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Impaired β-Cell Function and Inadequate Compensatory Increases in β-Cell Mass after Intrauterine Growth Restriction in Sheep

Research Centre for Early Origins of Adult Disease (K.G., S.N.B.M., M.L.H., M.J.D.B., J.S.R., J.A.O.), Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, South Australia 5005, Australia; and Department of Physiology, Development, and Neuroscience (A.L.F.), University of Cambridge, Cambridge CB2 3EG, United Kingdom

Address all correspondence and requests for reprints to: Professor Julie A. Owens, Research Centre for Early Origins of Adult Disease, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, South Australia 5005, Australia. E-mail: julie.owens{at}adelaide.edu.au.

Poor growth before birth increases the risk of non-insulin-dependent diabetes mellitus (NIDDM) and impairs insulin secretion relative to sensitivity. We investigated the effects of intrauterine growth restriction in sheep on insulin secretion, β-cell mass, and function from before birth to young adulthood and its molecular basis. Pancreas was collected from control and placentally restricted sheep as fetuses (d 143 gestation), lambs (aged 42 d), and young adults (aged 556 d), following independent measures of in vivo insulin secretion and sensitivity. β-Cells and islets were counted after immunohistochemical staining for insulin. In lambs, gene expression was measured by RT-PCR and expressed relative to 18S. β-Cell mass correlated positively with fetal weight but negatively with birth weight in adult males. Glucose-stimulated insulin disposition and β-cell function correlated negatively with fetal weight but positively with birth weight in adult males. Placental restriction increased pancreatic expression of IGF-II and IGF-I but decreased that of voltage-gated calcium channel, 1D subunit (CACNA1D) in lambs. In male lambs, pancreatic IGF-II and insulin receptor expression correlated strongly and positively with β-cell mass and CACNA1D expression with glucose-stimulated insulin disposition. Restricted growth before birth in the sheep does not impair insulin secretion, relative to sensitivity, before birth or in young offspring. IGF-II and insulin receptor are implicated as key molecular regulators of β-cell mass compensation, whereas impaired expression of the voltage-gated calcium channel may underlie impaired β-cell function after intrauterine growth restriction. With aging, the insulin secretory capacity of the β-cell is impaired in males, and their increases in β-cell mass are inadequate to maintain adequate insulin secretion relative to sensitivity.