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Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice

  • Muscle physiology
  • Published:
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Abstract

Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.

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Abbreviations

4-HNE:

4-Hydroxynonenal

AG:

Acylated ghrelin

Akt:

Protein kinase B

AS160:

Akt substrate of 160 kDa

AMPKα:

AMP-activated protein kinase alpha

UnAG:

Unacylated ghrelin

db/+:

Non-diabetic group

db/db :

Diabetic group

Glut 4:

Glucose transporter type 4

IMCL:

Intramyocellular lipid

IR:

Insulin receptor

IRS:

Insulin receptor substrate

LC3:

Microtubule-associated protein 1 light chain 3

MAPK:

Ras-mitogen-activated protein kinase

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

munc18:

Mammalian uncoordinated-18

p62:

Sequestosome 1

PBS:

Phosphate-buffered saline

PDH:

Pyruvate dehydrogenase

PDK1:

3-phosphoinositide-dependent protein kinase 1

PI3K:

Phosphatidylinositol 3-kinase

PKCλ/ζ:

Atypical protein kinase C

RALA:

Ras-related protein Ral-A

RLG:

Right lateral gastrocnemius

Ulk1:

Unc-51 like autophagy activating kinase 1

VAMP-2:

Vesicle-associated membrane protein 2

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Acknowledgments

This study was supported by The Hong Kong Polytechnic University and Hong Kong Research Grants Council General Research Fund (PolyU 5632/10M). The authors acknowledge the animal husbandry support received from the Centralised Animal Facilities of The Hong Kong Polytechnic University.

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  1. Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

    Bjorn T. Tam, Xiao M. Pei, Benjamin Y. Yung, Shea P. Yip, Lawrence W. Chan, Cesar S. Wong & Parco M. Siu

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Tam, B.T., Pei, X.M., Yung, B.Y. et al. Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice. Pflugers Arch - Eur J Physiol 467, 2555–2569 (2015). https://doi.org/10.1007/s00424-015-1721-5

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