Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada; N6A 5C1.
Endocrinology. 2013 Oct;154(10):3702-18. doi: 10.1210/en.2013-1155. Epub 2013 Jul 31.
Glycogen synthase kinase 3 β (GSK-3β) is an essential negative regulator or "brake" on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3β results in perinatal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type 2 diabetes.
糖原合酶激酶 3β（GSK-3β）是许多合成代谢信号通路（包括 Wnt 和胰岛素）的重要负调控因子或“制动器”。GSK-3β 的全局缺失会导致围产期致死和各种骨骼缺陷。我们研究的目的是确定 GSK-3β 在细胞自主和骨骼发育中的作用。我们使用 3.6kb 的 Col1a1 启动子在骨骼细胞中失活 Gsk3b 基因（Col1a1-Gsk3b 敲除）。突变小鼠表现出体脂肪减少和出生后骨骼生长延迟，以及几种骨骼成分发育迟缓。令人惊讶的是，尽管代谢组织中 GSK-3β 的表达正常，但突变小鼠的循环葡萄糖和胰岛素水平降低。我们表明这些效应是由于整体胰岛素敏感性增加所致。大多数雄性突变小鼠在断奶后死亡。在死亡之前，血糖从低到高变化，表明可能从胰岛素敏感性转变为抵抗。这些雄性小鼠死于膀胱极度肿大，之前尿路生殖道受损，这也是 2 型糖尿病的特征。我们的数据表明，骨骼特异性 GSK-3β 缺失会影响全身代谢，并使雄性小鼠易患 2 型糖尿病。
