Normal glucose metabolism is critical to immune function but the effects of short-term hyperglycemia on immunity are not well described. To study this phenomenon, we induced hyperglycemia in healthy subjects for 2h with intravenous dextrose and octreotide. An RNA-seq analysis of whole blood RNA demonstrated alterations in multiple immune pathways and transcripts during acute hyperglycemia including decreased transcription of IL-6, an important component of both innate and adaptive immune responses. Additional in vitro studies of human peripheral blood mononuclear cells (PBMCs) exposed to high glucose confirmed decreased IL-6 expression, most prominently in CD14(+)CD16(+) intermediate monocytes. Hyperglycemia also reduced IL-17A expression suggesting further impairment of immune responses during acute hyperglycemia. These findings demonstrate multiple defective immune responses in acute hyperglycemia and suggest a novel role for intermediate monocytes as metabolically sensitive innate immune cells.