Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice

Diabetologia. 2016 Nov;59(11):2426-2434. doi: 10.1007/s00125-016-4071-8. Epub 2016 Aug 15.


Aims/hypothesis: Recently, incretin-related agents have been reported to attenuate insulin resistance in animal models, although the underlying mechanisms remain unclear. In this study, we investigated whether anagliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor, attenuates skeletal muscle insulin resistance through endothelial nitric oxide synthase (eNOS) activation in the endothelial cells. We used endothelium-specific Irs2-knockout (ETIrs2KO) mice, which show skeletal muscle insulin resistance resulting from a reduction of insulin-induced skeletal muscle capillary recruitment as a consequence of impaired eNOS activation.

Methods: In vivo, 8-week-old male ETIrs2KO mice were fed regular chow with or without 0.3% (wt/wt) DPP-4 inhibitor for 8 weeks to assess capillary recruitment and glucose uptake by the skeletal muscle. In vitro, human coronary arterial endothelial cells (HCAECs) were used to explore the effect of glucagon-like peptide 1 (GLP-1) on eNOS activity.

Results: Treatment with anagliptin ameliorated the impaired insulin-induced increase in capillary blood volume, interstitial insulin concentration and skeletal muscle glucose uptake in ETIrs2KO mice. This improvement in insulin-induced glucose uptake was almost completely abrogated by the GLP-1 receptor (GLP-1R) antagonist exendin-(9-39). Moreover, the increase in capillary blood volume with anagliptin treatment was also completely inhibited by the NOS inhibitor. GLP-1 augmented eNOS phosphorylation in HCAECs, with the effect completely disappearing after exposure to the protein kinase A (PKA) inhibitor H89. These data suggest that anagliptin treatment enhances insulin-induced capillary recruitment and interstitial insulin concentrations, resulting in improved skeletal muscle glucose uptake by directly acting on the endothelial cells via NO- and GLP-1-dependent mechanisms in vivo.

Conclusions/interpretation: Anagliptin may be a promising agent to ameliorate skeletal muscle insulin resistance in obese patients with type 2 diabetes.

Keywords: DPP-4 inhibitor; Endothelial cells; GLP-1; Insulin resistance; Skeletal muscle glucose uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins / deficiency
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology
  • Male
  • Mice
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrogen Oxides / metabolism*
  • Pyrimidines / blood
  • Pyrimidines / pharmacology*
  • Tandem Mass Spectrometry


  • Dipeptidyl-Peptidase IV Inhibitors
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Nitrogen Oxides
  • Pyrimidines
  • Nitric Oxide Synthase Type III
  • Dipeptidyl Peptidase 4
  • anagliptin