Aim: To evaluate the effect of linagliptin (a DPP4 inhibitor) on high glucose induced inflammatory and fibrotic markers in human endothelial cells

Background:  Diabetes mellitus (DM) is increasing and a third of patients will suffer diabetic nephropathy (DN) as a complication.Linagliptin is an oral diabetic agent used to lower blood glucose in type 2 DM. It inhibits the cleavage of endogenous incretin hormones GLP-1 and GIP, raising their levels and thus promoting insulin release and inhibiting glucagon secretion, resulting in the lowering of blood glucose. DPP4 inhibitors may have benefits other than glucose lowering as DPP4 also cleaves a host of additional peptides (not just GLP-1/ GIP), thus regulating their biological function resulting in a range of possible outcomes.  It would be desirable to have anti-diabetic therapies with additional vascular effects beyond glucose lowering.

Methods:  HMEC-1 cells were exposed to control (5mM) or high glucose (30mM) +/- linagliptin (30nM) for up to 72 hours. Cells were harvested for nuclear binding assays, protein and supernatants were collected for ELISA. Relevant Inflammatory/fibrotic markers such as monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappa Beta (NFкB) and transforming growth factor beta (TGF-β) were measured as endpoints.

Results:  Linagliptin significantly reduced high glucose induced MCP-1 secretion and had a non-significant reduction in NFкB. High glucose increased ICAM-1 expression and this was exacerbated with linagliptin. Linagliptin had no significant effect on other markers measured in this study.  

Conclusions:  Linagliptin cleaves a host of biological molecules and hence the net effect may be dependent on the stimulus and cell type. Our current studies involve exposing HMEC-1 cells to tumor necrosis factor alpha and high mobility group box protein 1.