GLP‑1 improves palmitate‑induced insulin resistance in human skeletal muscle via SIRT1 activity

Jeon,Ja Young; Choi,Sung‑E; Ha,Eun Suk; Lee,Han Byeol; Kim,Tae Ho; Han,Seung Jin; Kim,Hae Jin; Kim,Dae Jung; Kang,Yup; Lee,Kwan‑Woo

doi:10.3892/ijmm.2019.4272

GLP‑1 improves palmitate‑induced insulin resistance in human skeletal muscle via SIRT1 activity

Authors:
- Ja Young Jeon
- Sung‑E Choi
- Eun Suk Ha
- Han Byeol Lee
- Tae Ho Kim
- Seung Jin Han
- Hae Jin Kim
- Dae Jung Kim
- Yup Kang
- Kwan‑Woo Lee
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Affiliations: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea, Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea, Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul 02076, Republic of Korea, Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul 02076, Republic of Korea
Published online on: July 9, 2019 https://doi.org/10.3892/ijmm.2019.4272
Pages: 1161-1171

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Abstract

The present study investigated whether glucagon like peptide‑1 (GLP‑1) improves glucose uptake through glucose transporter type 4 (GLUT4), mediated by the activation of sirtuin 1 (SIRT1), in skeletal muscle cells with palmitate induced‑insulin resistance. The levels of glucose uptake, GLUT4, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP) were determined in human skeletal muscle myotubes (HSMMs) exposed to palmitate and GLP‑1. Then, to determine whether PKA/cAMP were downstream signals of GLP‑1, a PKA inhibitor was used. To determine whether SIRT‑1 contributes to GLP‑1 action in HSMMs with palmitate‑induced insulin resistance, the levels of peroxisome proliferator‑activated receptor γ coactivator 1α (PGC1α) deacetylation and SIRT‑1 activity were assessed using a SIRT1 inhibitor and small interfering RNA (siRNA). The phosphorylation levels of protein kinase B (Akt) and insulin receptor substrate 1 (IRS‑1) as insulin signaling pathways, were assessed in GLP‑1‑treated HSMMs exposed to palmitate. The influence of SIRT1 on the GLP‑1‑induced activation of insulin signaling pathway was determined using a SIRT1 inhibitor. GLP‑1 restored the palmitate‑induced reductions in the levels of glucose uptake, GLUT4 mRNA, GLUT4 promoter activity, and GLUT4 protein in HSMMs. PKA and cAMP, as GLP‑1 downstream signals, played a role in this process. GLP‑1 increased the deacetylation levels of PGC1α, and stimulated SIRT1 in HSMMs. Moreover, the SIRT1 inhibitor and siRNA of SIRT1 suppressed the effect of GLP‑1 on GLUT4 expression in HSMMs exposed to palmitate. The SIRT1 inhibitor also prevented the GLP‑1‑induced phosphorylation of IRS‑1 and Akt in palmitate‑treated HSMMs. The present findings suggest that in palmitate‑induced insulin‑resistant HSMM, GLP‑1 activates SIRT1 through the PKA/cAMP pathway, which in turn enhances glucose uptake through GLUT4 and the insulin signaling pathway.

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