Cinti S, Eberbach S, Castellucci M, Accili D
Istituto di Morfologia Umana Normale, Facoltá di Medicina e Chirurgia, Universitá di Ancona, Italy.
Diabetologia. 1998 Feb;41(2):171-7. doi: 10.1007/s001250050886.
Lack of insulin receptors in mice is associated with near-normal intrauterine growth, unlike patients with leprechaunism, in whom growth deficiency is a prominent clinical feature. Genetic crosses of insulin receptor- and insulin-like growth-factor-1 (IGF-1) receptor-deficient mice indicate, however, that insulin receptors play an important role in late gestational growth, and that absence of growth retardation in insulin receptor-deficient (IR-/-) mice may be due to a compensatory increase in IGF-1 receptor levels. In human fetuses, insulin has a paramount role in the generation and maintenance of adipose tissue, as demonstrated by changes associated with genetic and maternally caused fetal hyperinsulinaemia. In the present study, we have investigated whether genetic ablation of insulin receptors affects differentiation and trophism of white adipose tissue, the main target organ for the growth-promoting actions of fetal insulin. Histological, immunohistochemical, and ultrastructural analyses of white dermal adipose tissue were performed in newborn IR-/- mice, as well as normal (IR +/+ ) and heterozygous controls (IR+/-). Stereological measurements revealed a marked decrease of the adipose area in IR-/- mice compared to IR+/+ and IR+/- mice. Fat cell depletion resulted mainly from a reduction of adipocyte volume ( approximately 90 %), with a small decrease of adipocyte number. Electron microscopy analysis detected all stages of differentiation of the adipocyte precursor in IR-/- mice, suggesting that lack of insulin receptors is not associated with selective impairment of the adipocyte differentiation process. These data are consistent with a bi-modal action of fetal insulin receptors, one to mediate embryonic growth in response to IGF-2, and one to mediate adipose cell formation in response to insulin.
与妖精貌综合征患者不同，小鼠缺乏胰岛素受体会导致子宫内生长接近正常，而生长发育迟缓是妖精貌综合征患者的一个突出临床特征。然而，胰岛素受体和胰岛素样生长因子-1（IGF-1）受体缺陷小鼠的基因杂交实验表明，胰岛素受体在妊娠后期生长中起重要作用，胰岛素受体缺陷（IR-/-）小鼠没有生长迟缓可能是由于IGF-1受体水平的代偿性增加。在人类胎儿中，胰岛素在脂肪组织的生成和维持中起至关重要的作用，这一点已通过与遗传性和母体引起的胎儿高胰岛素血症相关的变化得到证实。在本研究中，我们调查了胰岛素受体的基因敲除是否会影响白色脂肪组织的分化和营养作用，白色脂肪组织是胎儿胰岛素促生长作用的主要靶器官。对新生IR-/-小鼠以及正常（IR +/+ ）和杂合对照组（IR+/-）的白色真皮脂肪组织进行了组织学、免疫组织化学和超微结构分析。体视学测量显示，与IR+/+ 和IR+/-小鼠相比，IR-/-小鼠的脂肪面积显著减少。脂肪细胞减少主要是由于脂肪细胞体积减小（约90%），脂肪细胞数量略有减少。电子显微镜分析检测到IR-/-小鼠脂肪细胞前体的所有分化阶段，这表明缺乏胰岛素受体与脂肪细胞分化过程的选择性损害无关。这些数据与胎儿胰岛素受体的双模态作用一致，一种作用是介导对IGF-2的胚胎生长反应，另一种作用是介导对胰岛素的脂肪细胞形成反应。
