Department of Biology, State University of New York at New Paltz, New Paltz, NY, USA.
Cell Cycle. 2010 Aug 1;9(15):3063-71. doi: 10.4161/cc.9.15.12458. Epub 2010 Aug 20.
In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.
在黑腹果蝇（Drosophila melanogaster）中，类似于哺乳动物胰腺β细胞的神经分泌胰岛素样肽产生细胞（IPCs）参与葡萄糖稳态。扩展这些发现，我们在成年果蝇中开发了口服葡萄糖耐量试验，并证明 IPCs 确实负责执行急性葡萄糖清除反应。为了进一步将黑腹果蝇发展成为研究与年龄相关的代谢紊乱的相关系统，我们着手确定成年特异性 IPC 部分消融（IPC 敲低）对胰岛素样肽（ILP）作用、代谢结果和寿命的影响。有趣的是，虽然 IPC 敲低的果蝇表现为高血糖和葡萄糖不耐受，但这些果蝇在胰岛素注射后外周葡萄糖清除率和关键胰岛素信号分子 Akt 的丝氨酸磷酸化测量时仍保持胰岛素敏感性。在成年 IPC 敲低的果蝇中，储存的糖原和甘油三酯水平以及循环脂质水平的显著升高表明能量代谢发生了深刻的调节。在这些果蝇中测量的其他生理结果包括对饥饿的抵抗力增加和雌性生育力受损。最后，在 IPC 敲低的果蝇中测量到的寿命延长和死亡率降低表明，有可能在成年果蝇中调节 ILP 作用以延长寿命而不产生胰岛素抵抗。总之，我们已经建立并验证了一种无脊椎动物遗传系统，以进一步研究由成年 IPC 调节的胰岛素作用、代谢稳态和衰老调控。
