Sex-specific perinatal programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size.

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (male=21, female=17) young adult guinea pigs from litters of two to four pups. A subset (male=10, female=8) were infused with D-[3-3 H]-glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. In males, the insulin sensitivity of whole body glucose uptake ( r=0.657, P=0.002) and glucose utilization ( r=0.884, P=0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10-28 ). In females, the insulin sensitivity of whole body and partitioned glucose metabolism were not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10-28 ( r= -0.815, P=0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including of glucose utilization, occurs after IUGR in males, and impaired hepatic insulin sensitivity after rapid neonatal growth in females.