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Improved Lactational Nutrition and Postnatal Growth Ameliorates Impairment of Glucose Tolerance by Uteroplacental Insufficiency in Male Rat Offspring

Departments of Physiology (A.L.S., A.M., K.T.W., M.E.W.) and Pharmacology (L.P.), The University of Melbourne, Victoria 3010, Australia; School of Pediatrics and Reproductive Health (M.J.D.B., J.A.O.), Disciplines of Obstetrics and Gynecology, University of Adelaide, South Australia 5005, Australia; and Department of Pharmacology (M.J.M.), University of New South Wales, New South Wales 2052, Australia

Address all correspondence and requests for reprints to: Dr. Andrew Siebel, Department of Physiology, University of Melbourne, Parkville, 3010, Australia. E-mail: asiebel{at}unimelb.edu.au.

Intrauterine growth restriction and accelerated postnatal growth predict increased risk of diabetes. Uteroplacental insufficiency in the rat restricts fetal growth but also impairs mammary development and postnatal growth. We used cross fostering to compare the influence of prenatal and postnatal nutritional restraint on adult glucose tolerance, insulin secretion, insulin sensitivity, and hypothalamic neuropeptide Y content in Wistar Kyoto rats at 6 months of age. Bilateral uterine vessel ligation (restricted) to induce uteroplacental insufficiency or sham surgery (control) was performed on d-18 gestation. Control, restricted, and reduced (reducing litter size of controls to match restricted) pups were cross fostered onto a control or restricted mother 1 d after birth. Restricted pups were born small compared with controls. Restricted males, but not females, remained lighter up to 6 months, regardless of postnatal environment. By 10 wk, restricted-on-restricted males ate more than controls. At 6 months restricted-on-restricted males had increased hypothalamic neuropeptide Y content compared with other groups, and together with reduced-on-restricted males had increased retroperitoneal fat weight (percent body weight) compared with control-on-controls. Restricted-on-restricted males had impaired glucose tolerance, reduced first-phase insulin secretion, but unaltered insulin sensitivity, compared with control-on-controls. In males, being born small and exposed to an impaired lactational environment adversely affects adult glucose tolerance and first-phase insulin secretion, but improving lactation partially ameliorates this condition. This study identifies early life as a target for intervention to prevent later diabetes after prenatal restraint.