SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018 - 211A

Scientific Abstracts

F-087

F-088
Chronic IGF1 Infusions Increase Pancreatic Insulin Concentrations
But Not Beta-Cell Mass in Fetal Sheep. Alicia White†,2 Samantha
Louey,1 Eileen Chang,2 Brit Boehmer,2 Sonnet Jonker,1 Paul Rozance.2
1
Oregon Health & Science University, Portland, OR, United States;
2
University of Colorado School of Medicine, Aurora, CO, United States.
INTRODUCTION: Fetal insulin secretion is critical for growth
regulation and is partly determined by the amount of β-cells present
and their insulin content. Insulin-like growth factor-1 (IGF1) is a fetal
growth factor which regulates β-cell mass. The extent to which circulating
concentrations of IGF1 impact fetal β-cell mass and pancreatic insulin
content is unknown. We hypothesized that chronic infusions of IGF1
into the fetal sheep circulation would increase β-cell mass and pancreatic
insulin content.
METHODS: Late gestation fetal sheep were infused for one week with
either 6.6 ug/kg/hr of IGF1 Long R3 derivative (LR3, n=8) or saline as a
control (CON, n=10). On the last day of infusions (133±0 days gestation;
term=148 days), fetal arterial oxygen, glucose, and insulin were measured.
The splenic portion of the pancreas was fixed in paraformaldehyde
and the hepatic portion was snap frozen. Four pancreas sections were
immunostained with an anti-insulin antibody and two sections were
stained with a GS1 agglutinin to determine the β-cell area and vascularity,

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respectively. β-cell mass was calculated as the product of β-cell area and
pancreatic mass. Pancreatic insulin was measured by ELISA and mRNA
by real-time quantitative PCR.
RESULTS: Pancreatic insulin concentrations were 80% higher in IGF1
fetuses (P<0.05, Student's t-test), but there were no differences in β-cell
area, β-cells mass, or pancreatic vascularity. Pancreatic expression
of IGF1, IGF2, VEGFA, and HGF mRNA were 70-90% higher in
IGF1 fetuses (P<0.05, Student's t-test). Plasma oxygen, glucose, and
insulin concentrations were 25%, 22%, and 84% lower in IGF1 fetuses,
respectively (P<0.05, Student's t-test).
CONCLUSION: Fetal infusions of IGF1 LR3 for one week late in
gestation increases pancreatic insulin concentrations and expression
of several paracrine growth factors but does not impact pancreatic
vascularity or β-cell mass. Furthermore, IGF1 LR3 infusions lower fetal
plasma insulin concentrations. The previously described role for IGF1
as a β-cell growth factor may be more relevant for local paracrine action
in the pancreas compared to circulating endocrine actions. Alternatively,
fetal hypoglycemia and hypoxemia may have prevented the expected
increase in β-cell mass despite elevated pancreatic insulin and paracrine
growth factor expression.

F-089
Maternal Insulin Resistance Affects Fetal Body Composition. Satoru
Ikenoue,2,3 Feizal Waffarn,3 Kaeko Sumiyoshi,3,4 Masanao Ohashi,3,4
Chigusa Ikenoue,3 Karen Lindsey,3 Buss Claudia,1,3 Sonja Entringer,1,3
Pathik D Wadhwa.3 1Charité University Medicine, Berlin, Germany;
2
Saitama City Hospital, Saitama, Japan; 3University of California, Irvine,
Irvine, CA, United States; 4University of Miyazaki, Miyazaki, Japan.
INTRODUCTION: The adverse consequences of childhood obesity are
well established. The origins of obesity can, in part, be traced back to
developmental processes in the fetus. By the early third trimester, fetal
fat deposition has been shown to correlate with later newborn adiposity.
However, the underlying mechanisms and maternal biomarkers that could
affect fetal fat deposition are less well known. Changes in maternal glucose
homeostasis in pregnancy has been proposed as one of the factors that
influences fetal size and growth. The objective of the present study was
to investigate the influence of maternal insulin resistance across gestation
on fetal adiposity.
METHODS: In a longitudinal study of 137 low-risk pregnancies,
maternal blood test and fetal ultrasonography were performed at 12,
20 and 30 weeks gestation. Maternal homeostasis model assessment
of insulin resistance (HOMA-IR) was calculated by fasting insulin ×
fasting glucose / 405. Estimated fetal adiposity (EFA) was calculated
by integrating measurements of cross-sectional arm and thigh percent
fat area and anterior abdominal wall thickness. The association between
HOMA-IR and EFA was determined by multiple linear regression adjusted
for potential confounding factors including maternal age, parity, race/
ethnicity, pre-pregnancy body mass index, gestational weight gain per
week and sex.
RESULTS: Maternal HOMA-IR was 2.79 ± 1.79 (12 weeks), 2.78 ±
1.54 (20 weeks), and 3.77 ± 2.30 (30 weeks). HOMA-IR at 20 weeks (r
= 0.215, p = 0.011) and 30 weeks (r = 0.285, p = 0.001) were significantly
and positively associated with EFA at 30 weeks. The percent arm fat area
had the greatest influence on the observed effect of HOMA-IR on fetal
fat deposition. This relationship remained significant even after adjusted
for confounding factors.
CONCLUSION: Maternal insulin resistance could be an independent
prospective marker of fetal adiposity in the low-risk pregnancy. Maternal
HOMA-IR measurements in mid-gestation could provide a basis for
clinical intervention during pregnancy that modifies newborn adiposity
and childhood obesity.

