title: The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy.
abstract: OBJECTIVE
  Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear.
  
  
  METHODS
  Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software.
  
  
  RESULTS
  Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans.
  
  
  CONCLUSIONS
  Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dietrich
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kolibabka
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Busch
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Bugert
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kaiser
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Jihong
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Medicine I, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
authors.affiliation: Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlotterer
authors.affiliation: 5th Medical Department, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069476:Linagliptin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D011765:Pyruvaldehyde; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4