Investigation of Mechanisms for Transmission of Impaired Glucose Metabolism in Infants Exposed to Diabetes in Utero

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.

Inclusion Criteria (Mother):

- BMI between 20 kg/m2 and 40 kg/m2 prior to the current pregnancy (determined by
self-report and confirmation of pregravid BMI of the index pregnancy from the prenatal
record)

- Completion of standardized glucose tolerance testing (between 24-28 weeks gestation)
in the index pregnancy; either a single 2 hour, 75g glucose tolerance test or the
two-step: 1 hour 50g and 3 hour 100g glucose tolerance test to confirm diagnosis of
gestational diabetes mellitus or normal glucose tolerance

- Prior history of Cesarean section or planned Cesarean section for current pregnancy

- Medically cleared for participation in the study by primary care obstetrician or
midwife

- Medically cleared for participation by the Medical Investigator

- Medical record release (prenatal record, hospital delivery record) for study staff to
access information in the medical record related to the current and if applicable, the
prior pregnancy.

- Willingness to enroll the infant in the study provided inclusion/exclusion criteria
pertaining to the infant are met

Inclusion criteria (Infant):

- Born full-term (>37,0 weeks gestation)

- Available for clinical assessments between 10-30 days old

- Healthy

Exclusion Criteria (Mother):

- Use of insulin therapy in the index pregnancy

- History of preterm birth

- History of intrauterine growth-restriction

- Evidence of gestational hypertension (SBP >160 mmHg & DBP >110 mmHg)

- HIV or AIDS (self-reported)

- Planned termination of pregnancy or adoption or unwillingness to enroll the infant in
the study

Exclusion Criteria (Infant):

- Using medications to treat a chronic condition (does not include use of vitamin
supplements or PRN medication for flatulence)

- Unwilling or unable to be fed 2 fl oz of infant formula

- Diagnosed with a congenital abnormality or disability that would render testing unsafe
or would interfere with data collection