Back in August of this year, I started a series on “Diabetes in Pregnancy.” A recent reader reminded me that I hadn’t gotten around to finishing that series (which is true because I got distracted by other topics). In the first three installments of that series, we discussed general overviews of diabetes and the growing ‘epidemic’, glucose metabolism, and the changes in insulin sensitivity accompanying normal pregnancy that can complicate or precipitate diabetes. In this post, let’s discuss the different types of diabetes and see how gestational diabetes fits into the spectrum of disease.
Although glucose intolerance as manifested by high ‘blood sugar’ levels is the common denominator that defines an individual as diabetic, the two major groups of diabetes, type 1 and type 2, have very different underlying etiologies. Only about 10% of diabetes in North America is type 1. This form of diabetes is primarily an autoimmune disorder that is associated with the production of antibodies and auto-reactive T cells directed against and subsequent destruction of the pancreatic islet cells (?-cells) that produce insulin. Other conditions can also lead to the destruction of the pancreatic islets and type 1 diabetes, but these are much less common. Type 1 diabetes was formerly called juvenile onset diabetes (or insulin-dependent diabetes) and occurs before the age of 20 in about 50% of cases and most before the age of 30, although there is a life-long risk of developing this type of diabetes. There appears to be a complex polygenic inheritance pattern to the tendency to develop the autoimmune condition, and there is variable penetrance of expression suggesting a role for environmental factors in addition to the genetic predisposition. In this regard, a variety of different viruses (e.g., Coxsackie B4; cytomegalovirus) have been implicated, but not absolutely proven to play a role, in the precipitation of diabetes in certain individuals.
Twin studies support the contributions of both genetic background and ‘shared environment’ as sources for expression of type 1 diabetes. Monozygotic twins (identical twins from the same egg) have a 30-50% concordance for developing diabetes. Dizygotic twins (from separate eggs) have a higher rate of concordance than is seen in ordinary first degree relatives as well (Kyvik, et al., BMJ 1995;311:913-7). The earlier the onset of diabetes in the index twin, the greater the likelihood of the second twin (mono-or dizygotic) will eventually develop diabetes (Hyttinen, et al., Diabetes 2003;52:1052-5). Males seem to be at greater risk for developing diabetes and for concordance of disease in both monozygotic and dizygotic twins (Kumar, et al., 1993;42: 1351-63). Antibodies to the islet cells can be found in 90% of type 1 diabetics at the time of diagnosis and these are often directed against the glutamic acid decarboxylase enzyme as well as cytoplasmic antigens and insulin. Certain human leukocyte antigen (HLA) DQ haplotypes appear to have the strongest association with risks for developing type 1 diabetes and these are correlated with both autoantibody production and subsequent disease expression (Redondo, et al., J Clin Endocrinol Metab 2006;91:1705-13). Interestingly, there appears to be a predisposition to paternal treansmission of these haplotypes.
Type 2 diabetes is a more ‘heterogeneous’ condition than type 1 diabetes and represents about 90% of the disease seen in North America. It is characterized by both a decreased sensitivity to insulin in skeletal muscle and liver and a decreased production of insulin by the pancreatic ?-cells in response to hyperglycemia, a condition that seems to worsen over time and with poor control of blood glucose levels. Typically, type 2 diabetes has been associated with genetic predisposition (family history), obesity, and advancing age. On a worldwide basis, it is clear that genetic predisposition is perhaps the greatest contributor to overt manifestation of type 2 diabetes. As in type 1 diabetes, there is a strong concordance of type 2 diabetes in twins in the range of 50% or more. In North America, and in other countries that are being affected by the ‘pandemic’, obesity is perhaps the single greatest cause leading to expression of the disease, particularly in younger individuals. About 10-15% of individuals with type 2 diabetes have specific gene mutations associated with autosomal dominant inheritance patterns. These conditions are currently classified as maturity onset diabetes of the young (MODY). The most common of these (MODY2) is related to a variety of glucokinase gene mutations and is commonly found in European populations. MODY1 and MODY3 are secondary to mutations of hepatic nuclear factors; heritable deletions or mutations of mitochondrial DNA can also lead to type 2 diabetes in and diabetes.
Although obesity has classically been correlated with both expression and severity of type 2 diabetes, a large proportion of individuals with type 2 diabetes in Europe and Asia are not obese. In these individuals, many have a disproportionately greater decrease in insulin production and less insulin resistance than that seen in obese type 2 diabetics. This suggests that the underlying predisposition to the development of type 2 diabetes is decreased insulin production and obesity contributes to the progression of disease by increasing insulin resistance. The latter may occur by a variety of mechanisms that may have differential expression and significance in certain individuals, contributing to the heterogeneity of presentation and severity of type 2 diabetes. For example, excess fatty acids can block insulin signaling in skeletal muscle and stimulate glucose production by the liver. In recent years, obesity has also been characterized by a chronic ‘inflammatory’ state with the increased production of tumor necrosis factor-? and interleukin-6 that can also contribute to insulin resistance in skeletal muscle.
However, the most exciting findings that have been widely published in the scientific literature within the past year may actually have identified the root cause of the genetic predisposition to type 2 diabetes. Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene have been clearly correlated with type 2 diabetes around the world in individuals with different ethnic and genetic backgrounds (Chandak, et al., Diabetologia 2007;50:1-4; De Silva, et al., Diabet Med 2007;24:1067-72; Chang, et al., Diabetes 2007;56:2631-7; Hayashi, et al., Diabetologia 2007;50:980-4). These polymorphisms are associated with both decreased insulin production and increased insulin resistance in non-obese and obese individuals, but seem to play a greater role in the expression of diabetes in the former. This finding opens the door to novel and specific approaches to therapy that have eluded the management of type 2 diabetes to this point. For those readers who have an interest in this subject, let me commend to you several recent review articles (Vaag, et al., Appl Physiol Nutr Metab 2007;32:912-20; Florez, Curr Opin Clin Nutr Metab Care 2007;10-391-6).
So, where does pregnancy fit into the big scheme of things. As we discussed in one of those August posts, pregnancy in the second and third trimesters is associated with increasing insulin resistance that is correlated with the hormonal milieu of pregnancy. In that respect, the ‘stress’ of pregnancy can, and typically does, worsen control of women who embark on pregnancy with either type 1 or type 2 diabetes. Women who only overtly develop diabetes during pregnancy (gestational diabetes mellitus – GDM), however, have features that are most characteristic of type 2 diabetes. Indeed, the overall 2-14% incidence of gestational diabetes in different populations characteristically reflects the incidence of type 2 diabetes in the background population (and I will bet now, the genetic background as well). We now look at GDM as a crystal ball to identify women at risk for developing full-blown type 2 diabetes later (sometimes sooner than later) in life. Indeed, one of our major points of emphasis in counseling women with GDM is that the keys to diabetic control we provide to them to optimize pregnancy outcome should be carried forward in their lives after the pregnancy is completed to help minimize their future risks for diabetes. In the next post on this subject (hopefully not 3 months from now!), we will discuss the diagnosis and management of gestational diabetes…