Morten K, Field P, Ashley N, Williams K A, Harris D, Hartley M, Clark A, Poulton J
Nuffield Dept. of Obstetrics and Gynaecology, the Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Am J Physiol Endocrinol Metab. 2005 Dec;289(6):E1115-8. doi: 10.1152/ajpendo.00226.2005. Epub 2005 Jul 12.
Zidovudine (AZT) lowers the perinatal transmission of HIV but can impair mitochondrial function by depleting mitochondrial DNA (mtDNA). AZT therapy and perinatal nutritional deprivation affect the body fat distribution, which influences glucose tolerance. We sought to model intrauterine exposure to AZT in humans to determine whether it interacts with low-protein diet (LPD) to impact on birth weight and glucose homeostasis in the offspring. Pregnant dams and their offspring were given AZT, an LPD, or AZT and an LPD (LPD + AZT). AZT reduced mtDNA copy number in liver and birth weight in the offspring and increased their fasting glucose and insulin (P = 0.021, 0.03, 0.001, and 0.011 respectively) at 6-8 wk of age. LPD decreased litter size and birth weight (P = 0.01 and 0.012). In the LPD + AZT group, birth weight and litter size were reduced compared with untreated controls, and fasting blood glucose and insulin were raised. There was a significant interaction between LPD and AZT on fasting insulin levels (P = 0.025). Islet size was not significantly affected, but the mean beta-cell area/islet was reduced in the LPD + AZT group compared with controls (P < 0.05). Early exposure to AZT interacts with LPD to impair fetal development in this model. This combination appeared to impair the supply of insulin and, hence, glucose homeostasis, perhaps as a result of impaired mitochondrial function. Although it is not certain that this can be extrapolated to humans, maternal nutritional deprivation combined with AIDS therapy could influence both birth weight and onset of diabetes.
齐多夫定（AZT）可降低围产期HIV传播，但会通过消耗线粒体DNA（mtDNA）损害线粒体功能。AZT治疗和围产期营养缺乏会影响身体脂肪分布，进而影响葡萄糖耐量。我们试图建立人类子宫内暴露于AZT的模型，以确定其是否与低蛋白饮食（LPD）相互作用，影响后代的出生体重和葡萄糖稳态。给怀孕的母鼠及其后代给予AZT、LPD或AZT加LPD（LPD+AZT）。AZT降低了后代肝脏中的mtDNA拷贝数和出生体重，并在6-8周龄时增加了它们的空腹血糖和胰岛素水平（分别为P=0.021、0.03、0.001和0.011）。LPD减少了窝仔数和出生体重（P=0.01和0.012）。在LPD+AZT组中，与未治疗的对照组相比，出生体重和窝仔数降低，空腹血糖和胰岛素升高。LPD和AZT对空腹胰岛素水平有显著的相互作用（P=0.025）。胰岛大小没有受到显著影响，但与对照组相比，LPD+AZT组的平均β细胞面积/胰岛减小（P<0.05）。在这个模型中，早期暴露于AZT与LPD相互作用会损害胎儿发育。这种组合似乎损害了胰岛素的供应，从而影响了葡萄糖稳态，这可能是线粒体功能受损的结果。虽然不确定这是否可以外推到人类，但母亲营养缺乏与艾滋病治疗相结合可能会影响出生体重和糖尿病的发病。
