Plagemann A, Harder T, Janert U, Rake A, Rittel F, Rohde W, Dörner G
Institute of Experimental Endocrinology, Humboldt University Medical School (Charité), Berlin, Germany.
Dev Neurosci. 1999;21(1):58-67. doi: 10.1159/000017367.
Insulin is a potent modulator of central nervous development and is suggested to influence the differentiation and maturation of hypothalamic structures involved in the regulation of body weight and metabolism. Hyperinsulinemic offspring of mothers with impaired glucose tolerance during pregnancy (gestational diabetes, GD) have an increased risk to develop overweight and diabetes mellitus during life, while the underlying pathophysiological mechanisms are still unknown. To investigate the effects of perinatal hyperinsulinism on the organization of hypothalamic regulators of body weight and metabolism, GD was induced in rats by application of streptozotocin on the day of conception (25 mg/kg, i.p.). On the 21st day of life, offspring of GD rats were overweight (p < 0.05) and hyperinsulinemic (p < 0.01). Using computer-assisted morphometric measurements, significantly decreased mean areas of neuronal nuclei and neuronal cytoplasm within the paraventricular hypothalamic nucleus (PVN; p < 0.01) and the ventromedial hypothalamic nucleus (VMN; p < 0.05) were observed in GD offspring. Analysis of topographically distinct parts revealed that these alterations particularly occurred in the parvocellular part of the PVN, as well as in the anterior, central, and dorsomedial part of the VMN. No morphometric alterations were found within the lateral hypothalamic area and the dorsomedial hypothalamic nucleus. In the arcuate hypothalamic nucleus, the mean area of neuronal cytoplasm was decreased (p < 0.05), while the number of neurons expressing tyrosine hydroxylase was clearly elevated (p < 0.002). For astrocytes, a tendency towards an increased glia/neuron ratio was observed in the periventricular hypothalamic area. These observations suggest disturbed differentiation and organization of distinct hypothalamic nuclei and subnuclei, respectively, in hyperinsulinemic offspring of GD rats, possibly leading to dysfunctions of hypothalamic regulators of body weight and metabolism which might contribute to the lifelong increased risk to develop overweight and diabetogenic disturbances.
胰岛素是中枢神经发育的一种强效调节剂，据推测它会影响参与体重和新陈代谢调节的下丘脑结构的分化与成熟。孕期糖耐量受损（妊娠期糖尿病，GD）母亲所生的高胰岛素血症后代在一生中患超重和糖尿病的风险增加，但其潜在的病理生理机制仍不清楚。为了研究围产期高胰岛素血症对体重和新陈代谢的下丘脑调节因子组织的影响，在受孕当天给大鼠腹腔注射链脲佐菌素（25 mg/kg）诱导其患妊娠期糖尿病。在出生后第21天，妊娠期糖尿病大鼠的后代超重（p < 0.05）且高胰岛素血症（p < 0.01）。使用计算机辅助形态测量法，在妊娠期糖尿病后代中观察到下丘脑室旁核（PVN；p < 0.01）和下丘脑腹内侧核（VMN；p < 0.05）内神经元细胞核和神经元细胞质的平均面积显著减小。对不同区域的分析表明，这些改变尤其发生在室旁核的小细胞部，以及腹内侧核的前部、中部和背内侧部。在下丘脑外侧区和下丘脑背内侧核内未发现形态测量学改变。在弓状核中，神经元细胞质的平均面积减小（p < 0.05），而表达酪氨酸羟化酶的神经元数量明显增加（p < 0.002）。对于星形胶质细胞，在下丘脑室周区观察到胶质细胞/神经元比率有增加的趋势。这些观察结果表明，妊娠期糖尿病大鼠的高胰岛素血症后代中，不同的下丘脑核团和亚核团分别存在分化和组织紊乱，这可能导致下丘脑体重和新陈代谢调节因子功能失调，进而可能导致一生中患超重和糖尿病性疾病的风险增加。
