The Infant of the Diabetic Mother: Metabolic Imprinting

Abstract

Diabetes during pregnancy is thought to contribute to metabolic changes in the fetus, which predispose the offspring of diabetic mothers to obesity, insulin resistance, diabetes and cardiovascular disease. Altered maternal fuels, including but not limited to glucose, may affect the development of the endocrine pancreas in the fetus, resulting in increased adiposity and decreased beta cell mass and/or function. Prospective studies in the Pima Indians and at Northwestern University in Chicago have demonstrated increased adiposity among children exposed to diabetes in utero, although not all studies have replicated this relationship. Impaired glucose tolerance (IGT), which can result from either reduced insulin secretion or increased insulin resistance, has also been associated with exposure to diabetes in utero. Type 2 diabetes is more common in offspring of mothers with diabetes than in offspring of nondiabetic and prediabetic women among the Pima Indians. Further, a diabetic intrauterine environment has been shown to induce biochemical alterations in the cardiovascular system, and children born to diabetic mothers have increased cardiovascular risk factors compared with children not exposed to diabetes in utero. Type 2 diabetes has a known genetic component and tends to cluster in families. As a result, obesity, IGT and type 2 diabetes may be more common in offspring of diabetic mothers due to maternal genes rather than metabolic imprinting during fetal development. In order to disentangle genetic vs. environmental causes of type 2 diabetes, several methods were employed. The offspring of mothers with early onset type 2 diabetes have been compared by exposure to intrauterine diabetes, with a higher prevalence of type 2 diabetes demonstrated in exposed Pima Indian children compared with unexposed children. Adjustment for maternal obesity, which is a marker for genetic predisposition to type 2 diabetes, does not explain the increased risk of obesity in the offspring of diabetic mothers, further supporting an environmental contribution of excess maternal fuel. A comparison of offspring with maternal vs. paternal type 2 diabetes also allows for the disentangling of genetic and environmental causes, since fathers would transmit the same genetic risk of type 2 diabetes as mothers. However, the strongest evidence for the role of intrauterine diabetes in the development of type 2 diabetes in the offspring of diabetic mothers has come from the comparison of siblings born before and after the development of maternal diabetes. Animal studies have allowed for the investigation of experimentally manipulated intrauterine environment on metabolism and glucose homeostasis in the offspring. Hyperglycemia can be induced either to a mild degree late in pregnancy to mimic gestational diabetes or to a severe degree early in pregnancy to mimic type 1 diabetes. An additional genetic model of diabetes has been examined using rats selectively bred for IGT. These animal models have allowed for insight into the effects of maternal hyperglycemia on beta cell mass and pancreatic development. Diabetes prevalence is increasing worldwide, and it is one of the most pressing public health issues due to the increased costs, comorbidity and mortality associated with diabetes. The exposure to diabetes in utero may create a vicious cycle where the offspring of diabetic mothers are more likely to develop obesity and glucose intolerance, leading to an increased risk of developing gestational diabetes or type 2 diabetes during pregnancy themselves, and therefore perpetuate a destructive cycle of metabolic dysfunction. Reducing obesity and type 2 diabetes must be a primary goal of public health organizations and clinicians.