Fat Metabolism in Pregnancy and Neonatal Heart Function in Diabetes

Background: In the United States, there are approximately 1.2 million children born to women with diabetes mellitus (DM) each year. This number is increasing due to the epidemic of type 2 diabetes and obesity in Western society. Infants born to diabetic women (IBDW) have alterations in cardiac morphology and function, which may predispose them to long-term adverse cardiovascular health. At present, mechanisms for adverse cardiovascular outcomes in IBDW are unknown. Abnormal maternal glucose metabolism in DM during pregnancy was previously thought to affect fetal cardiac development. However, recent findings indicate that IBDW with good 3rd trimester glucose control still develop cardiac abnormalities. In fact, other aspects of maternal nutrient metabolism and partitioning (other than glycemic control) may regulate fetal cardiac development. For example, abnormal fatty acid, triglyceride, and lipoprotein metabolism are common in DM, and maternal serum lipid levels in pregnant diabetics predict neonatal birth weight. The investigators propose that maternal fatty acid metabolism is dysregulated in diabetic pregnancy. This increases fatty acid delivery to the fetus and leads to fetal myocardial lipid accumulation, and altered neonatal heart morphology and function in IBDW. To date, this has not been explored in humans. The proposal stems from the "lipotoxicity" paradigm: chronic elevations in maternal blood lipid (i.e. fatty acid, triglyceride, very low density lipoprotein) levels during pregnancy lead to increased lipid delivery to and cause myocardial lipid deposition in the developing fetus. These lipids displace glucose utilization by the fetal myocardium; the preferred fetal heart substrate in a healthy pregnancy. Abnormal fetal heart lipid deposition and accumulation of lipid metabolic intermediates (e.g. ceramide) may lead to myocardial insulin resistance and contractile dysfunction in IBDW. The relationship between abnormal nutrient metabolism during pregnancy and adverse cardiovascular and metabolic health in diabetes may be important in other conditions such as childhood obesity in which this project could provide insight.

Specific Aims: In 25 women who have pre-gestational type 2 DM and 25 healthy non-diabetic body mass index-matched controls during the 3rd trimester of pregnancy, the investigators will address the following Aims:

Specific Aim 1: To characterize maternal lipid metabolism kinetics (fatty acid oxidation rate, lipolytic rate, fatty acid clearance rate) and maternal and fetal serum lipid concentrations (free fatty acid, triglyceride and very low density lipoprotein (VLDL)).

Hypothesis 1: Women with DM during pregnancy will have higher whole-body lipolytic rates and serum lipid concentrations, and lower whole-body fatty acid oxidation and clearance rates than healthy women without DM during pregnancy.

Specific Aim 2A: To examine the relationship among maternal lipid kinetics, maternal and fetal plasma lipid concentrations, and neonatal cardiac morphology and function in neonates born to these women.

Specific Aim 2B: To determine whether maternal lipid metabolism kinetics, maternal serum lipid levels and clinical markers of maternal glycemic control alone or in combination can predict abnormal neonatal cardiac function.

Hypothesis 2A:. Altered maternal lipid metabolism kinetics (higher lipolytic and lower fatty acid oxidation rates) will be related to elevated maternal and fetal serum lipid concentrations and abnormal neonatal cardiac function.

Hypothesis 2B. The combination of maternal lipid metabolism kinetics (lipolytic and fatty acid oxidation rates) and serum fatty acid level will be superior to markers of glycemic control (HBA1C and fructosamine) for predicting neonatal cardiac function.

Design: Whole-body lipid metabolism kinetics (fatty acid oxidation, lipolytic, clearance rates) will be measured during clinical metabolism studies using stable isotope tracer methodology and mass spectrometry performed in the Clinical Research Unit and Biomedical Mass Spectrometry Facility at Washington University School of Medicine. Umbilical cord blood will be collected at parturition and serum lipid (fatty acid, triglyceride and VLDL) and other nutrient as well as growth-related hormone levels will be quantified. Neonatal heart function (within 2 weeks of parturition) will be examined using 2D, Doppler, tissue Doppler and strain/strain rate echocardiography performed at St. Louis Children's Hospital.

Potential Impact: Currently, nothing is known regarding the role of lipid metabolism in cardiac abnormalities in IBDW. This translational proposal will address an important knowledge gap regarding the potential role of abnormal lipid metabolism in the development of cardiac abnormalities in IBDW. These associations are a critical step towards understanding the mechanisms of cardiac morphologic and functional alterations in IBDW, in order to identify clinical prognostic markers for cardiac abnormalities in IBDW, develop targeted interventions for these cardiac deficits, and to decrease the future risk of cardiovascular disease and heart failure in IBDW. The potential impact of these findings could extend not only to women and children with pre-gestational diabetes, but to other children born to women with clinical complications including gestational diabetes, obesity, intrauterine growth retardation, and HIV.