title: Acute Effects of Linagliptin on Progenitor Cells, Monocyte Phenotypes, and Soluble Mediators in Type 2 Diabetes.
abstract: BACKGROUND
  Circulating cells, including endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications.
  
  
  OBJECTIVE
  We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes.
  
  
  METHODS
  This was a randomized, crossover, placebo-controlled trial.
  
  
  METHODS
  The study was conducted at a tertiary referral diabetes outpatient clinic.
  
  
  METHODS
  Forty-six type 2 diabetes patients with (n = 18) or without (n = 28) chronic kidney disease (CKD) participated in the study.
  
  
  METHODS
  Intervention included a 4-day treatment with linagliptin 5 mg or placebo during two arms separated by a 2-week washout.
  
  
  METHODS
  Before and after each treatment, we determined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators.
  
  
  RESULTS
  Compared with placebo, linagliptin increased CD34(+)CD133(+) progenitor cells (placebo subtracted effect 40.4 ± 18.7/10(6); P = .036), CD34(+)KDR(+) EPCs (placebo subtracted effect 22.1 ± 10.2/10(6); P = .036), and CX3CR1(bright) monocytes (placebo subtracted effect 1.7 ± 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1α, and reduced monocyte chemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+)CD133(+) cells and had borderline reduced CD34(+) and CD34(+)KDR(+) cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected.
  
  
  CONCLUSIONS
  DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Benedetta Maria
authors.initials: BM
authors.lastname: Bonora
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cappellari
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Vedovato
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iori
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Marescotti
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.affiliation: Division of Metabolic Diseases (G.P.F., B.M.B., R.C., L.M., M.V., E.I., M.C.M., M.A., A.A.), Department of Medicine, University of Padova, and Venetian Institute of Molecular Medicine (G.P.F., L.M., M.A., A.A.), 35128 Padova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
mesh_terms: D000368:Aged; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000069476:Linagliptin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects*; D010641:Phenotype; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4