title: Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Anagliptin may be a promising agent to ameliorate skeletal muscle insulin resistance in obese patients with type 2 diabetes.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. nkubota-tky@umin.ac.jp.|Department of Clinical Nutrition Therapy, University of Tokyo, Tokyo, Japan. nkubota-tky@umin.ac.jp.|Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan. nkubota-tky@umin.ac.jp.|Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. nkubota-tky@umin.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.|Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan.|Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.|Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kaito
authors.initials: K
authors.lastname: Iwayama
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.affiliation: Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.affiliation: Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugi
authors.affiliation: Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nakaya
authors.affiliation: Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
authors.forename: Moritaka
authors.initials: M
authors.lastname: Goto
authors.affiliation: Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Jomori
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. kadowaki-3im@h.u-tokyo.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D009589:Nitrogen Oxides; D011743:Pyrimidines; D052250:Nitric Oxide Synthase Type III; D018819:Dipeptidyl Peptidase 4; C583175:anagliptin
keywords: DPP-4 inhibitor; Endothelial cells; GLP-1; Insulin resistance; Skeletal muscle glucose uptake