Maternal methyl donor and cofactor supplementation in late pregnancy increases β-cell numbers at 16 days of life in growth-restricted twin lambs

Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at days 12-14 in singleton controls (CON, n = 7 lambs from 7 ewes), twins (IUGR, n = 8 lambs from 8 ewes), and twins from ewes that received MMDS (2 g rumen-protected methionine, 300 mg folic acid, 1.2 g sulfur, 0.7 mg cobalt) daily from 120 days after mating (~0.8 of term) until delivery (IUGR+MMDS, n = 8 lambs from 4 ewes). Body composition and pancreas morphometry were assessed in lambs at day 16 IUGR reduced size at birth and increased neonatal fractional growth rate. MMDS normalized long bone lengths but not other body dimensions of IUGR lambs at birth. IUGR did not impair glucose control or insulin action at days 12-14, compared with controls. MMDS increased metabolic clearance rate of insulin and increased β-cell numerical density and tended to improve insulin sensitivity, compared with untreated IUGR lambs. This demonstrates that effects of late-pregnancy methyl donor supplementation persist until at least the third week of life. Whether these effects of MMDS persist beyond early postnatal life and improve metabolic outcomes after IUGR in adults and the underlying mechanisms remain to be determined.