Fat Metabolism in Pregnancy and Neonatal Heart Function in Diabetes
Condition: Type 2 Diabetes; Pregnancy
MeSH terms: Diabetes Mellitus
Study type: Observational

Summary: 
      Background: The health of the next generation is likely programmed in the womb (i.e.in
      utero), and our understanding of how that programming happens will allow us to favorably
      influence the health of future generations. The focus of this proposal is to examine the
      effect of in utero programming on heart function in children born to women with type 2
      diabetes (T2DM). Specifically, neonates born to diabetic women have abnormal heart structure
      and weaker heart function at birth, which may predispose them to long-term heart problems in
      childhood, adolescence and adulthood. At present, the reason for these heart abnormalities in
      children born to women with diabetes is unknown and is the focus of this proposal.

      Objective(s) and Hypothesis(es): The objectives are to examine the relationships among
      maternal lipid (fatty acid, triglyceride, very low density lipoprotein) metabolism and
      neonatal heart structure and function in diabetes and to identify clinical markers during
      pregnancy for heart dysfunction in infants born to diabetic women. The overall hypothesis is
      that maternal lipid metabolism is abnormal in diabetes, and this metabolic dysregulation
      increases fatty acid delivery to the fetus in utero and leads to abnormal accumulation of
      lipid in the fetal heart, resulting in altered neonatal heart structure and function in
      infants born to diabetic women. In addition, the investigators hypothesize that decreased
      maternal fatty acid oxidation (fat "burning") rate, elevated lipolytic (fat breakdown) rate
      and elevated blood total free fatty acid level predicts abnormal neonatal heart structure and
      function in infants born to women with type 2 diabetes.

      Methods and Procedures: The investigators will test these hypotheses by using clinical
      metabolism studies (infusion of stable isotope labeled fatty acid, serial blood and breath
      sampling, and mass spectrometry) to quantify whole-body fat (fatty acid oxidation, lipolysis,
      and serum fatty acid , triglycerides, VLDL-cholesterol levels) metabolism in 25 diabetic
      women during the 3rd trimester of pregnancy, and compare these lipid metabolism kinetics to
      25 body mass index matched healthy non-diabetic women during pregnancy and determine if
      alterations in maternal lipid metabolism predict abnormal neonatal heart function in children
      born to these women.

      Potential Impact: Type 2 diabetes is an epidemic in the United States and is steadily
      increasing worldwide. Diabetes has detrimental health effects in pregnant women and in their
      offspring. The investigators know that children born to women with diabetes have an increased
      risk for developing diabetes, obesity and cardiovascular disease, than children born to
      healthy women. This proposal will address an important knowledge gap regarding the role of
      maternal lipid (and potentially other nutrients) metabolism on the cardiovascular health of
      the global and increasing population of children born to diabetic women. Findings from this
      project will be novel and innovative, and will likely point to clinical interventions that
      target and correct lipid and other metabolic abnormalities in women with pre-gestational
      diabetes. The impact will be great because the long-term goal is to ameliorate heart problems
      in children born to diabetic (both pre-gestational and gestational) women. In addition, this
      project will establish a small cohort of children that can be followed long-term to address
      novel questions about the progression of heart and other metabolic abnormalities in children
      born to diabetic women.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Participants: All women who seek pre-natal care at the Women's Health Clinic Barnes Jewish
        Hospital in St. Louis, Missouri are screened by history at the first visit for a
        pre-existing diagnosis of diabetes mellitus (DM) (B or C type DM). Patients with a
        diagnosis of pre-gestational diabetes are transferred to a specialty clinic dedicated
        specifically to pre-natal care for women with diabetes. All patients with on-going
        pregnancies and diabetes will be approached for enrollment. Non-DM subjects have a routine
        screen for gestational diabetes at 24 wk gestation. After a normal result, these subjects
        will be approached for enrollment as controls.
      
Biospecimen description: 
      Maternal and umbilical cord serum
    
Keywords: diabetes; pregnancy; left ventricular dysfunction; neonatal; lipid; lipotoxicity; neurodevelopment