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Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 12, pp 2555–2569 | Cite as

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

  • Bjorn T. Tam
  • Xiao M. Pei
  • Benjamin Y. Yung
  • Shea P. Yip
  • Lawrence W. Chan
  • Cesar S. Wong
  • Parco M. SiuEmail author
Muscle physiology

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.

Keywords

Insulin resistance Unacylated ghrelin Autophagy 

Abbreviations list

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

Notes

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Bjorn T. Tam
    • 1
  • Xiao M. Pei
    • 1
  • Benjamin Y. Yung
    • 1
  • Shea P. Yip
    • 1
  • Lawrence W. Chan
    • 1
  • Cesar S. Wong
    • 1
  • Parco M. Siu
    • 1
    Email author
  1. 1.Department of Health Technology and InformaticsFaculty of Health and Social Sciences, The Hong Kong Polytechnic UniversityKowloonChina

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