Plant-insect interaction is a dynamic system, insects evolved adaptive plasticity to minimize the effects of the chemical defenses of their host plants. Nevertheless, the expressional response and adaptation of phytophagous specialists for long-term adaption and short-term response to host phytochemicals remains largely unexplored. The mulberry (Morus alba) -silkworm (Bombyx mori) interaction is an old and well-known model of plant-insect interaction. In this study, we examined the long-term adaption and short-term response of the mulberry-specialist silkworm to two sugar-mimic alkaloids in mulberry: the commonly encountered 1-deoxynojirimycin (1-DNJ) and occasionally encountered 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1), respectively. Global transcriptional patterns revealed that the physiological responses induced by the selective expression of genes involved in manifold cellular processes, including detoxification networks, canonical digestion processes, target enzymes and other fundamental physiological processes, were crucial for regulating metabolic homeostasis. Comparative network analysis of the effects of exposure to D-AB1 and 1-DNJ supported the contention that B. mori produced similar and specific trajectories of changed gene expression in response to different sugar-mimic alkaloids. D-AB1 elicited a substantial proportion of downregulated genes relating to carbohydrate metabolism, catabolic process, lipid metabolism, and glycan biosynthesis and metabolism. This study dramatically expands our knowledge of the physiological adaptations to dietary sugar-mimic alkaloid intake and uncovered both metabolic evolutionarily responses and unique adaptive mechanisms previously unknown in insects.