Pediatr Res. 2016 Dec;80(6):861-869. doi: 10.1038/pr.2016.168.

Brief neonatal nutritional supplementation has sex-specific effects on glucose tolerance and insulin regulating genes in juvenile lambs.

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BACKGROUND: The nutritional plane and composition during fetal life can impact upon growth and epigenetic regulation of genes affecting pancreatic beta-cell development and function. However, it is not clear whether beta-cell development can be altered by nutritional factors or growth rate after birth. We therefore investigated the effect of neonatal nutritional supplements on growth, glucose tolerance, and pancreatic development in lambs. METHODS: Newborn lambs were randomized to daily nutritional supplements, calculated to increase macronutrient intake to a similar degree as human breast milk fortifier, or an equivalent volume of water, for 2wk while continuing to suckle ewe milk. Intravenous glucose tolerance test (IVGTT) was performed at 4 mo of age, and pancreata collected for molecular analysis. RESULTS: Supplemented lambs had slower weight gain than controls. In supplemented lambs, insulin response to IVGTT was increased in males but decreased in females, compared to same sex controls, and was unrelated to growth rate. mRNA expression of key genes in beta-cell development showed sexually dimorphic effects. Epigenetic change occurred in the promotor region of PDX1 gene with decreased suppression and increased activation marks in supplemented lambs of both sexes. CONCLUSION: Nutritional interventions in early life have long-term, sex-specific effects on pancreatic function.


Additional information

Insulin production and secretion by β cells in the pancreatic islets is key to glucose regulation. The nutritional environment in utero can impact on pancreatic development; for example, maternal nutrient deficiency resulting in poor fetal growth has been shown in several species to decrease the number of β cells, limiting insulin secreting capacity [1-3], while maternal ‘overnutrition’ or obesity in sheep is associated with β cell proliferation [4]. Both may contribute to an increased risk of the offspring developing type 2 diabetes in later life.

It is less clear whether manipulations of dietary composition after birth can similarly alter pancreatic function, particularly in large mammals and humans in whom pancreatic development is relatively advanced at birth. Although the recommended food for newborn babies is breast milk, some infants receive alternative or supplemental feeds which alter caloric intake, growth rate and the macronutrient composition of their diet, any or all of which may in turn impact on β cell development.

In newborn healthy term lambs, we investigated the effect on growth and pancreatic function of giving nutritional supplements containing protein and carbohydrate, similar to breast milk fortifier used to promote growth in human neonates but adjusted for ewe milk composition, in the first two weeks after birth. During this time and after the period of supplementation, lambs continued to suckle milk from the ewe until they were weaned onto pasture and separated from the ewe at 12 weeks of age.

Growth rate was monitored. Intravenous glucose tolerance tests were performed when the lambs were 4 months old. This age was chosen as the lambs were weaned but still prepubertal. Pancreata were collected on completion of the glucose tolerance test.

Contrary to our expectations, supplemented lambs gained weight more slowly than unsupplemented lambs, despite similar caloric intake. (Figure 1)

The glucose tolerance tests showed an increased insulin response to glucose in supplemented males, but decreased response in females compared with same sex unsupplemented lambs. (Figure 2; glucose bolus given intravenously at time 0).

The fact that mRNA expression of genes involved in β cell development was also altered in a sexually dimorphic manner suggests that the nutritional environment in the developmentally plastic period after birth affects pancreatic development and function differently in males and females. Growth and body composition are different between the sexes, therefore nutrients will be used differently under the influence of sex hormones and other factors which modify metabolism. This study demonstrates how powerful even brief dietary interventions affecting macronutrient balance can be during key developmental ‘windows’. The findings suggest that nutritional interventions in the neonatal period may have to have to be designed differently for males and females.

1. Jensen, E.C., et al., Metabolic effects of IGF-I in the growth retarded fetal sheep. Journal of Endocrinology., 1999. 161(3): p. 485-94.
2. Beringue, F., et al., Endocrine pancreas development in growth-retarded human fetuses. Diabetes., 2002. 51(2): p. 385-91.
3. Sandovici, I., et al., Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes. Cellular & Molecular Life Sciences, 2013. 70(9): p. 1575-95.
4. Ford, S.P., et al., Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. American Journal of Physiology – Regulatory Integrative & Comparative Physiology, 2009. 297(3): p. R835-43.