Li H Y, Oh Y S, Lee Y-J, Lee E-K, Jung H S, Jun H-S
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Songdo-dong, Yeonsu-ku, Incheon, Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, Korea.
Exp Clin Endocrinol Diabetes. 2015 Apr;123(4):221-6. doi: 10.1055/s-0034-1395583. Epub 2014 Dec 11.
In this study, we investigated whether Smad4 signaling is involved in the regulation of beta-cell function using a high fat diet (HFD)-induced obesity mouse model.
Beta-cell-specific Smad4-knockout mice (Smad4(-/-)RIP-Cre(+); β-Smad4KO) were generated by mating Smad4 (flox/flox) mice with rat insulin promoter (RIP)-Cre mice. Mice were fed a HFD beginning at 6 weeks of age for 16 weeks. Body weight, food intake, fasting and fed glucose levels, and glucose and insulin tolerance were measured.
The expression of Smad4 mRNA was significantly decreased in the islets of β-Smad4KO mice. In wild-type mice, Smad4 mRNA was significantly decreased at 18 weeks of age as compared with 8 weeks of age. On a regular chow diet, β-Smad4KO mice showed no differences in body weight, fed and fasting blood glucose levels, and glucose tolerance compared with wild-type mice. When fed a HFD, body weight gain was significantly reduced in β-Smad4KO mice as compared with wild-type mice, although the amount of food intake was not different. During the HFD, fed and fasting blood glucose levels, glucose stimulated insulin secretion, disposition index and glucose tolerance were significantly improved in β-Smad4KO mice as compared with wild-type mice. However, insulin tolerance tests showed no differences between the 2 groups.
Inhibition of Smad4 in beta-cells conferred mild but significant improvements in glucose levels and glucose tolerance in HFD-induced obese mice. Therefore, regulation of Smad4 expression may be one of the mechanisms regulating physiological expansion of beta-cells during development of type 2 diabetes.
在本研究中，我们使用高脂饮食（HFD）诱导的肥胖小鼠模型，研究了Smad4信号通路是否参与β细胞功能的调节。
通过将Smad4（flox/flox）小鼠与大鼠胰岛素启动子（RIP）-Cre小鼠交配，产生β细胞特异性Smad4基因敲除小鼠（Smad4(-/-)RIP-Cre(+); β-Smad4KO）。小鼠在6周龄时开始喂食HFD，持续16周。测量体重、食物摄入量、空腹和进食血糖水平以及葡萄糖和胰岛素耐受性。
β-Smad4KO小鼠胰岛中Smad4 mRNA的表达显著降低。在野生型小鼠中，与8周龄相比，18周龄时Smad4 mRNA显著降低。在常规饲料喂养下，β-Smad4KO小鼠与野生型小鼠相比，体重、进食和空腹血糖水平以及葡萄糖耐受性均无差异。喂食HFD时，β-Smad4KO小鼠的体重增加与野生型小鼠相比显著减少，尽管食物摄入量没有差异。在HFD期间，与野生型小鼠相比，β-Smad4KO小鼠的进食和空腹血糖水平、葡萄糖刺激的胰岛素分泌、处置指数和葡萄糖耐受性均显著改善。然而，胰岛素耐受性试验显示两组之间没有差异。
抑制β细胞中的Smad4可使HFD诱导的肥胖小鼠的血糖水平和葡萄糖耐受性得到轻度但显著的改善。因此，调节Smad4表达可能是2型糖尿病发展过程中调节β细胞生理扩张的机制之一。
