The gliptins, dipeptidyl peptidase inhibitors (DPP-4 inhibitors) are a relatively new class of antidiabetic drugs that, via their inhibition of DPP-4, a cell membrane–associated serine-type protease enzyme, promote the effects of the endogenous incretins such as glucagon-like peptide 1 (GLP-1) and enhance glucose disposal. The advantage of the gliptins over GLP-1 analogues is that they are orally effective whereas the clinically used incretins, exenatide and liraglutide, have to be administered via sub-cutaneous injection. The first gliptin, sitagliptin, was approved by the FDA in 2006 and six other gliptins have subsequently been approved – vildagliptin (2007 in Europe); saxagliptin (2009, FDA); linagliptin (2011, FDA); anagliptin (2012, Japan); teneligliptin (2012, Japan); alogliptin (2013, FDA). There is a close association between diabetes and cardiovascular disease (CVD) and vascular complications associated with diabetes are responsible for 75% of the deaths of diabetics. Therefore it is important that for any new class of antidiabetic drugs introduced for clinical use that we determine whether such drugs not only show therapeutic efficacy as antidiabetic drugs, but also that they are vasculoprotective and reduce both cardiovascular morbidity and mortality. Endothelial dysfunction that can be functionally defined as a reduced vasorelaxation response to an endothelium-dependent vasodilator, such as acetylcholine, or, at the molecular level, a reduction in the bioavailability of nitric oxide (NO) and/or reduced activity of the enzyme responsible for the generation of NO, namely, endothelial nitric oxide synthase (eNOS). Endothelial dysfunction is a very early indicator of the onset of vascular disease and thus determining whether the gliptins also reduce endothelial dysfunction is very important. The literature concerning the vasculoprotective effects of the gliptins is contradictory with some of the clinical data suggesting a negative effect of the gliptins on vascular function. Thus, the objective of this study was to determine whether the gliptins possess positive or negative effects on endothelial function. In the present study we used a cell culture protocol with mouse vascular endothelial endothelial cells (MS1-VEGF; CRL-2460, from ATCC, USA) of micro-vascular endothelial origin. The endothelial cells, MMECs, were either cultured under normoglycaemic (NG) conditions for a mouse, 11 mM, or high glucose 40 mM (HG) – a level that equates to the plasma glucose levels that are seen in mouse models of type 2 diabetes, such as the db/db leptin receptor mutant model of type 2 diabetes. The gliptin, alogliptin was chosen for this study and the protocols were designed to determine whether this gliptin reduced, or prevented, the high glucose induced reduction in eNOS phosphorylation at serine 1177 (p-eNOSser1177) as determined by western immunoblot densitometry quantification. A reduction in p-eNOSser1177 will result in a reduced activity of eNOS and hence a reduction in the generation of NO. Thus, the quantification of p-eNOSser1177 serves as a measure of endothelial function. The band densities of the western blot images for eNOS and p-eNOSser1177 were quantified using the basic Quantity One software (Biorad, Inc. CA, USA). Statistical analysis was performed using one-way analysis of variance (ANOVA) and post-hoc comparisons between groups were performed by Tukey's multiple comparison tests. ‘p’ values less than 0.05 were considered to be statistically significant. Our data indicates that a 24-hour exposure to HG reduced p-eNOSser1177 phosphorylation, but the presence of alogliptin reverses the effects of HG and significantly increased the phosphorylation of eNOS, suggesting that this gliptin does protect the microvascular endothelium against hyperglycaemia-induced endothelial dysfunction. Furthermore, the effects of alogliptin were concentration-dependent and were significant with 50 or 100 μM, but not 10 μM alogliptin. Our findings indicate that, in a concentration-dependent manner, alogliptin protects endothelial cells against the negative effects that hyperglycaemia (high glucose) has on endothelial function as measured by alogliptin-induced changes in the phosphorylation of eNOS at serine 1177. Further studies are underway, using a functional myograph assay, to determine whether alogliptin can also prevent hyperglycaemia-induced endothelial dysfunction in mouse aortic vessels.


This work was supported by a Summer Student Research Fellowship (SSRF) from Weill Cornell Medicine-Qatar and an Undergraduate Research Experience Program grant, UREP 18-055-3-012 from the Qatar National Research Fund (QNRF). The statements made herein are solely the responsibility of the authors.


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