for diabetes soon after pregnancy and periodically thereafter. Optimal timing of such testing has not been established. Diabetes prevalence rates of ∼10% in the first few months postpartum54 support testing at that time. Diabetes incidence rates in the range of 5–10% per year (Fig. 8.3) support annual retesting. Oral glucose tolerance tests are more sensitive for detecting diabetes, as it is currently defined, than is measurement of fasting glucose levels.55

A160858_1_En_8_Fig3_HTML.gif

Fig. 8.3

Relationship between initial fractional reduction in insulin secretory demand and corresponding diabetes incidence rates during drug treatment in the troglitazone arm of the TRIPOD study (round symbols; median treatment 31 months) and in the PIPOD study (square symbols; median treatment 35 months). Insulin output was assessed as the total area under the insulin curve during intravenous glucose tolerance tests performed at enrollment and then at initial on-treatment IVGTT, which occurred after 3 months in TRIPOD and after 1 year in PIPOD. Symbols represent the low, middle and high tertiles of change in each study. Lines represent best linear fits of data for each study. Reproduced from Xiang et al44

The type of diabetes that develops after GDM has generally not been rigorously investigated. It is reasonable to assume that the factors that contribute to poor β-cell compensation in GDM (discussed above) are likely to be involved in the pathogenesis of diabetes after GDM as well. Type 2 diabetes almost certainly predominates, given the overall prevalence of the disease in relation to other forms of diabetes and the fact that risk factors such as obesity, weight gain, and relatively older age are shared between GDM and type 2 diabetes. However, immune and monogenic forms of diabetes occur as well. These latter subtypes of diabetes should be considered in women who do not appear to be insulin resistant (e.g., lean patients). Antibodies to glutamic acid decarboxylase 65 (GAD-65) can be measured clinically and can identify women who likely have evolving type 1 diabetes. While there is as yet no specific intervention to delay or prevent that disease, patients should be followed closely for development of hyperglycemia, which may occur relatively rapidly after pregnancy.14 If unrecognized and untreated, the condition can deteriorate to life-threatening ketoacidosis.

Clinical testing for variants that cause monogenic forms of diabetes is becoming available, but interpretation of the results can be complicated; consultation with an expert in monogenic diabetes is advised. Early-onset diabetes with an appropriate family history ─ autosomal dominant inheritance for MODY, maternal inheritance for mitochondrial mutations ─ may provide a clue to the presence of a monogenic etiology. Like autoimmune diabetes, there is no specific disease-modifying treatment for these forms of diabetes, although patients with MODY due to mutations in hepatic nuclear factor 1-alpha appear to respond well to treatment with insulin secretagogues.56 Patients with mutations in glucokinase (MODY 2) tend to have a relatively mild and nonprogressive form of hyperglycemia. Also, their genetic information may be useful in future pregnancies. Fetuses who inherit the MODY 2 mutation are relatively resistant to the growth-promoting effects of maternal diabetes; they do not require the same aggressive glycemic management usually recommended for diabetic pregnancies.57 Thus, genetic counseling may be appropriate for patients with monogenic diabetes and their families.

Results from the Diabetes Prevention Program (DPP), and the Troglitazone in Prevention of Diabetes (TRIPOD) and Pioglitazone in Prevention of Diabetes (PIPOD) studies suggest approaches that can be used to delay or prevent diabetes in women whose clinical characteristics suggest a risk of type 2 diabetes. In the DPP,58 intensive lifestyle modification to promote weight loss and increased physical activity resulted in a 58% reduction in the risk of type 2 diabetes in adults with impaired glucose tolerance. GDM was one of the risk factors that led to inclusion in the study. Protection against diabetes was observed in all ethnic groups. Treatment with metformin in the same study also reduced the risk of diabetes, but to a lesser degree, and primarily in the youngest and most overweight participants. Analysis of data from parous women who entered the DPP with or without a history of GDM59 revealed that (a) the women with prior GDM were younger than women with no history of GDM, (b) the women with prior GDM had a 60% greater cumulative incidence of diabetes after three years of follow-up, (c) intensive lifestyle modification reduced the risk of diabetes by a similar degree in women with and without prior GDM, and (d) metformin was more effective in reducing the risk of diabetes in women with a history of GDM than in women who had no such history (50 vs. 14% risk reductions, respectively).

In the TRIPOD study, assignment of Hispanic women with prior GDM to treatment with the insulin-sensitizing thiazolidinedione drug, troglitazone, was associated with a 55% reduction in the incidence of diabetes. As discussed above, protection from diabetes was closely linked to initial reductions in endogenous insulin requirements (Fig. 8.3) and ultimately associated with stabilization of pancreatic β cell function.46 Stabilization of β cell function was also observed when troglitazone treatment was started at the time of initial detection of diabetes by annual glucose tolerance testing.60

In the PIPOD study, administration of another thiazolidinedione drug, pioglitazone, revealed a low diabetes rate and stabilization of β-cell function that had been falling during placebo treatment in the TRIPOD Study.61 Again, there was a close association between reduced insulin requirements and a low risk of diabetes (Fig. 8.3). The DPP, TRIPOD, and PIPOD studies support clinical management that focuses on aggressive treatment of insulin resistance to reduce the risk of type 2 diabetes after GDM. Treatment options include weight loss and exercise, which compose the initial therapy of choice, and metformin and/or thiazolidinedione drugs if weight loss fails to prevent diabetes. Monitoring of glycemia (e.g., A1C levels) may be useful in assessing response to these interventions. However, the focus in this context is not a particular target A1C, as is the case for prevention of diabetic complications, but stabilization of A1C at a low risk level, reflecting stabilization of β-cell compensation for insulin resistance.

8.8 Summary and Future Directions

Available data suggest that GDM results from a spectrum of metabolic abnormalities that is representative of causes of hyperglycemia in relatively young individuals. In most women with GDM, the abnormalities are chronic in nature and detected by routine glucose screening in pregnancy. The abnormalities are frequently progressive, leading to rising glucose levels and, eventually, to diabetes mellitus. Thus, GDM can be viewed largely as diabetes in evolution that is detected during pregnancy. As such, GDM offers an important opportunity for the development, testing, and implementation of clinical strategies for diabetes prevention.

Acknowledgments

Work cited in this chapter was supported by research grants from the National Institutes of Health (R01DK46374, R01DK61628, and M01-RR00043), the American Diabetes Association (Distinguished Clinical Scientist Award to TAB), Parke-Davis Pharmaceutical Research (the TRIPOD study) and Takeda Pharmaceuticals North America (the PIPOD Study).

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