Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition

1 Centre for Reproduction and Early Life, School of Human Development, University Hospital, Nottingham; 2 Department of Clinical Biochemistry, Addenbrookes Hospital, University of Cambridge, Cambridge; 3 School of Nursing, University of Nottingham, Mansfield, United Kingdom; and 4 Department of Animal Sciences, University of Missouri, Columbia, Missouri Submitted 17 February 2005 ; accepted in final form 10 June 2005 The present study examines the effects of late vs. early gestation undernutrition on adult glucose-insulin homeostasis in sheep and investigates whether the lower birth weight of twins alters glucose-insulin handling in adult life. Pregnant sheep were fed to requirement (100% intake) from day 0 of gestation to term [ 147 days of gestation (dGA), control singles (CS) n = 5; control twins (CT) n = 5] or to 50% requirement from days 0 – 30 dGA [nutrient restricted during early gestation (NRE); n = 5] or day 110 -term [NR during late nutrition (NRL); n = 4]. At all other times, NR sheep received 100% intake. All sheep lambed naturally; offspring were weaned at 10 wk and were reared on pasture until 1 yr of age. At this time, indwelling catheters were inserted, and 2–4 days later, basal metabolic and endocrine status and responses to an intravenous glucose tolerance test (IVGTT) and feeding were assessed. Adipose and skeletal muscle were then sampled after humane euthanasia and were analyzed for expression of insulin-signaling proteins and GLUT4. Between groups, birth weight of singletons was similar and increased relative to twins. At 1 yr of age, weights were similar between groups. The areas under the curve for glucose and insulin during the IVGTT were greater in NRL vs. other groups, indicating glucose intolerance. This was associated with reduced adipose, but not muscle, GLUT4, and increased adipose tissue mass. Adult glucose-insulin homeostasis in sheep was unaffected by fetal number. In conclusion, prenatal undernutrition, specifically during late gestation, affects adult offspring intermediary metabolism, and, in particular, glucose-insulin homeostasis. type 2 diabetes; maternal nutrition; adipose; glucose tolerance test; leptin Address for reprint requests and other correspondence: D. Gardner, School of Human Development, Academic Div. of Child Health, Univ. Hospital, Nottingham, NG7 2UH, UK (e-mail: david.gardner{at}nottingham.ac.uk )