The development of diabetic encephalopathy (DE) is enhanced by inflammatory macrophages, and is suppressed by macrophage autophagy. However, the molecular signaling that controls macrophage autophagy in DE remains ill-defined. Here, DE is induced in rats that received intraperitoneal injection of streptozotocin (STZ). In macrophages isolated from the brain of the rats, we detected downregulated autophagy activity and enhanced PI3k/Akt/mTOR/S6K1 signaling. In order to examine the role of autophagy and PI3k/Akt/mTOR signaling in DE development, an mTOR inhibitor, rapamycin, or an autophagy inhibitor, chloroquine (CQ), were administered to the rats that that received STZ. We found that rapamycin significantly enhanced DE development through mTOR suppression-induced augmentation of macrophage autophagy, while CQ significantly decreased DE development through suppression of macrophage autophagy. Together, our data suggest that PI3k/Akt/mTOR signaling may promote the development of DE through suppression of macrophage autophagy.