Investigation of Mechanisms for Transmission of Impaired Glucose Metabolism in Infants Exposed to Diabetes in Utero
Condition: Pregnancy; Gestational Diabetes Mellitus
MeSH terms: Diabetes, Gestational; Diabetes Mellitus
Study type: Observational

Summary: 
      This proposed study; Investigation of mechanisms for transmission of impaired glucose
      metabolism in infants exposed to diabetes in utero, will test the overarching hypothesis that
      impaired maternal substrate oxidation (metabolic inflexibility) and placental lipotoxicity
      are characteristics of diabetic pregnancies and in utero development within these conditions
      programs a metabolically inflexible phenotype in the offspring.
    

Detailed description: 
      This translational research study will obtain paired measures of metabolic flexibility
      (postprandial RQ minus basal RQ) in response to a standardized meal by indirect calorimetry
      in mother:infant dyads of diabetic and non-diabetic pregnancies. The downstream effects of
      the intrauterine exposure to diabetes and gestational lipotoxicity will be tested in the
      infant: 1) at birth by studying adipogenic pathways and mitochondrial function in umbilical
      cord mesenchymal stem cells cultured in myogenic conditions[13], and 2) by studying metabolic
      flexibility in the infant in a whole body infant calorimeter in response to a standardized
      meal.

      Mothers will be enrolled between (33-35 weeks of gestation) and their infants will be
      enrolled between 10-30 days of life with the following aims.

      Aim 1. Characterize metabolic flexibility and lipotoxicity in diabetic and non-diabetic
      pregnancies.

      Hypothesis 1A: In response to a standardized meal in late pregnancy, diabetic pregnancies
      will be metabolically inflexible (blunted switch in RQ from the fasted state to the
      postprandial state) compared to non-diabetic pregnancies matched for maternal age and
      pregravid BMI.

      Hypothesis 1B: Placenta from diabetic pregnancies will have higher lipid content, reduced
      mitochondrial content and lower rates of mitochondrial oxygen consumption compared to
      placenta from non-diabetic pregnancies.

      Aim 2. Test whether intrauterine exposure to maternal diabetes infers disordered substrate
      oxidation in offspring at birth (in myocytes cultured from umbilical cord mesenchymal stem
      cells) and early in postnatal life (metabolic flexibility in response to a standardized
      meal).

      Hypothesis 2A: Umbilical cord mesenchymal stem cells cultured in myogenic conditions from
      diabetic pregnancies will have greater lipid content, reduced mitochondrial content, and
      lower rates of mitochondrial electron transport oxygen consumption and fatty acid oxidation.

      Hypothesis 2B: In response to a standardized meal, offspring of diabetic pregnancies will be
      metabolically inflexible (blunted switch in RQ from the pre- to postprandial state) compared
      to offspring of non-diabetic pregnancies.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Up to 20 pregnant women with and without gestational diabetes mellitus with a BMI between
        20 kg/m2 and 40 kg/m2 prior to the current pregnancy.
      
Biospecimen description: 
      Maternal Blood Collection: Approximately 33mL of blood will be collected during the visit.

      Infant Blood Collection: Approximately 2mL of blood will be collected during the visit.