Hyperglycemia, intracellular hyaluronan synthesis, cyclin D3 and autophagy.

Hyperglycemia is one of the factors that induces autophagy. Our recent studies demonstrate that dividing cells in hyperglycemic medium initiate an intracellular stress response that involves synthesis of hyaluronan and its extrusion extracellularly into structures that are recognized by inflammatory cells. During the later phase, a complex with cyclin D3, CDK4 and C/EBPalpha was observed in the hyperglycemic cultures, and cyclin D3 and C/EBPalpha colocalized in coalesced perinuclear honeycomb-like structures with embedded hyaluronan. Further, microtubule-associated protein 1 light chain 3 (LC3), a marker for autophagy, colocalizes with these structures. These results suggest that cyclin D3 is a central coordinator that controls the organization of a complex set of proteins that regulate autophagy and subsequent formation of the monocyte-adhesive hyaluronan matrix. However, the early intracellular accumulation of hyaluronan could have a critical role in initiating or regulating these downstream events.

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