Maternal and Sex Dependency of Insulin Resistance: Longitudinal PET and Echocardiography Study from the Healthy Fetus to the Adult Minipig

Abstract

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 5 11), 6 mo (n 5 9), and 9 mo (n 5 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 6 5 vs. 58 6 8 mmol/min/kg at 6 mo, P 5 0.03; 29 6 8 vs. 60 6 7 mmol/min/kg at 9 mo, P 5 0.02). Cardiac function progressively deteriorated in male animals from 1 mo (radial strain, 260% 6 7%; strain rate, 25.4 6 0.9 s 21 ) to 6 mo (radial strain, 241% 6 5%; strain rate, 22.5 6 0.2 s 21 , P , 0.05 vs. 1 mo) and 9 mo (radial strain, 232% 6 5%; strain rate, 21.6 6 0.2 s 21 , P , 0.01 vs. 1 mo) and was significantly different from that in female animals (radial strain, 248% 6 4%; strain rate, 23.1 6 0.2 s 21 , 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). Conclusion: 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.

Developmental ORIgins of Healthy and Unhealthy AgeiNg: The Role of Maternal Obesity - Introduction to DORIAN

“…In a small study on minipigs, we introduced the use of positron emission tomography as a way to measure (repeatedly over time) organ-specific insulin sensitivity. Our results showed that mother and offspring had very similar metabolic features at the time of birth and lactation, but strong factors, such as sex and growth (rate of weight change), may come into play after weaning [ 35 ].…”

Independent effects of circulating glucose, insulin and NEFA on cardiac triacylglycerol accumulation and myocardial insulin resistance in a swine model

“…injection and a 60 min dynamic scan was started. Arterial blood samples were taken every 30 min for the measurement of plasma glucose, TG, cholesterol, NEFA, β-hydroxybutyrate (3-OHB) and [U- 13 C]palmitate enrichment in the NEFA and TG pools as previously described [18,19]. Vital signs, haematocrit, blood pressure and heart rate (HR) were monitored throughout the study.…”

“…The infusion protocols were started, and at t=230 min a transmission scan was performed to measure photon attenuation. At t=240 min, the glucose analogue 18 F-FDG (284±15 MBq, mean±SEM) was administered by rapid i.v. injection and a 60 min dynamic scan was started.…”

“…The injected 18 F-FDG dose was discounted for the average 20% of 18 F-FDG found in the urine, as measured in a subset of animals. The resulting dose was divided by the integral of plasma activity from t=0 to t=∞ to obtain the metabolic glucose clearance rate.…”

“…Regions of interest were drawn on images corresponding to three consecutive planes of the left ventricle to obtain myocardial 18 F-FDG time-activity curves, and at the base of the left ventricular chamber of the heart to obtain corresponding input functions, representing the amount of tracer available in the circulation for organ extraction over time. The curves were corrected for residual spillover and partial volume effects [20].…”