Diabetes in pregnancy is still generally classified using the original system proposed by Priscilla White over 70 years ago,
3 even when applied to contemporary patient populations.
4,5 White classification relates the onset of diabetes, its duration, and the degree of vasculopathy to the outcome of pregnancy. Because there were differences and some confusion in the interpretation of class A diabetes, particularly when the patient required insulin for therapy, a revision made by Hare and White proposed that class A diabetes should include women known to have diabetes before pregnancy and who are treated with diet alone.
6 Thus, White class A classification includes only patients with preexisting diabetes and defines gestational diabetes as a completely separate group.
The current, widely used definition of GDM is glucose intolerance diagnosed in the second or third trimester of pregnancy that is not clearly preexisting diabetes.
12,13,14,15 Although the causes of this glucose intolerance remain unclear, a key feature of GDM is varying degrees of hyperglycemia.
Etiology
Significant advances in the understanding of genetic features of diabetes mellitus have been achieved in the last 50 years.
16,17,18 Because diabetes mellitus is a heterogeneous disorder rather than a single disease, the different types of diabetes are distinguishable
from each other. Currently, the American Diabetes Association (ADA) classifies diabetes into four major categories
19:
-
type 1 diabetes mellitus, an immune-mediated disease in which the beta-cells are destroyed by the patient’s immune system, leading to an absolute deficiency in insulin;
-
type 2 diabetes mellitus, a progressive loss of adequate insulin secretion by beta-cells, usually in the context of insulin resistance;
-
GDM, a discrete form specific to pregnancy, which was not overt prior to gestation and resolves shortly after parturition; and
-
specific types of diabetes due to other causes (
Table 30.3).
Approximately 463 million adults worldwide have diabetes.
20 Type 1 accounts for 5% to 10% of all cases of diabetes in the general population, with type 2 diabetes comprising 90% to 95% of all cases, and other forms of diabetes representing 1% to 2% of cases.
21,22 According to the International Diabetes Federation, in 2019, the top 10 countries with the highest prevalence of diabetes in adults were China (116.4 million), India (77 million), the United States (31 million), Pakistan (19.4 million), Brazil (16.8 million), Mexico (12.8 million), Indonesia (10.7 million), Germany (9.5 million), Egypt (8.9 million), and Bangladesh (8.4 million).
20 In the United States, approximately 7.3 million people are estimated to have undiagnosed diabetes and 88 million adults are thought to have prediabetes.
21 Hyperglycemia during pregnancy is estimated to affect approximately 15.8% of all live births.
20
Ninety percent of all pregnant patients with diabetes have GDM, whereas type 1 and type 2 account for the majority of the remaining 10%.
20 The focus of this chapter will be these three predominant forms of diabetes in pregnancy as a broader discussion of the rarer manifestations of the disease is beyond the scope of this text.
Genetics of Type 1 Diabetes Mellitus
Almost 50 years ago, it was discovered that type 1 diabetes is a human leukocyte antigen (HLA)-linked
disorder, whereas type 2 is not, and thus they are two different diseases genetically.
23 Genome-wide studies have revealed that HLA gene loci account for only 30% to 70% of genetic basis of type 1 diabetes and greater appreciation for non-HLA genes in the etiology of the disease have been revealed over the last decade-plus, with more than 50 loci now having a reported association with the condition.
24 The insulin gene (
INS) has the next-strongest association with type 1 diabetes, and variations within a specific region of the gene are thought to mediate immune tolerance to insulin.
24 Other non-HLA genes with an identified association with type 1 diabetes also play critical roles in T-cell function.
24 Although autoimmunity plays a key role in type 1 diabetes and the presence of autoantibodies to beta-cell proteins (eg, insulin, islet antigen 2, and zinc transporter 8, among others) is a hallmark of the condition, it is now appreciated that only those having more than one antibody progress to clinical disease.
25
Type 1 diabetes is a heritable disease, with lifetime risk in siblings of 6% to 7% and 30% to 70% in monozygotic twins, 1.3% to 4% in children of women with type 1 diabetes, and 6% to 9% in children whose fathers have the disease.
