Maternal and sex dependency of insulin resistance: longitudinal PET and echocardiography study from the healthy fetus to the adult minipig.
Cardiovascular and metabolic vulnerability have an early developmental origin. We evaluated the potential influence of innate life factors, including the metabolism of the mother and the sex of the offspring, on cardiometabolic risk, including organ-specific insulin resistance, subclinical cardiac dysfunction, and DNA oxidative damage throughout the lifespan.


METHODS
Two female minipigs were studied during late pregnancy, and their offspring were restudied at the ages of 1 mo (n = 11), 6 mo (n = 9), and 9 mo (n = 10, 6 offspring and 4 age-matched animals). We measured insulin-mediated glucose disposal in skeletal muscle, adipose tissue, liver, and myocardium using (18)F-FDG PET; cardiac function using 2-dimensional strain echocardiography; and DNA damage using the comet assay.


RESULTS
Glucose metabolism showed the 2 sows to have differences similar to those in their respective 1-mo-old offspring. Over time, compared with female animals, male animals developed myocardial insulin resistance (male animals vs. female animals: 34 ± 5 vs. 58 ± 8 μmol/min/kg at 6 mo, P = 0.03; 29 ± 8 vs. 60 ± 7 μmol/min/kg at 9 mo, P = 0.02). Cardiac function progressively deteriorated in male animals from 1 mo (radial strain, -60% ± 7%; strain rate, -5.4 ± 0.9 s(-1)) to 6 mo (radial strain, -41% ± 5%; strain rate, -2.5 ± 0.2 s(-1), P < 0.05 vs. 1 mo) and 9 mo (radial strain, -32% ± 5%; strain rate, -1.6 ± 0.2 s(-1), P < 0.01 vs. 1 mo) and was significantly different from that in female animals (radial strain, -48% ± 4%; strain rate, -3.1 ± 0.2 s(-1), P < 0.05 and P < 0.01, respectively). Oxidative damage was reduced in female animals and increased in male animals across age categories (P < 0.05).


CONCLUSIONS
The metabolism of minipig offspring is influenced by maternal insulin sensitivity during early life stages. Sex-related effects prevail thereafter in healthy minipigs, documenting a precocious onset of cardiometabolic vulnerability in male offspring.
Institute of Clinical Physiology, National Research Council, Pisa, Italy.
Letizia
L
Guiducci
Silvia
S
Burchielli
Vlad
V
Chubuchny
Rosa
R
Sicari
Tiziana
T
Liistro
Anca I
AI
Corciu
Silvia
S
Pardini
Pietro
P
Di Cecco
Samantha
S
Manfredi
Marco
M
Bucci
Piero A
PA
Salvadori
Maria Grazia
MG
Andreassi
Patricia
P
Iozzo
D000818:Animals; D004249:DNA Damage; D005260:Female; D005333:Fetus / Q000000981:diagnostic imaging* / Q000378:metabolism; D006262:Health; D006321:Heart / Q000000981:diagnostic imaging / Q000502:physiology; D007333:Insulin Resistance; D008137:Longitudinal Studies; D008297:Male; D009035:Mothers; D009928:Organ Specificity; D018384:Oxidative Stress / Q000235:genetics; D049268:Positron-Emission Tomography; D011247:Pregnancy; D012727:Sex Characteristics; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D016216:Ultrasonography, Prenatal