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The nonglycemic actions of dipeptidyl peptidase-4 inhibitors.

Kim NH, Yu T, Lee DH - Biomed Res Int (2014)

Bottom Line: In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects.DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments.Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Hanbang Body-Fluid Research Center and College of Oriental Medicine, Wonkwang University, 460 Iksandae-ro, Iksan 570-749, Republic of Korea.

ABSTRACT
A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

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Nonglycemic actions of DPP-4 inhibitor in relation with pathophysiology of CV disease. Despite its many salutary effects on the CV system, DPP-4 inhibitor therapy in patients with type 2 diabetes and CV disease did not show a secondary prevention effect. Some unfavorable actions of DPP-4 inhibitor need to be further characterized to improve DPP-4 inhibitor therapy in patients with type 2 diabetes. ACEi, ACE inhibitor.
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fig1: Nonglycemic actions of DPP-4 inhibitor in relation with pathophysiology of CV disease. Despite its many salutary effects on the CV system, DPP-4 inhibitor therapy in patients with type 2 diabetes and CV disease did not show a secondary prevention effect. Some unfavorable actions of DPP-4 inhibitor need to be further characterized to improve DPP-4 inhibitor therapy in patients with type 2 diabetes. ACEi, ACE inhibitor.

Mentions: Finally, some of unfavorable actions of DPP-4 inhibitors need to be addressed in this paper (as described in italics in Table 3). In an interesting study, DPP-4 inhibition lowered BP during acute administration of the low dose angiotensin-converting enzyme (ACE) inhibitor enalapril, but abolished the acute antihypertensive effects of high dose enalapril in patients with metabolic syndrome [31]. In a recent study, when vildagliptin was administered to cynomolgus monkeys at high dose, skin lesions on the distal extremities (hands, feet, ears, and tail) appeared after three weeks of treatment and consisted of blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and tail sores. These lesions were mediated by endothelial and medial hypertrophy/hyperplasia of arterioles at various levels of the dermis. These pathologic changes were related to increased NPY-Y1 receptor signaling [33]. In humans, Boschmann et al. showed that vildagliptin administration increased plasma norepinephrine (NE) concentrations in response to meals without causing a change in epinephrine levels [38]. Use of DPP-4 inhibitors may cause a small increase in resting heart rate as well as plasma NE when used in conjunction with a high-dose of the ACE inhibitor enalapril [31]. DPP-4 may have more roles in the inactivation of substance P when ACE is inhibited. Substance P acts as a vasodilator but also increases sympathetic outflow [100]. In a recent human study, substance P-stimulated heart rate and sympathetic activity (as assessed by venous plasma NE) was significantly higher during combined ACE and DPP-4 inhibition than during DPP-4 inhibition alone [100]. In addition, DPP-4 inhibition diminished substance P-induced tissue plasminogen activator release in women [100]. DPP-4 inhibition causes arterial PYY(1–36) and NPY(1–36) to enhance Angiotensin II- (Ang II-) induced renal vasoconstriction more effectively in genetically susceptible kidneys [39]. This finding strongly suggests that renovascular DPP-4 inactivates NPY(1–36) so that low concentrations cannot enhance the renovascular effects of Ang II. However, when DPP-4 is inhibited, this inactivation is impaired and even low concentrations of NPY(1–36) may potentiate renovascular responses to Ang II. Taken together, DPP-4 inhibition in certain conditions may cause sympathetic activation and selective enhancement of the NPY-Y1 receptor pathway, leading to vasoconstriction and BP elevation. Further studies are required to determine whether some of these unfavorable effects translate into negative CV outcomes (Figure 1).


The nonglycemic actions of dipeptidyl peptidase-4 inhibitors.

Kim NH, Yu T, Lee DH - Biomed Res Int (2014)

Nonglycemic actions of DPP-4 inhibitor in relation with pathophysiology of CV disease. Despite its many salutary effects on the CV system, DPP-4 inhibitor therapy in patients with type 2 diabetes and CV disease did not show a secondary prevention effect. Some unfavorable actions of DPP-4 inhibitor need to be further characterized to improve DPP-4 inhibitor therapy in patients with type 2 diabetes. ACEi, ACE inhibitor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129137&req=5

fig1: Nonglycemic actions of DPP-4 inhibitor in relation with pathophysiology of CV disease. Despite its many salutary effects on the CV system, DPP-4 inhibitor therapy in patients with type 2 diabetes and CV disease did not show a secondary prevention effect. Some unfavorable actions of DPP-4 inhibitor need to be further characterized to improve DPP-4 inhibitor therapy in patients with type 2 diabetes. ACEi, ACE inhibitor.
Mentions: Finally, some of unfavorable actions of DPP-4 inhibitors need to be addressed in this paper (as described in italics in Table 3). In an interesting study, DPP-4 inhibition lowered BP during acute administration of the low dose angiotensin-converting enzyme (ACE) inhibitor enalapril, but abolished the acute antihypertensive effects of high dose enalapril in patients with metabolic syndrome [31]. In a recent study, when vildagliptin was administered to cynomolgus monkeys at high dose, skin lesions on the distal extremities (hands, feet, ears, and tail) appeared after three weeks of treatment and consisted of blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and tail sores. These lesions were mediated by endothelial and medial hypertrophy/hyperplasia of arterioles at various levels of the dermis. These pathologic changes were related to increased NPY-Y1 receptor signaling [33]. In humans, Boschmann et al. showed that vildagliptin administration increased plasma norepinephrine (NE) concentrations in response to meals without causing a change in epinephrine levels [38]. Use of DPP-4 inhibitors may cause a small increase in resting heart rate as well as plasma NE when used in conjunction with a high-dose of the ACE inhibitor enalapril [31]. DPP-4 may have more roles in the inactivation of substance P when ACE is inhibited. Substance P acts as a vasodilator but also increases sympathetic outflow [100]. In a recent human study, substance P-stimulated heart rate and sympathetic activity (as assessed by venous plasma NE) was significantly higher during combined ACE and DPP-4 inhibition than during DPP-4 inhibition alone [100]. In addition, DPP-4 inhibition diminished substance P-induced tissue plasminogen activator release in women [100]. DPP-4 inhibition causes arterial PYY(1–36) and NPY(1–36) to enhance Angiotensin II- (Ang II-) induced renal vasoconstriction more effectively in genetically susceptible kidneys [39]. This finding strongly suggests that renovascular DPP-4 inactivates NPY(1–36) so that low concentrations cannot enhance the renovascular effects of Ang II. However, when DPP-4 is inhibited, this inactivation is impaired and even low concentrations of NPY(1–36) may potentiate renovascular responses to Ang II. Taken together, DPP-4 inhibition in certain conditions may cause sympathetic activation and selective enhancement of the NPY-Y1 receptor pathway, leading to vasoconstriction and BP elevation. Further studies are required to determine whether some of these unfavorable effects translate into negative CV outcomes (Figure 1).

Bottom Line: In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects.DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments.Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Hanbang Body-Fluid Research Center and College of Oriental Medicine, Wonkwang University, 460 Iksandae-ro, Iksan 570-749, Republic of Korea.

ABSTRACT
A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

Show MeSH
Related in: MedlinePlus