Rubiscolin-6 activates opioid receptors to enhance glucose uptake in skeletal muscle

J Food Drug Anal. 2019 Jan;27(1):266-274. doi: 10.1016/j.jfda.2018.06.012. Epub 2018 Aug 14.


Rubiscolin-6 is an opioid peptide derived from plant ribulose bisphosphate carboxylase/oxygenase (Rubisco). It has been demonstrated that opioid receptors could control glucose homeostasis in skeletal muscle independent of insulin action. Therefore, Rubiscolin-6 may be involved in the control of glucose metabolism. In the present study, we investigated the effect of rubiscolin-6 on glucose uptake in skeletal muscle. Rubiscolin-6-induced glucose uptake was measured using the fluorescent indicator 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose (2-NBDG) in L6 and C2C12 cell lines. The protein expressions of glucose transporter 4 (GLUT4) and AMP-activated protein kinase (AMPK) in L6 cells were observed by Western blotting. The in vivo effects of rubiscolin-6 were characterized in streptozotocin (STZ)-induced diabetic rats. Rubiscolin-6 induced a concentration-dependent increase in glucose uptake levels. The increase of phospho-AMPK (pAMPK) and GLUT4 expressions were also observed in L6 and C2C12 cells. Effects of rubiscolin-6 were blocked by opioid receptor antagonists and/or associated signals inhibitors. Moreover, Rubiscolin-6 produced a dose-dependent reduction of blood glucose and increased GLUT4 expression in STZ-induced diabetic rats. In conclusion, rubiscolin-6 increases glucose uptake, potentially via an activation of AMPK to enhance GLUT4 translocation after binding to opioid receptors in skeletal muscle.

Keywords: AMPK; GLUT4; Glucose uptake; Opioid receptor; Rubiscolin-6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Biological Transport
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Humans
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Peptide Fragments / administration & dosage*
  • Rats
  • Rats, Wistar
  • Receptors, Opioid / genetics
  • Receptors, Opioid / metabolism*
  • Ribulose-Bisphosphate Carboxylase / administration & dosage*


  • Glucose Transporter Type 4
  • Peptide Fragments
  • Receptors, Opioid
  • rubiscolin 6
  • AMP-Activated Protein Kinases
  • Ribulose-Bisphosphate Carboxylase
  • Glucose

Grants and funding

This research was supported in part by KAKENHI Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI) No. 16H06404 (A.I).