Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Virology and Gene Therapy Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA.
Dis Model Mech. 2018 Jun 13;11(6):dmm033316. doi: 10.1242/dmm.033316.
High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear. Here, we employed a β-cell-targeted gene transfer vector and determined the impact of β-cell-specific increase in GCK expression on β-cell function and glucose handling and Overexpression of GCK enhanced glycolytic flux, ATP-sensitive potassium channel activation and membrane depolarization, and increased proliferation in Min6 cells. β-cell-targeted GCK transduction did not change glucose handling in chow-fed C57BL/6 mice. Although adult mice fed a HFD showed reduced islet GCK expression, impaired glucose tolerance and decreased glucose-stimulated insulin secretion (GSIS), β-cell-targeted GCK transduction improved glucose tolerance and restored GSIS. Islet perifusion experiments verified restored GSIS in isolated HFD islets by GCK transduction. Thus, our data identify impaired β-cell GCK expression as an underlying mechanism for dysregulated β-cell function and glycemic control in HFD-induced diabetes. Our data also imply an etiological role of GCK in diet-induced diabetes.This article has an associated First Person interview with the first author of the paper.
高脂肪饮食（HFD）喂养的小鼠模型已被广泛用于研究 2 型糖尿病的早期发病机制。在 HFD 诱导的糖尿病中，β细胞葡萄糖激酶（GCK）的表达降低。然而，由于 GCK 在肝脏和胰岛β细胞中的葡萄糖代谢中具有重要作用，因此，GCK 表达降低对 HFD 诱导的糖尿病发展的贡献尚不清楚。在这里，我们采用了一种β细胞靶向基因转移载体，并确定了β细胞中 GCK 表达增加对β细胞功能和葡萄糖处理的影响。GCK 的过表达增强了 Min6 细胞中的糖酵解通量、ATP 敏感性钾通道的激活和膜去极化，并增加了增殖。β细胞靶向的 GCK 转导并未改变正常饮食喂养的 C57BL/6 小鼠的葡萄糖处理能力。尽管 HFD 喂养的成年小鼠胰岛 GCK 表达降低、葡萄糖耐量受损和葡萄糖刺激的胰岛素分泌（GSIS）减少，但β细胞靶向的 GCK 转导改善了葡萄糖耐量并恢复了 GSIS。胰岛灌流实验验证了 GCK 转导可恢复 HFD 胰岛的 GSIS。因此，我们的数据表明，β细胞 GCK 表达受损是 HFD 诱导的糖尿病中β细胞功能和血糖控制失调的潜在机制。我们的数据还提示 GCK 在饮食诱导的糖尿病中具有病因作用。本文附有该论文第一作者的第一人称采访。
