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15.08.2016 | Article

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

verfasst von: Hiroyuki Sato, Naoto Kubota, Tetsuya Kubota, Iseki Takamoto, Kaito Iwayama, Kumpei Tokuyama, Masao Moroi, Kaoru Sugi, Keizo Nakaya, Moritaka Goto, Takahito Jomori, Takashi Kadowaki

Erschienen in: Diabetologia | Ausgabe 11/2016

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Abstract

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.

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Titel: Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice
verfasst von: Hiroyuki Sato
Naoto Kubota
Tetsuya Kubota
Iseki Takamoto
Kaito Iwayama
Kumpei Tokuyama
Masao Moroi
Kaoru Sugi
Keizo Nakaya
Moritaka Goto
Takahito Jomori
Takashi Kadowaki
Publikationsdatum: 15.08.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 11/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-4071-8

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