24 The exact mechanism of the inheritance of type 1 diabetes is not known; however, it appears that the disease itself is not inherited but susceptibility to the disease is, and that the progression to overt type 1 diabetes depends on a confluence of factors, including genetics and epigenetics, metabolomics, and the patient’s own microbiome and immune system.
25 Research has shown that the HLA-D region is associated with susceptibility to type 1 diabetes and that variants within this region, specifically those within or close to the DR3 and/or DR4 and/or DQ-α or β alleles, are linked to approximately 50% of the heritability of the disease.
26
Genetics of Type 2 Diabetes Mellitus
There are clear genetic and immunologic differences between type 1 and type 2 diabetes. Type 2 diabetes is not linked to HLA and does not seem to be an autoimmune or endocrine disease. However, the development of overt type 2 diabetes does, similar to type 1 diabetes, depend on a combination of genetic and epigenetic factors.
Until the mid-2000s, an appreciation for the genetic contributions to type 2 diabetes susceptibility had not been widely held, although the heritability of the disease had been documented for many years in the literature. Early studies reported a risk of type 2 diabetes in monozygotic twins of women with the disease of nearly 100%; more recent work has shown this rate to be between 52% and 72%.
27,28 One of the first genes with a reported association with type 2 diabetes was a variant of transcription factor 7-like 2 (
TCF7L2) gene, which was implicated in blood glucose homeostasis and identified in multiple studies and in a number of racial/ethnic populations.
26 The advent of genome-wide linkage and association studies afforded investigators opportunities to interrogate other potential loci, and currently upward of 113 have been identified,
29 although studies remaining lacking as to the actual functional roles—if any—of these genes and type 2 diabetes.
Genetics of Gestational Diabetes Mellitus
Historically, GDM was believed to be a variant of type 2 diabetes; however, available data now support the concept that GDM is a heterogeneous disorder representing, at least in part, patients who are destined to develop either type 1 or type 2 diabetes in later life.
30,31 The exact percentage difference of each subgroup is unknown, but it appears that most GDM cases represent a preclinical state of type 2 diabetes. Immunologic studies have shown that in, at most, 10% of GDM cases, the glucose intolerance may stem from the presence of circulating autoantibodies indicative of type 1 diabetes, including glutamic acid decarboxylase autoantibody (GADA), ICA, insulin autoantibody, tyrosine phosphatase-like islet antigen autoantibody, and zinc transporter 8 autoantibody, although the titers of these antibodies is much lower than that of patients with overt type 1 diabetes.
32 Several genome association studies have uncovered a number of shared genetic variants between GDM and type 2 diabetes, with one of the more notable being TCF7L2.
33,34,35
The heritability of GDM has been difficult to ascertain for several reasons, the major one being that GDM screening and diagnosis differ significantly, rendering large prospective and retrospective studies challenging to interpret or applicable to broad populations.
36 Although genome-based studies have provided unique insights into potential genetic causes of GDM, these investigations have also garnered a greater appreciation for previously unrecognized forms of diabetes, such as latent autoimmune diabetes in adults (LADA; discussed below) and maturity-onset diabetes of the young, which share features with both type 1 and type 2 diabetes and manifest as milder hyperglycemia indicative of GDM.
26
Latent Autoimmune Diabetes in Adults
LADA represents a heterogeneous form of diabetes sharing clinical and genetic features with both type 1 and type 2 diabetes. It was first described in the literature in the late 1970s but not named until the early 1990s. As of this writing, the only two prospective studies of patients with LADA are the Norwegian Nord-TrØndelag Health (HUNT) Study and the Swedish Epidemiological Study
of Risk Factors for LADA and Type 2 diabetes (ESTRID) Study, although other studies have been conducted in Europe, the United Arab Emirates, China, and the United States. Similar to patients with type 1 diabetes, risk for LADA has been linked to variants in the HLA-D locus; similar to those with type 2 diabetes, risk for LADA has also been associated with variants in
TCF7L2.
37 As a condition that straddles both type 1 and type 2 diabetes, patients with LADA exhibit autoantibodies to GADA, although to a lesser extent than those with type 1 diabetes; have lower insulin secretion than patients with type 2 diabetes and require insulin therapy sooner; and tend to have higher body mass indices (BMIs) and less physical activity as risk factors, similar to patients who develop type 2 diabetes.
