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The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose.

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

ABSTRACT
The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1 μM TRAM-34, 1 μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

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Plasma glucose concentrations measured from 1–10 weeks after administration of STZ (50 mg/kg IV).Linagliptin treatment (2 mg/kg po per day) commenced 6 weeks after STZ administration. Linagliptin did not affect plasma glucose in normal or STZ treated rats.
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pone.0143941.g001: Plasma glucose concentrations measured from 1–10 weeks after administration of STZ (50 mg/kg IV).Linagliptin treatment (2 mg/kg po per day) commenced 6 weeks after STZ administration. Linagliptin did not affect plasma glucose in normal or STZ treated rats.

Mentions: Blood glucose over the 10 week treatment period is shown in Fig 1 and body weight, blood glucose and HbA1c levels of rats at the time of tissue collection in the 4 groups are shown in Table 1. Ten weeks after treatment with streptozotocin or vehicle, the body weight in normal rats was significantly higher than in diabetic rats (Table 1). Furthermore, in diabetic rats, the blood glucose and HbA1c levels were significantly greater than in normal rats. Four weeks treatment with linagliptin had no significant effect on body weight, HbA1c or blood glucose levels in either normal or diabetic rats.


The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose.

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Plasma glucose concentrations measured from 1–10 weeks after administration of STZ (50 mg/kg IV).Linagliptin treatment (2 mg/kg po per day) commenced 6 weeks after STZ administration. Linagliptin did not affect plasma glucose in normal or STZ treated rats.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664283&req=5

pone.0143941.g001: Plasma glucose concentrations measured from 1–10 weeks after administration of STZ (50 mg/kg IV).Linagliptin treatment (2 mg/kg po per day) commenced 6 weeks after STZ administration. Linagliptin did not affect plasma glucose in normal or STZ treated rats.
Mentions: Blood glucose over the 10 week treatment period is shown in Fig 1 and body weight, blood glucose and HbA1c levels of rats at the time of tissue collection in the 4 groups are shown in Table 1. Ten weeks after treatment with streptozotocin or vehicle, the body weight in normal rats was significantly higher than in diabetic rats (Table 1). Furthermore, in diabetic rats, the blood glucose and HbA1c levels were significantly greater than in normal rats. Four weeks treatment with linagliptin had no significant effect on body weight, HbA1c or blood glucose levels in either normal or diabetic rats.

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

ABSTRACT
The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1 μM TRAM-34, 1 μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

Show MeSH
Related in: MedlinePlus