The genetics of gestational diabetes mellitus: evidence for relationship with type 2 diabetes mellitus

Abstract

Gestational diabetes is a major public health problem because of its prevalence, its associated complications during pregnancy, and its increased risk for type 2 diabetes later in life. Insulin resistance is one of many physiological changes occurring during pregnancy, and when insulin resistance is accompanied by pancreatic ␤-cell insufficiency, gestational diabetes may develop. Several lines of evidence suggest that gestational diabetes shares a common etiology with type 2 diabetes and support the hypothesis that gestational diabetes serves as a window to reveal a predisposition to type 2 diabetes. Pregnancy is an environmental stressor that may catalyze the progression to a diabetic state in genetically predisposed women; therefore, identification of these women during pregnancy could decrease the occurrence of type 2 diabetes through targeted prevention. This review presents an overview of the genetics of gestational diabetes, focusing on human association studies with candidate genes common to both type 2 diabetes and gestational diabetes. Genet Med 2008:10(4):240 -250. Key Words: gestational diabetes mellitus, type 2 diabetes, genetics, pregnancy, association studiesGestational diabetes mellitus (GDM) is a major public health problem because of its prevalence and its associated complications during pregnancy. It is estimated that 4% of pregnancies in the United States are complicated by GDM, although the prevalence of GDM varies considerably among racial and ethnic groups. 1 Uncontrolled GDM increases the risk of adverse neonatal outcomes such as macrosomia, birth injuries, neonatal hypoglycemia, neonatal cardiac dysfunction, and stillbirth. 2 In addition to increasing the risk of adverse infant outcomes, GDM also has high predictive value for later development of type 2 diabetes (T2D) in the mother and in her offspring. Women who experience GDM have increased risk of developing T2D after pregnancy, ranging from 17% to 63% within 5-16 years after pregnancy depending on the population and other risk factors. 3 Additionally, offspring of mothers with GDM are more likely to be obese and display impaired glucose tolerance during adolescence than are offspring of nondiabetic mothers. Thus, diabetes during pregnancy is not only associated with the later risk of diabetes in mothers but also with metabolic changes that may lead to the development of diabetes in their offspring. 4 This observed connection between GDM and risk of T2D strongly suggests that GDM can serve as a window revealing a predisposition to T2D, with pregnancy as the environmental stressor that catalyzes progression to a diabetic state in predisposed individuals. 5 Several lines of evidence support the above hypothesis. First, GDM shares several risk factors with T2D, including high body mass index (BMI), history of abnormal glucose tolerance, diabetes in a first-degree relative, and membership in an ethnic group with a high risk of T2D. 6 Second, GDM and T2D share similar pathophysiologies: women undergo major physiological changes during pregn...

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

“…Furthermore, it is well known that women with GDM are at a greater risk of developing type 2 diabetes later in life [7][8][9]. However, knowledge regarding the genetics of GDM is limited [7,10]. Several studies have examined candidate genes in women with and without GDM.…”

Type 2 diabetes-associated genetic variants of FTO, LEPR, PPARg, and TCF7L2 in gestational diabetes in a Brazilian population

“…GDM and T2DM have similar pathophysiologic features, suggesting that GDM is also a polygenic disease (5). Therefore, studies on the etiology of GDM have primarily been based on T2DM-associated genetic variants (6).…”

Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia

“…Furthermore, causal variants of T2D may also affect fitness indirectly, through their association with other syndromes occurring earlier in life, notably insulin resistance and cardiovascular diseases 7 or gestational diabetes. 8 As a result, one would expect these variants to be selected against by natural selection, and therefore the high prevalence of T2D as well as its variability among populations has remained a puzzle in evolutionary biology. 9 Several hypotheses have been put forward to explain this paradox.…”