title: Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes.
abstract: OBJECTIVE
  Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves and inactivates glucagon-like peptide 1 (GLP-1), is a glucose-lowering strategy in type 2 diabetes. Since DPP-4 is a ubiquitously distributed enzyme, we examined whether it is expressed in islets and whether an islet effect to inhibit DPP-4 may result in stimulated insulin secretion.
  
  
  METHODS
  We investigated DPP-4 expression and activity in the islets of mouse models of obesity as well as human islets from non-diabetic and type 2 diabetic donors. We further investigated whether inhibition with DPP-4 inhibitors could promote insulin secretion via islet GLP-1 in isolated islets.
  
  
  RESULTS
  DPP-4 was readily detected in mouse and human islets with species-specific cellular localisation. In mice, DPP-4 was expressed predominantly in beta cells, whereas in humans it was expressed nearly exclusively in alpha cells. DPP-4 activity was significantly increased in islets from diet-induced obese mice compared with mice fed a control diet. In humans, DPP-4 activity was significantly lower in islets from type 2 diabetic donors than in non-diabetic donors. In human islets, there was a significant positive correlation between DPP-4 activity and insulin secretory response to 16.7 mmol/l glucose. Treatment of mouse islets with the DPP-4 inhibitors, NVPDPP728 and vildagliptin, resulted in a significant potentiation of insulin secretion in a GLP-1-dependent manner, as this was inhibited by the GLP-1 receptor antagonist, Exendin (9-39), and was retained in glucose-dependent insulinotropic polypeptide (GIP) receptor-deficient mice but lost in mice lacking GLP-1 receptors or both incretin receptors. Human islets treated with the DPP-4 inhibitor, vildagliptin, showed increased secretion of insulin and intact GLP-1.
  
  
  CONCLUSIONS
  We conclude that DPP-4 is present and active in mouse and human islets, is regulated by the disease state, and that inhibition of islet DPP-4 activity can have direct effects on islet function. Inhibiting islet DPP-4 activity may therefore contribute to the insulin-secretory and glucose-lowering action of DPP-4 inhibition.
authors.affiliation: Department of Clinical Sciences, Biomedical Center, C11, Lund University, SE22184, Lund, Sweden, bilal.omar@med.lu.se.
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Omar
authors.forename: Liu
authors.initials: L
authors.lastname: Liehua
authors.forename: Yuchiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: B
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D000077597:Vildagliptin
chemical_list: D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D005947:Glucose; D000218:Adamantane