Perinatal programming of metabolic health in guinea pigs

Abstract

Intrauterine growth restriction (IUGR) and neonatal catch-up growth are risk factors for the development of metabolic disease in later life. Developmental programming of insulin resistance is hypothesised to underpin many of these disorders. Animal models are required to investigate the mechanisms underlying this programming of insulin resistance and metabolic disease. Therefore, the current study assessed the effects of spontaneous growth restriction due to natural variation in litter size in the guinea pig on programming of adult metabolic outcomes. Increasing litter size reduced birth weight, birth length and birth weight to length ratio while head dimensions at birth were relatively conserved, indicating head sparing and asymmetrical IUGR. Offspring from larger litters displayed faster neonatal fractional growth and faster absolute and fractional juvenile growth. Relative feed intake in juveniles was increased in offspring from larger litters, and increased neonatal growth also predicted hyperphagia in juveniles. Rapid neonatal growth also correlated with increased visceral adiposity in adult males, but not females, suggesting sex-specific programming of postnatal phenotype. Thus, the spontaneously IUGR guinea pig exhibits key features of human IUGR including neonatal catch-up growth, postnatal hyperphagia and increased fat deposition (Chapter 2). To enable further study of the effects of litter size and neonatal growth on insulin sensitivity, methodology for the hyperinsulinaemic euglycaemic clamp (HEC) was validated for use in the guinea pig. The dose-response curve for whole-body glucose uptake using recombinant human insulin was characterised and HECs with D-[3-3H]-glucose infusion were performed to characterise insulin sensitivities of whole body glucose uptake and partitioning of glucose metabolism in males and females at ~half maximal and near maximal insulin doses. Insulin infusion at 7.5 mU.min-1.kg-1 increased glucose utilisation and storage, while suppressing glucose production, while insulin at 30 mU.min-1.kg-1 also increased the rate of glycolysis. Fasting plasma glucose, metabolic clearance of insulin and rates of glucose utilisation, storage and production during insulin stimulation were higher in female than male guinea pigs, but insulin sensitivity of these and whole body glucose uptake did not differ between sexes (Chapter 3). HEC was then used to assess whole body insulin sensitivity and partitioned glucose metabolism in young adult offspring from varying litter sizes. In males, insulin sensitivities of whole body glucose uptake and glucose utilisation correlated positively, while that of endogenous glucose production tended to correlate positively with birth weight, and these associations were independent of neonatal catch-up growth, adult adiposity and muscle mass. Whole body and partitioned glucose metabolism in young adult females were not related to birth weight, however, the insulin sensitivity of endogenous glucose production correlated negatively with neonatal catch-up growth independently of birth weight. These results suggest a contribution of intrinsic deficits in skeletal muscle and liver to sex-specific perinatal programming of insulin resistance in this species (Chapter 4). Overall, these studies demonstrate that increasing litter size in the guinea pig results in asymmetrical IUGR. The spontaneously growth restricted guinea pig exhibits sex-specific programming of postnatal growth, appetite, adiposity and insulin sensitivity, occurring primarily in males, not unlike that in humans and other animal models. This therefore provides a model for investigating the causal mechanisms and effects of ageing on the perinatal programming of obesity and insulin resistance in liver and skeletal muscle.