Department of Obstetrics and Gynecology (C.S.B., C.Y.), Baylor College of Medicine, Houston, Texas 77030; and Division of Reproductive Endocrinology (K.S., V.C.), Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555.
Endocrinology. 2014 Aug;155(8):3036-46. doi: 10.1210/en.2014-1094. Epub 2014 May 5.
Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet-exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet-fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor substrate-1, and AS160 phosphorylation and impaired glucose transporter type 4 translocation.
2 型糖尿病源于多种遗传和环境因素。最近的研究表明，不良的子宫环境，如妊娠期低蛋白（LP）饮食，会导致成年后代出现胰岛素抵抗。妊娠期蛋白质限制引起胰岛素抵抗的机制尚不清楚。我们的目的是研究胰岛素信号分子在妊娠期 LP 饮食暴露雄性后代腓肠肌中的作用，以了解它们在 LP 诱导的胰岛素抵抗中的作用。从妊娠第 4 天到分娩，妊娠 Wistar 大鼠分别给予对照（20%蛋白）或等热量 LP（6%）饮食，断奶后给予正常饮食。本研究仅使用雄性后代。葡萄糖耐量试验后评估葡萄糖和胰岛素反应。4 个月时评估腓肠肌中参与胰岛素信号的分子的 mRNA 和蛋白水平。肌肉在体外用胰岛素孵育，以评估胰岛素诱导的胰岛素受体（IR）、胰岛素受体底物-1、Akt 和 AS160 的磷酸化。LP 饮食喂养的大鼠在妊娠期间体重增加较少。来自 LP 饮食喂养母亲的雄性幼仔较小，但表现出追赶生长。葡萄糖耐量试验时，LP 后代的血浆葡萄糖和胰岛素水平升高；然而，空腹水平相当。LP 后代腓肠肌中 IR 和 AS160 的表达增加。体外用胰岛素处理肌肉显示对照中 IR（Tyr972）的磷酸化增加，但 LP 大鼠表现出更高的基础磷酸化。胰岛素受体底物-1（Tyr608、Tyr895、Ser307 和 Ser318）和 AS160（Thr642）的磷酸化在 LP 后代中存在缺陷。此外，LP 后代的葡萄糖转运蛋白 4 易位也受损。妊娠期 LP 饮食通过一种机制导致成年后代胰岛素抵抗，该机制涉及 IR、胰岛素受体底物-1 和 AS160 磷酸化效率低下以及葡萄糖转运蛋白 4 易位受损。
