Hyperglyceamia (HG) is a hallmark of diabetes and is a critical factor in the initiation of diabetic complications. Macrophages are key innate immune cells that regulate inflammatory responses which are responsible for the development of micro- and macrovascular complications. Increased expression of toll-like receptor 4 (TLR4) has been inked to type 2 diabetes (T2D). Here for the first time, we systemically addressed the role of hyperglyceamia in the regulation of TLR system in primary human macrophages. Expression of TLR 1-9 was examined in primary human monocytes-derived homeostatic M(NS), inflammatory M1(IFNgamma) and healing M(IL4) macrophages in normoglycemic and hyperglycemic (HG) conditions by RT-PCR and flow cytometry. HG induced upregulation in expression of TLR1 and TLR8 in M0 macrophages, TLR1, TLR2 and TLR6 in M1, and TLR4 and TLR5 in M2. HG potentiated TLR4-mediated response of M2 to LPS and significantly enhanced production of IL1beta. In M (IL4), HG in combination with PAM3CSK4 (PAM3), synthetic triacylated lipopeptide, ligand for TLR1/TLR2 amplified expression of TLR4, enhanced production of IL1beta, and supressed production of IL10. We found that hyperglycemia alone enhances inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglyceamia can switch the inflammatory program in healing (M2) macrophages towards supporting vascular inflammatory complications in diabetes.