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.

Inclusion Criteria:

- Diabetes Mellitus:

1. Women will be diagnosed with type 2 DM (pre-gestational, White classification B
or C class). Since the majority of women with B or C class DM are on insulin
therapy in our clinic, the investigators will recruit only women on insulin
therapy (i.e. no oral diabetes medications).

2. HbA1C ≤ 8 for greater than 3 months 32, 33.

3. All women will have confirmed singleton pregnancies.

4. Receive care at the Women's Health Clinic at Barnes Jewish Hospital.

5. Pre-pregnancy BMI is anticipated to be > 30 (i.e. obese) from the data regarding
the patient population of our clinic. Women with pre-pregnancy BMI between 23-40
will be included.

Control Participants:

1. No diagnosis of type 1 or 2 diabetes or previous gestational DM.

2. Women with pre-pregnancy BMI between 23-40: control participants will be BMI matched
to women with DM.

3. A normal routine, standard of care 1 hour 50 gram gestational diabetes screen.

4. Receive care at the Women's Health Clinic at Barnes Jewish Hospital.

5. Patients will have a singleton pregnancy with no fetal abnormalities (as determined by
routine standard of care ultrasonography).

Exclusion Criteria:

1. Multiple gestation pregnancy.

2. Oral diabetes medications.

3. Inability to provide voluntary informed consent.

4. Currently using illegal drugs (cocaine, methamphetamine, opiates).

5. Current smoker who does not agree to stop.

6. Participants with diabetes who have a BMI > 40.

7. Participants who participate in a routine (> 1x/week) exercise program.

8. History of heart disease.