Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β cell crosstalk
Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic β cell crosstalk
复制标题
DOI：
10.1172/jci31785
复制
发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Spiegelman, Bruce M.
中科院分区：
文献类型：
--
作者：
Handschin, Christoph;Choi, Cheol Soo;Spiegelman, Bruce M.
转录辅激活因子PPAR γ辅激活因子1 α（PGC-1 α）是线粒体生物发生和氧化代谢的强激活因子。虽然PGC-1 α及其许多线粒体靶基因的表达在2型糖尿病患者的骨骼肌中降低，但PGC-1 α表达降低与葡萄糖代谢异常之间没有因果关系。为了解决这个问题，我们产生了骨骼肌特异性PGC-1 α基因敲除小鼠（MKO），其葡萄糖耐量显著受损，但外周胰岛素敏感性正常。令人惊讶的是，在进食和禁食条件下，MKO均具有扩大的胰腺β细胞质量，但显著降低血浆胰岛素水平。来自MKO的肌肉组织显示几种促炎基因的表达增加，这些小鼠的循环IL-6水平也升高。我们进一步证明，IL-6处理的小鼠胰岛抑制葡萄糖刺激的胰岛素分泌。这些数据清楚地说明了肌肉PGC-1 α在维持葡萄糖稳态中的因果作用，并突出了骨骼肌和胰岛之间意外的精氨酸介导的串扰。
The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGC-1 alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1 alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1a expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1 alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1 alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.