38 Evaluation remains challenging, with several reports of patients misdiagnosed initially as having either type 1 or type 2 diabetes although, once diagnosed, treatment with insulin and diet and exercise are effective.
39
Metabolic Changes in Diabetic Pregnancies
The metabolic disturbances in pregnant patients with diabetes are expressed in increased concentrations of circulating metabolic fuels, including carbohydrates, proteins, and fats. This increased circulating maternal level can be transferred to the fetus by the placenta. Although a detailed discussion of placental transfer of nutrients appears in
Chapter 6, a brief overview of changes in insulin and glucose metabolism in pregnancy is provided here.
Insulin is the major hormonal signal regulating metabolic responses to feeding and tissue use of carbohydrates; it is also the major glucose-lowering hormone. It is produced by the beta-cells of the pancreas and is secreted into the hepatic portal circulation, from which it reaches and acts on the liver and other peripheral tissues (ie, muscle and fat). Insulin suppresses endogenous glucose production by inhibiting hepatic glycogenolysis and gluconeogenesis. On the other hand, it stimulates glucose uptake and fuel storage of glycogen and triglyceride in the liver, muscle, and adipose tissue.
40
During normal pregnancy, insulin sensitivity decreases by approximately 50% to 60% as gestation advances.
41,42 In the first trimester of pregnancy, insulin action is enhanced by estrogen and progesterone; thus, an increase in peripheral glucose use leads to lower fasting plasma glucose (FPG) levels,
43 a decrease that may explain the clinical observation of increased episodes of hypoglycemia experienced by patients with preexisting diabetes in early pregnancy. Late pregnancy is characterized by accelerated growth of the fetoplacental unit, rising plasma concentrations of several diabetogenic hormones, including human placental lactogen and estrogens, and increasing insulin resistance, especially in the periphery (muscle and, in women with obesity, also at the hepatic level).
42
Impaired insulin sensitivity appears to underlie a number of alterations in maternal metabolism necessary for fetal development as well as the eventual demands of labor and delivery in normal pregnancy. The concentration of several factors, including circulating free fatty acids, cholesterol, triglycerides, and phospholipids, contribute to changes in glucose metabolism. Although the mechanisms explaining alterations in glucose processing remain unclear, the advent of the field of metabolomics has revealed a number of potential intermediates in the insulin signaling pathway, which may explain these normal adaptations of pregnancy.
44,45
The expression of insulin receptors and insulin-like growth factor (IGF) receptors in the placenta has been suggested to mediate to the metabolic aberrations observed in diabetic pregnancies.
46,47,48 Over the course of pregnancy, expression of these receptors appears to change location—first favoring maternal-derived insulin and expressed on the maternal-facing side of the placental interface, and later favoring fetal-derived insulin.
48 Dysregulation of the insulin/IGF signaling cascades have been reported in pregnancies affected by GDM and type 1 diabetes
48 and linked to fetal overgrowth and adiposity, hyperinsulinemia, and hyperlipidemia. Although a detailed discussion of these signaling pathways falls outside the scope of this chapter, some of the major pathways are those involved in cellular proliferation, survival, and programmed cell death (apoptosis).
46,47 Of particular note, these same signaling cascades have been identified in animal studies as having causal roles in the mechanisms underlying diabetes-induced birth defects (see below).
During development, the fetus produces very little endogenous glucose and, therefore, relies upon active transport of maternal glucose across the placenta. As of this writing, six glucose transporter (GLUT) proteins have been detected in the
placenta the expression of which vary as pregnancy progresses and in the presence of maternal diabetes.
49 Furthermore, expression of GLUT proteins has been associated with IGF.
50 Altered placental expression of GLUT-1, 4, and 9 have been reported in pregnancies complicated by preexisting and gestational diabetes, as compared with nondiabetic pregnancies, and a positive correlation between expression of all three GLUT members and fetal overgrowth in women with preexisting diabetes and GLUT-4 expression in women with GDM have also been published.
51 However, the role and importance of the GLUT proteins in diabetic pregnancies remains unclear as investigators have reported divergent results
50 and still others have postulated that it is the maternal-to-fetal glucose gradient, and not the active transport of glucose across the placenta, which mediates the effects of maternal hyperglycemia on fetal development.
52