The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Attenuates Inflammation and Accelerates Epithelialization in Wounds of Diabetic <i>ob/ob</i> Mice

Schürmann, Christoph; Linke, Andreas; Engelmann-Pilger, Kerstin; Steinmetz, Cornelia; Michael, Mark; Pfeilschifter, Josef; Klein, Thomas; Frank, Stefan

doi:10.1124/jpet.111.191098

Cited by 77 publications

(79 citation statements)

References 45 publications

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“…Consistently, DPP4-I with linagliptin resulted in accelerated wound healing in diabetic obese mice compared with untreated mice. This was associated with improved reepithelialization, reduced inflammation, and enhanced the formation of myofibroblasts, all features of a healthier granulation tissue (112).…”

Section: Dpp4-i and Diabetic Foot Ulcersmentioning

confidence: 90%

“…For the possible improvement in microvascular outcomes obtained with DPP4-I as outlined above, these drugs are novel candidates for the medical treatment of diabetic foot ulcers. Experimentally, it was shown that DPP-4 expression and activity are increased in the wounded skin of diabetic obese mice (112). In turn, excess DPP-4 activity is supposed to degrade the chemokine and angiocrine factor SDF-1a (CXCL12), thus impairing vascularization and growth of the granulation tissue.…”

Section: Dpp4-i and Diabetic Foot Ulcersmentioning

confidence: 99%

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The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

2014

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We performed a review of the literature to determine whether the dipeptidyl peptidase-4 inhibitors (DPP4-I) may have the capability to directly and positively influence diabetic microvascular complications. The literature was scanned to identify experimental and clinical evidence that DPP4-I can ameliorate diabetic microangiopathy. We retrieved articles published between 1 January 1980 and 1 March 2014 in English-language peer-reviewed journals using the following terms: (“diabetes” OR “diabetic”) AND (“retinopathy” OR “retinal” OR “nephropathy” OR “renal” OR “albuminuria” OR “microalbuminuria” OR “neuropathy” OR “ulcer” OR “wound” OR “bone marrow”); (“dipeptidyl peptidase-4” OR “dipeptidyl peptidase-IV” OR “DPP-4” OR “DPP-IV”); and (“inhibition” OR “inhibitor”). Experimentally, DPP4-I appears to improve inflammation, endothelial function, blood pressure, lipid metabolism, and bone marrow function. Several experimental studies report direct potential beneficial effects of DPP4-I on all microvascular diabetes-related complications. These drugs have the ability to act either directly or indirectly via improved glucose control, GLP-1 bioavailability, and modifying nonincretin substrates. Although preliminary clinical data support that DPP4-I therapy can protect from microangiopathy, insufficient evidence is available to conclude that this class of drugs directly prevents or decreases microangiopathy in humans independently from improved glucose control. Experimental findings and preliminary clinical data suggest that DPP4-I, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy. Further evidence is needed to confirm these effects in patients with diabetes.

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Section: Dpp4-i and Diabetic Foot Ulcersmentioning

confidence: 90%

Section: Dpp4-i and Diabetic Foot Ulcersmentioning

confidence: 99%

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

2014

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“…The anti-inflammatory effects of linagliptin have been elucidated in vivo [14,[27][28][29][30]. However, to the best of our knowledge, no study has examined these effects in vitro.…”

Section: Introductionmentioning

confidence: 99%

Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells

et al. 2016

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Background: Linagliptin, the only bile-excreted dipeptidyl peptidase-4 (DPP-4) inhibitor, is a therapeutic drug for patients with diabetes receiving hemodialysis, for whom inflammation is a prognosis-related factor, because of its potential anti-inflammatory effects. Although the anti-inflammatory effects of linagliptin in vivo are reported, no study has described these effects in vitro. DPP-4 degrades glucagon-like peptide-1 (GLP-1), which is known to have anti-inflammatory properties. Since GLP-1 is a gut hormone secreted by intestinal L cells, in vivo examination of the GLP-1-independent anti-inflammatory effects of DPP-4 inhibitors is difficult. We evaluated the mitogen-activated protein kinase (MAPK)-dependent, GLP-1-independent, anti-inflammatory effects of linagliptin in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) which do not secrete GLP-1. Furthermore, to determine whether linagliptin has unique pharmacological actions compared with other DPP-4 inhibitors, we assessed the anti-inflammatory effects of sitagliptin (a DPP-4 inhibitor without xanthine-related skeletal system activity), caffeine (a phosphodiesterase inhibitor), loxoprofen, and diclofenac sodium. Methods: HUVECs were cultured for 24 h at densities of 1-2 × 10 5 cells/mL. We pretreated HUVECs with or without linagliptin (1, 5, 10, 50, and 100 nM), 150 nM sitagliptin, 50 nM caffeine, 17 μM loxoprofen, or 1.3 μM diclofenac sodium for 1 h prior to incubation with LPS. The concentration of LPS used (1 μg/mL) was sufficient to induce an inflammatory response in HUVECs. Five hours after incubation with LPS, culture media was evaluated for interleukin (IL)-6 expression. Intranuclear p65 (a subunit of nuclear factor kappa-B (NFκB)) levels were measured 5 h after treatment with LPS and 50 nM linagliptin, while phosphorylated p38 MAPK levels were measured in the cytosolic fractions obtained 30 min after treatment with LPS and 50 nM linagliptin.

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“…DPP IV/CD26 inhibition with linagliptin also showed decreased blood glucose levels and accelerated skin re-epithelization in diabetic mice since levels of active GLP-1 in wound lysates increased. A reduced number of neutrophils and macrophages in linagliptin-treated mice were noted [29]. DPP IV/CD26 inhibitors also show pleiotropic effects by directly changing cytokine and growth factors expression, increasing plasma levels of SDF-1α and numbers of endothelial progenitor cells in circulation, which contributes to wound healing [30].…”

Section: Dpp Iv/cd26 Inhibitors In Treatment Of Diabetesmentioning

confidence: 99%

“…Previous research has proven that DPP IV/CD26 impacts wound healing, as CD26 deficient mice showed better wound closure and scab formations compared to wild-type mice. Inhibition of DPP IV/CD26 activity during skin regeneration improves the clearance of elevated blood glucose levels and reduces high DPP IV/CD26 activity in chronic wound tissue of diabetic mice [29]. Animal studies in diabetic mice revealed increased DPP IV/CD26 levels in the presence of enhanced wound inflammatory conditions [42].…”

Section: Role Of Dpp Iv/cd26 In Wound Healing In Diabetesmentioning

confidence: 99%

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26)

Pučar¹,

Kovač²,

Detel³

et al. 2017

J Tissue Sci Eng

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Dipeptidyl Peptidase IV or molecule CD26 (DPP IV/CD26) is a multifunctional protein, identified as a therapeutic target for type 2 diabetes, due to its ability to degrade incretins, insulin secretagogues. Delayed wound healing is a significant complication in diabetic patients that represents a major socio-economic health problem. It has been proposed that DPP IV/CD26 inhibition accelerates healing of chronic diabetic ulcers in those patients, through the induction of a histological pattern consistent with enhanced angiogenesis. Studies on mice models of diabetesdisturbed wound healing also suggested that the inhibition of DPP IV enzymatic activity may improve tissue regeneration processes. However, further research is needed to elucidate the role of DPP IV/CD26 in diabetic wound healing. The objective of this work was to discuss recent findings on the implications of DPP IV/CD26 in tissue regeneration and reparation in diabetic environment.

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The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Attenuates Inflammation and Accelerates Epithelialization in Wounds of Diabetic ob/ob Mice

Cited by 77 publications

References 45 publications

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26)

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