Friday Posters

Chronic Anemic Hypoxemia Reduces Muscle Growth in Late
Gestation Fetal Sheep. Laura D Brown,2 Stephanie R Wesolowski,2
Sonnet Jonker,1 Randall B Wilkening,2 William W Hay, Jr.,2 Paul J
Rozance*.2 1Oregon Health and Sciences Center, Portland, OR, United
States; 2University of Colorado School of Medicine, Aurora, CO, United
States.
INTRODUCTION: Fetal muscle hypertrophy requires myoblast
proliferation, differentiation, and fusion into myofibers in addition to
protein accretion. Among the nutrients that regulate this process, oxygen
is particularly important, as poor fetal growth is a characteristic of fetal
hypoxemia and ischemic placental disease. We aimed to determine the
effect of hypoxemia produced by anemia on protein accretion and muscle
growth in late gestation fetal sheep.
METHODS: Fetal catheters were placed into the descending aorta and
femoral and umbilical veins at 119 days gestational age (term ~147 days).
Fetal sheep were bled (Anemic, n=19) with isovolumetric replacement
by saline to a target arterial blood oxygen content of 2 mM (normal ~4
mM) for ~9 days and compared to controls (Con, n=16). A metabolic
study was performed to determine fetal protein metabolic rates. Myoblast
proliferation and myofiber area were determined in biceps femoris (BF),
tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles.
Nuclear PCNA was measured by Western blot and muscle differentiation
factors by qPCR in the BF.
RESULTS: Fetal arterial hematocrit, PO2, and O2 content were 32%,
14%, and 50% lower, respectively, in Anemic vs. Con (P<0.0001). Fetal
plasma concentration of IGF-1 was 28% lower (P<0.01), norepinephrine
was 80% higher (P<0.01), and insulin was not different in Anemic vs. Con.
Fetal weight and whole body protein synthesis, breakdown, and accretion
rates were not different between groups. Hindlimb length, however, was
7% shorter in Anemic (P<0.001). The FDS (P<0.01) and TA (P<0.05)
muscles weighed less and FDS myofiber area was 50% lower in Anemic
vs. Con (P<0.05). There was no difference in Pax7+ nuclei/myofiber, but
the percentage of Pax7+ myoblasts that expressed Ki-67 was 50% lower
in Anemic muscles (P<0.05). In the BF, there was less PCNA (P<0.05),
MYOD (P<0.05), and MYF6 (P=0.06) expression in Anemic vs. Con.
CONCLUSION: Chronic fetal anemic hypoxemia reduced hindlimb
length, muscle growth, myofiber size, myoblast proliferation, and
expression of MYOD. This was in the context of normal fetal weight
and whole body protein accretion rates, indicating that muscle growth
was preferentially limited by a direct effect of fetal hypoxemia and/or
mediated by lower IGF-1 or higher norepinephrine. We speculate that in
pregnancies affected by chronic hypoxemia, reduced muscle mass might
be prevented by strategies that increase fetal oxygenation.

Reproductive Sciences Vol. 25, Supplement 1, March 2018
Table of Contents for the Digital Edition of SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018
