OR13-3 Preterm Birth in Sheep Alters Adult Pancreatic Beta-Cell Mass and Expression of Key Genes Involved in Insulin Secretion and Hepatic Insulin Sensitivity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR13-Systemic Regulation of Islet Development & Function
Basic/Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:00 PM
Room 304 (Moscone Center)
Amita Bansal*1, Jane M Alsweiler1, Kristin L Connor2, Mike Dragunow1, Jane E Harding1 and Frank H Bloomfield3
1University of Auckland, Auckland, New Zealand, 2Mount Sinai Hospital, Toronto, ON, Canada, 3Gravida: National Centre for Growth & Development, Auckland, New Zealand
Background: Fetal exposure to a hyperglycemic environment predisposes offspring to impaired glucose tolerance (IGT) in adulthood. Preterm babies also commonly are hyperglycemic and treated with insulin, and are at risk of IGT in adulthood. Objective: We investigated in preterm lambs whether neonatal hyperglycemia has long-term effects on β-cell mass and on key genes involved in insulin secretion and hepatic insulin sensitivity, and whether restoration of euglycemia with insulin treatment reverses these effects. Methods: Pancreata and liver tissue were collected at 12 months of age from lambs born at term (148d; term controls) or preterm (137d) (n=12-13 per group), following antenatal glucocorticoids as given clinically. Preterm lambs were randomised to saline controls, hyperglycemic (50% dextrose infused intravenously for 12d to maintain blood glucose concentration (BGC) at 10-12 mmol/L), or insulin treated hyperglycemic (hyperglycemia treated with insulin to achieve euglycemia (BGC= 4-6 mmol/L)) groups. ß-cell mass and islet size were determined using Metamorph automated quantitative analysis of pancreatic sections triple-immunofluorescent stained for insulin, glucagon & somatostatin proteins. Data were analysed by 2-way ANOVA, with post-hoc Tukey’s test if p<0.05. mRNA levels, calculated as fold change with 99% confidence intervals, were determined by qPCR normalised to 3 housekeeping genes. Results: All preterm lamb groups had similar ß-cell mass which was approximately half that in term lambs, with significantly smaller islets (p<0.05). Preterm birth also reduced pancreatic mRNA expression of igf-2, glucokinase (gck) and insulin. Hyperglycemia further reduced mRNA expression of pdx1, igf-I and gck; this was not reversed with insulin treatment. Preterm birth increased hepatic mRNA expression of PEPCK and PPAR-α but not of SREBP1. Hyperglycemia reduced mRNA expression of GLUT2 and PPAR-α; insulin treatment restored GLUT2 and PPAR-α mRNA expression to levels of preterm controls. Conclusions: Preterm birth in sheep leads to reduced β-cell mass in adulthood, independent of neonatal hyperglycemia or its treatment with insulin. Preterm birth also altered expression of key genes involved in insulin secretion and hepatic insulin sensitivity; this was exacerbated by hyperglycemia and partially reversed with insulin treatment. These findings may inform mechanisms underlying IGT in adults born preterm.

Nothing to Disclose: AB, JMA, KLC, MD, JEH, FHB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: University of Auckland Doctoral Scholarship; Health Research Council, New Zealand; Lottery Health, Lottery Grants Board, New Zealand; Gravida: National Centre for Growth and Development, New Zealand.