Restriction of Placental Growth Increases Plasticity of Insulin Secretion in Response to Hyperglycemic Challenge in Adult Sheep

Presentation Number: SAT-0947
Date of Presentation: June 21st, 2014

Kathryn L Gatford*, Hong Liu, Zuleeza Ahmad, Miles J De Blasio, Gary K Heinemann, Tina Bianco-Miotto and Julie A Owens
University of Adelaide, Adelaide, Australia

Abstract

Restricted growth before birth (IUGR) increases the risk of diabetes in adulthood (1), implying that insulin secretion fails to adequately adapt and up-regulate in response to insulin resistance. Consistent with this, in adult IUGR men (2) and in sheep with IUGR induced by surgical placental restriction (3), insulin secretion is inadequate for the level of insulin resistance. Effects of IUGR on adaptive changes in insulin secretion in response to increased demand for insulin have not been directly tested, however. We have developed a direct test of the plasticity of insulin secretion, using chronic mild hyperglycemia to increase the demand for insulin in sheep (4). We hypothesised that PR would impair plasticity of insulin secretion when challenged by hyperglycemia in the adult sheep. We therefore measured glucose tolerance and insulin secretion and β-cell mass and function in adult sheep born from control (CON) pregnancies and growth-restricted (PR) pregnancies before and during 16 days of moderate hyperglycemia (HG) or euglycemia (EUG) (20 CON-EUG; 20 CON-HG; 15 PR-EUG; 15 PR-HG). Hyperglycemia impaired glucose tolerance (AUC glucose increased by 100%, P < 0.001) and increased insulin secretion (particularly second phase; two-fold, P < 0.001). Hyperglycemia also increased β-cell function (particularly second phase; 6.5-fold, P = 0.034) in males. Placental restriction did not alter glucose tolerance, β-cell mass or β-cell function but impaired insulin secretion (particularly second phase; P = 0.030) in male singletons. Placental restriction in the face of hyperglycemic challenge did not alter glucose tolerance or β-cell mass. However, hyperglycemia induced greater increases in first phase insulin secretion (+50%, P < 0.001) and β-cell function (particularly second phase, 4.5-fold, P = 0.016) in PR sheep than CON sheep. Contrary to our hypothesis, placental restriction enhanced the plasticity of insulin secretion in response to hyperglycemic challenge in young adult sheep. Together with the elevated glucose-stimulated insulin secretion we previously observed in vitro in islets from twin lambs, compared to those from singletons (5), this suggests that IUGR induces insulin hyper-secretion from β-cells, at least in young sheep. Whether this β-cell compensatory adaptation leads to exhaustion of β-cells with ageing and the onset of type 2 diabetes is yet to be investigated.

 

Nothing to Disclose: KLG, HL, ZA, MJD, GKH, TB, JAO