Introduction: Periodontitis in patients with diabetes mellitus results in chronic inflammation, which is the central issue in developing an efficient and consistent treatment plan. Dendritic cells (DC) are antigen presenting cells that initiate the immune inflammatory responses and contribute to the pathogenesis of both diseases. In this study, we investigated the impact of hyperglycemic microenvironment on DC immunometabolism, the cell phenotypes and immunogenic functions. Methodology: Human monocyte differentiated DC and mice bone marrow derived DC were cultured in the presence of 5.5-, 11-, and 25- mM glucose to simulate diabetic microenvironment. Cells were activated with advanced-glycation-end product (AGE) and lipopolysaccharides (LPS) from Porphyromanas gingivalis for 24 hours and processed for transcription, metabolic and microscopic analysis. Expression of activation markers (CD80, CD83, CD86, HLA-DR) and proteins involved in glycolysis (HK2, LDHA, GLUT1) in DC were calculated by qRT-PCR. Lactic acid production and OXPHOS assays, including Seahorse metabolic flux analyzer were utilized to determine the effects on metabolism. Impact on the phagocytic capacity was analyzed using fluorescent microspheres uptake. Cytokine expressions for tumor necrosis factor alpha [TNF- α ], interleukin [IL]-1 β , IL-6, IL-10, and Interferon gamma [IFN- γ ] were evaluated in cell supernatants from DC and DC-T cell coculture. Results: Under simulated hyperglycemic microenvironment an increase in cell dendrite extensions, and activation markers were upregulated in both monocytes differentiated DC and BMDC. There was a significant increase in glycolysis as evident from the gene expression, cell metabolic flux, and lactic acid production. Cell OXPHOS activities was reduced to compensate for the increase in glycolysis. Pro-inflammatory cytokines (TNF- α and IL-1 β ) were significantly increased and this increase was directly proportional to the glucose concentrations. Whereas, phagocytic capability of DC, and their ability to activate T cells decreased with hyperglycemia. Conclusions: Hyperglycemic microenvironment resulted in DC changes with increased expressions of activation markers, glycolytic metabolism, and increased pro-inflammatory cytokines, while impairing phagocytosis and adaptive immunity induction. BMDC and human monocyte differentiated-DC exhibit similar responses toward hyperglycemia, AGE, and LPS. This work emphasizes that diabetes mellitus has an inflammatory impact on DC immunometabolism and immunogenic functions.