The Oral Dipeptidyl-Peptidase-4 Inhibitor Sitagliptin Increases Circulating Levels Of Stromal-Derived Factor-1 Alpha

Papazafiropoulou, Athanasia; Παπάνας, Νικόλαος; Trikkalinou, Aikaterini; Fousteris, Evaggelos; Μelidonis, Αndreas

doi:10.1055/s-0043-118748

Cited by 11 publications

(11 citation statements)

References 30 publications

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“…Importantly, linagliptin was shown to elevate plasma SDF-1 in type 2 diabetes patients with or without chronic kidney disease in a randomized, crossover, placebo-controlled trial [125]. SDF-1 elevating effects have also been seen in small clinical studies of sitagliptin [126,127]. Abbreviations: K D , equilibrium dissociation constant; k on , rate constant for association of the DPP-4/inhibitor complex; k off , rate constant for dissociation of the DPP-4/inhibitor complex; V D , volume of distribution.…”

Section: Non-glp-1 Substrates Of Dpp-4mentioning

confidence: 99%

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Kanasaki

2018

Clinical Science

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Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

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Section: Non-glp-1 Substrates Of Dpp-4mentioning

confidence: 99%

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Kanasaki

2018

Clinical Science

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“…SDF-1 is mainly cleaved and inactivated by dipeptidyl peptidase-4 (DPP-4) enzyme in vivo [33]. DPP-4 inhibitors are a class of commonly used oral antidiabetic drugs [34], and clinical studies have shown that short-term administration of DPP-4 inhibitors can signi cantly increase plasma SDF-1 and EPCs levels in type 2 diabetic patients [35][36][37]. However, EPCs isolated from diabetic patients are structurally and functionally defective [38].…”

Section: Discussionmentioning

confidence: 99%

Association of Stromal Cell-derived Factor-1 With Diabetic Kidney Disease in Type 2 Diabetic Patients

Wang

et al. 2021

Preprint

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Background: The present study was designed to explore whether serum stromal cell-derived factor-1 (SDF-1) levels were associated with albuminuria, estimated glomerular filtration rate (eGFR) and diabetic kidney disease (DKD), and detect which clinical parameters might affect serum SDF-1 levels in patients with type 2 diabetes (T2D).Methods: Serum SDF-1 levels were measured by sandwich ELISA. Patients with an eGFR < 60ml/min/1.73m2 and/or a urinary albumin-to-creatinine ratio (UACR) ≥ 30mg/g who presented with diabetic retinopathy were identified as having DKD.Results: Serum SDF-1 levels in T2D patients were significantly higher than those in healthy controls (p < 0.05). Urinary albumin and UACR were positively correlated with serum SDF-1 levels (r = 0.216 and = 0.276, respectively, p < 0.01), and eGFR was inversely related with serum SDF-1 levels (r = -0.368, p < 0.001). Moreover, after adjusting for other clinical covariates by multiple linear regression analyses, the serum SDF-1 levels were independently associated with urinary albumin (β = 0.071, t = 2.185, p < 0.05), UACR (β = 0.071, t = 2.077, p < 0.05) and eGFR (β = -3.975, t = -3.375, p < 0.01). Furthermore, receiver operating characteristic analysis indicated that the optimal SDF-1 cutoff value for predicting macroalbuminuria was 5.735 ng/mL (its corresponding sensitivity was 50.00% and specificity was 81.46%), for predicting abnormal albuminuria was 4.321 ng/mL (its corresponding sensitivity was 58.46% and specificity was 70.78%) and for predicting DKD was 3.505 ng/mL (its corresponding sensitivity was 83.33% and specificity was 42.86%).Conclusions: The serum SDF-1 levels were positively associated with urinary albumin, UACR and cystatin C, and negatively associated with eGFR, which indicate that SDF-1 may play a critical role in the onset and progression of DKD.

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“…Moreover, evidence also suggests that DPP-4 significantly modulates secretion of different cytokines and chemokines, thus regulating tissue response to injury[ 20 , 21 ]. DPP-4i increases stromal derived factor-1 (or CXCL12) levels, which has several pleiotropic effects[ 22 ], e.g. , beneficial effects in ischemic myocardium[ 23 ], diabetic nephropathy[ 24 ] and stroke[ 25 ].…”

Section: The Interface Between Immune System and Dpp-4 Enzymementioning

confidence: 99%

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

Roy¹,

Sahoo²,

Narayanan³

et al. 2021

WJD

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Dipeptidyl peptidase-4 inhibitors (DPP-4i) have an important place in the management of type 2 diabetes. The DPP-4 enzyme is ubiquitously distributed throughout the human body and has multiple substrates through which it regulates several important physiological functions. DPP-4 regulates several immune functions, including T-cell activation, macrophage function, and secretion of cytokines. Studies have reported an increase in autoimmune diseases like bullous pemphigoid, inflammatory bowel disease, and arthritis with DPP-4i use. The relationship of DPP-4i and autoimmune diseases is a complex one and warrants further research into the effect of DPP-4 inhibition on the immune system to understand the pathogenesis more clearly. Whether a particular cluster of autoimmune diseases is associated with DPP-4i use remains an important contentious issue. Nevertheless, a heightened awareness from the clinicians is required to identify and treat any such diseases. Through this review, we explore the clinical and pathophysiological characteristics of this association in light of recent evidence.

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The Oral Dipeptidyl-Peptidase-4 Inhibitor Sitagliptin Increases Circulating Levels Of Stromal-Derived Factor-1 Alpha

Cited by 11 publications

References 30 publications

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Association of Stromal Cell-derived Factor-1 With Diabetic Kidney Disease in Type 2 Diabetic Patients

Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

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